|
1
|
Liu J, Jiang W, Yu Y, Gong J, Chen G, Yang Y, Wang C, Sun D, Lu X. Applying machine learning to predict bowel preparation adequacy in elderly patients for colonoscopy: development and validation of a web-based prediction tool. Ann Med 2025; 57:2474172. [PMID: 40065741 PMCID: PMC11899208 DOI: 10.1080/07853890.2025.2474172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 02/12/2025] [Accepted: 02/20/2025] [Indexed: 03/14/2025] Open
Abstract
BACKGROUND Adequate bowel preparation is crucial for effective colonoscopy, especially in elderly patients who face a high risk of inadequate preparation. This study develops and validates a machine learning model to predict bowel preparation adequacy in elderly patients before colonoscopy. METHODS The study adhered to the TRIPOD AI guidelines. Clinical data from 471 elderly patients collected between February and December 2023 were utilized for developing and internally validating the model, while 221 patients' data from March to June 2024 were used for external validation. The Boruta algorithm was applied for feature selection. Models including logistic regression, light gradient boosting machines, support vector machines (SVM), decision trees, random forests, and extreme gradient boosting were evaluated using metrics such as AUC, accuracy, sensitivity, and specificity. The SHAP algorithm helped rank feature importance. A web-based application was developed using the Streamlit framework to enhance clinical usability. RESULTS The Boruta algorithm identified 7 key features. The SVM model excelled with an AUC of 0.895 (95% CI: 0.822-0.969), and high accuracy, sensitivity, and specificity. In external validation, the SVM model maintained robust performance with an AUC of 0.889. The SHAP algorithm further explained the contribution of each feature to model predictions. CONCLUSION The study developed an interpretable and practical machine learning model for predicting bowel preparation adequacy in elderly patients, facilitating early interventions to improve outcomes and reduce resource wastage.
Collapse
Affiliation(s)
- Jianying Liu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China
| | - Wei Jiang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yahong Yu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China
| | - Jiali Gong
- Department of Gastroenterology and Hepatology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China
| | - Guie Chen
- Department of Gastroenterology and Hepatology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China
| | - Yuxing Yang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China
| | - Chao Wang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China
| | - Dalong Sun
- Department of Gastroenterology and Hepatology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xuefeng Lu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China
| |
Collapse
|
|
2
|
Wang C, Liang W, Zhong J, Liu J, Zhou C, Ma C, Liao Y, Gao Y, Zhao J, He Y. m6A-mediated regulation of CPSF6 by METTL3 promotes oxaliplatin resistance in colorectal cancer through enhanced glycolysis. Cell Signal 2025; 130:111676. [PMID: 40010558 DOI: 10.1016/j.cellsig.2025.111676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 12/16/2024] [Accepted: 02/14/2025] [Indexed: 02/28/2025]
Abstract
Oxaliplatin resistance poses a significant challenge in colorectal cancer (CRC) treatment. Recent studies have implicated CPSF6 in cancer progression and drug resistance, although its role in chemotherapy resistance and regulatory mechanisms is unclear. This study investigates CPSF6's involvement in oxaliplatin resistance in CRC and its regulation via m6A methylation by METTL3. We assessed CPSF6 expression in oxaliplatin-resistant (OxR) CRC cell lines (HT29-OxR and HCT116-OxR) compared to sensitive counterparts using qRT-PCR and Western blotting. CPSF6 was significantly upregulated in OxR cells, and its knockdown reduced cell viability, colony formation, and glycolytic activity while increasing apoptosis. m6A modification of CPSF6 mRNA was elevated in OxR cells, correlating with increased METTL3 expression. METTL3 knockdown decreased CPSF6 levels and m6A enrichment, enhancing mRNA degradation, while its overexpression stabilized CPSF6 mRNA, promoting resistance. Xenograft experiments showed that CPSF6 knockdown suppressed tumor growth and glycolysis. Thus, CPSF6 is identified as a mediator of oxaliplatin resistance in CRC, regulated by the METTL3/m6A axis, suggesting potential therapeutic targets to overcome resistance.
Collapse
Affiliation(s)
- Chengxing Wang
- Department of Gastrointestinal Surgery, Jiangmen Central Hospital, Guangdong 529000, China; Digestive Disease Research Center, Jiangmen Central Hospital, Guangdong 529000, China
| | - Weijun Liang
- Department of Gastrointestinal Surgery, Jiangmen Central Hospital, Guangdong 529000, China; Digestive Disease Research Center, Jiangmen Central Hospital, Guangdong 529000, China
| | - Jietao Zhong
- Digestive Disease Research Center, Jiangmen Central Hospital, Guangdong 529000, China; Department of Gastroenterology, Jiangmen Central Hospital, Guangdong 529000, China
| | - Jiachen Liu
- Department of Nuclear Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangdong 510000, China
| | - Chaorong Zhou
- Department of Gastrointestinal Surgery, Jiangmen Central Hospital, Guangdong 529000, China; Digestive Disease Research Center, Jiangmen Central Hospital, Guangdong 529000, China
| | - Changyi Ma
- Department of Radiology, Jiangmen Central Hospital, Guangdong 529000, China
| | - Yuehua Liao
- Department of Pathology, Jiangmen Central Hospital, Guangdong 529000, China
| | - Yuan Gao
- Department of Gastrointestinal Surgery, Jiangmen Central Hospital, Guangdong 529000, China; Digestive Disease Research Center, Jiangmen Central Hospital, Guangdong 529000, China
| | - Jinglin Zhao
- Department of Gastrointestinal Surgery, Jiangmen Central Hospital, Guangdong 529000, China; Digestive Disease Research Center, Jiangmen Central Hospital, Guangdong 529000, China.
| | - Yaoming He
- Department of Gastrointestinal Surgery, Jiangmen Central Hospital, Guangdong 529000, China; Digestive Disease Research Center, Jiangmen Central Hospital, Guangdong 529000, China.
| |
Collapse
|
|
3
|
Li J, Liu S, Chen J, Wang H, Feng X, Jia C, Li J, Yin H, Li J, Liu C, Cao Y, Ma C. Uncovering the underlying mechanism of yuanhuacine against colorectal cancer by transcriptomics and experimental investigations. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 140:156570. [PMID: 40023971 DOI: 10.1016/j.phymed.2025.156570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 02/15/2025] [Accepted: 02/24/2025] [Indexed: 03/04/2025]
Abstract
BACKGROUND Colorectal cancer (CRC) holds the third position in terms of incidence and ranks behind lung cancer in terms of mortality worldwide. Yuanhuacine, one of the main active ingredients of genkwa flos, has demonstrated promising application prospects in the field of cancer treatment. However, its underlying mechanism against CRC has not been fully clarified. PURPOSE This study aimed to investigate anti-tumor activity of yuanhuacine and clarify its underlying mechanism in CRC. METHODS CRC HCT116, HT-29, Caco-2, SW480, and LS174T cells were used to assess the in vitro anti-tumor activity of yuanhuacine by cell viability, proliferation, apoptosis, cycle distribution, migration, and colony formation assays. Meanwhile, an HT-29 xenograft mouse model was successfully constructed to investigate the anti-tumor effect of yuanhuacine in vivo. Transcriptomic assay and network pharmacology were applied to explore the underlying mechanism of yuanhuacine in combating CRC, which was further verified by quantitative reverse transcription polymerase chain reaction, western blot. The interaction of yuanhuacine with protein was performed by molecular docking, molecular dynamics simulation, and cell thermal shift assays. RESULTS Yuanhuacine significantly induced apoptosis and reduced viability of CRC cells with IC50 values ranging from 28.09 to 56.16 μM. Moreover, it suppressed the colony formation ability of CRC cells and inhibited the expression of proliferation marker Ki67 in CRC cells and tissues. Meanwhile, the impairment of cell migration by yuanhuacine has been identified by wound healing assay and transwell migration assay. Furthermore, cell cycle assay showed that yuanhuacine resulted in significant G2/M phase arrest. Yuanhuacine significantly inhibited the tumor growth of HT-29 xenograft mice without obvious pathological changes in major organs. Mechanistically, the differentially expressed genes were enriched in cell cycle by both Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment analyses. The mRNA and protein expressions of PLK1, CCNA2, and TTK were inhibited by yuanhuacine. Cell thermal shift assay further validated the direct interactions between yuanhuacine and each of PLK1, CCNA2, and TTK. The anti-proliferation activity and cell cycle arrest induced by yuanhuacine were reversed by overexpression of PLK1. CONCLUSIONS Yuanhuacine is a promising candidate compound in combating CRC by inhibiting proliferation of CRC cells. The major underlying mechanism involves regulating PLK1, which results in G2/M phase arrest.
Collapse
Affiliation(s)
- Jingchu Li
- Institute of Vascular Anomalies, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, 230 Baoding Road, Shanghai 200082, China
| | - Shanshan Liu
- Institute of Vascular Anomalies, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, 230 Baoding Road, Shanghai 200082, China
| | - Jian Chen
- Institute of Vascular Anomalies, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, 230 Baoding Road, Shanghai 200082, China
| | - Hanxue Wang
- Institute of Vascular Anomalies, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, 230 Baoding Road, Shanghai 200082, China
| | - Xia Feng
- Institute of Vascular Anomalies, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, 230 Baoding Road, Shanghai 200082, China
| | - Chenglin Jia
- Institute of Vascular Anomalies, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, 230 Baoding Road, Shanghai 200082, China
| | - Jiacheng Li
- Institute of Vascular Anomalies, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, 230 Baoding Road, Shanghai 200082, China
| | - Hao Yin
- Institute of Vascular Anomalies, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, 230 Baoding Road, Shanghai 200082, China
| | - Jie Li
- Institute of Vascular Anomalies, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, 230 Baoding Road, Shanghai 200082, China
| | - Chang Liu
- Department of Chinese Medicine Authentication, Faculty of Pharmacy, Naval Medical University, People's Liberation Army Navy, 325 Guohe Road, Shanghai 200433, China.
| | - Yongbing Cao
- Institute of Vascular Anomalies, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, 230 Baoding Road, Shanghai 200082, China.
| | - Chao Ma
- Institute of Vascular Anomalies, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, 230 Baoding Road, Shanghai 200082, China; Department of Oncology, Department of Pharmacy, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai 200032, China.
| |
Collapse
|
|
4
|
Kim JS, Cho S, Jeong MY, Rivera-Piza A, Kim Y, Wu C, Yoon YE, Lee I, Choi JW, Lee HL, Shin SW, Shin J, Gil H, Lee MG, Keum N, Kim JA, Lee D, Jung YH, Chung S, Shin MJ, Hong S, Chi SG, Lee SJ. β-Ionone suppresses colorectal tumorigenesis by activating OR51E2, a potential tumor suppressor. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 140:156599. [PMID: 40088737 DOI: 10.1016/j.phymed.2025.156599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Revised: 02/19/2025] [Accepted: 03/01/2025] [Indexed: 03/17/2025]
Abstract
BACKGROUND Olfactory receptors (ORs) are present in non-olfactory tissues and contribute to diverse biological roles beyond smell perception. Among them, OR51E2 has been associated with cancer biology, and its activator, β-ionone, a natural terpenoid, is known to have anticancer effects. PURPOSE This study aimed to clarify the tumor-suppressive role of OR51E2 in colorectal cancer (CRC), unravel the regulatory mechanism underlying its downregulation, and evaluate the therapeutic potential of β-ionone, an OR51E2 ligand, in CRC progression. STUDY DESIGN AND METHODS OR51E2 expression was analyzed in human CRC tissues, matched adjacent normal tissues, and cell lines. The involvement of N6-methyladenosine (m6A) modification of OR51E2 mRNA stability was examined using METTL3/14 and YTHDF1/2/3 knockdown experiments. β-Ionone-mediated effects on intracellular calcium signaling, cell proliferation, migration, and apoptosis were evaluated in an OR51E2-dependent manner. The therapeutic efficacy of β-ionone was further evaluated in vivo using a xenograft model in nude mice. RESULTS OR51E2 mRNA expression and immunoreactivity were significantly reduced in CRC cells and tissues due to decreased mRNA stability. Knockdown of METTL3/14 or YTHDF1/2/3 increased OR51E2 mRNA and protein expression and inhibited CRC cell proliferation. Treatment with STM2457, an METTL3 inhibitor, restored OR51E2 expression and suppressed CRC cell proliferation. β-Ionone, a ligand of OR51E2, increased intracellular calcium levels, decreased MEK/ERK phosphorylation, and inhibited CRC cell proliferation while inducing apoptosis. These effects were abolished in OR51E2 knockdown cells. In a xenograft model, β-ionone administration (5 and 10 mg/kg body weight) significantly reduced tumor growth. CONCLUSION This study identifies m6A modification as a critical mechanism underlying the downregulation of OR51E2 in CRC. Activation of OR51E2 by β-ionone suppresses CRC cell proliferation and induces apoptosis by elevating intracellular calcium levels, which inhibits the MEK-ERK pathway. These findings highlight OR51E2 as a potential therapeutic target and suggest that β-ionone or m6A inhibition may represent novel strategies for CRC treatment.
Collapse
Affiliation(s)
- Ji-Sun Kim
- Department of Biotechnology, Graduate school of Biotechnology, Korea University, Seoul 02841, South Korea
| | - Sungyun Cho
- Department of Biotechnology, Graduate school of Biotechnology, Korea University, Seoul 02841, South Korea; Department of Pharmacology, Weill Cornell Medicine, Cornell University, New York, NY 10065, USA; Department of Pharmacology, Korea University College of Medicine, Seoul 02841, South Korea
| | - Mi-Young Jeong
- Department of Biotechnology, Graduate school of Biotechnology, Korea University, Seoul 02841, South Korea
| | - Adriana Rivera-Piza
- Department of Biotechnology, Graduate school of Biotechnology, Korea University, Seoul 02841, South Korea
| | - Yeonji Kim
- Department of Biotechnology, Graduate school of Biotechnology, Korea University, Seoul 02841, South Korea
| | - Chunyan Wu
- Department of Biotechnology, Graduate school of Biotechnology, Korea University, Seoul 02841, South Korea
| | - Ye Eun Yoon
- Department of Biotechnology, Graduate school of Biotechnology, Korea University, Seoul 02841, South Korea
| | - InRyeong Lee
- Department of Biotechnology, Graduate school of Biotechnology, Korea University, Seoul 02841, South Korea
| | - Jung-Won Choi
- Department of Biotechnology, Graduate school of Biotechnology, Korea University, Seoul 02841, South Korea
| | - Ha Lim Lee
- Department of Biotechnology, Graduate school of Biotechnology, Korea University, Seoul 02841, South Korea
| | - Sung Won Shin
- Department of Biotechnology, Graduate school of Biotechnology, Korea University, Seoul 02841, South Korea
| | - Jaeeun Shin
- Department of Biotechnology, Graduate school of Biotechnology, Korea University, Seoul 02841, South Korea
| | - Hyeonmin Gil
- Department of Life Science, Pohang University of Science and Technology (POSTECH), Pohang 37673, South Korea
| | - Min-Goo Lee
- Department of Molecular Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, South Korea
| | - NaNa Keum
- Department of Food Science and Biotechnology, Dongguk University, Gyeonggi 10325, South Korea
| | - Jin-A Kim
- School of Mechanical Engineering, Korea University, Seoul 02841, South Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, South Korea
| | - Dain Lee
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, South Korea
| | - Yong Hun Jung
- School of Mechanical Engineering, Korea University, Seoul 02841, South Korea
| | - Seok Chung
- School of Mechanical Engineering, Korea University, Seoul 02841, South Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, South Korea
| | - Min-Jeong Shin
- School of Biosystems and Biomedical Sciences, Korea University, Seoul 02841, South Korea; Interdisciplinary Program in Precision Public Health, BK21 Four Institute of Precision Public Health, Korea University, Seoul 02841, South Korea
| | - SungHoi Hong
- School of Biosystems and Biomedical Sciences, Korea University, Seoul 02841, South Korea; Interdisciplinary Program in Precision Public Health, BK21 Four Institute of Precision Public Health, Korea University, Seoul 02841, South Korea
| | - Sung-Gil Chi
- Department of Molecular Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, South Korea
| | - Sung-Joon Lee
- Interdisciplinary Program in Precision Public Health, BK21 Four Institute of Precision Public Health, Korea University, Seoul 02841, South Korea; Department of Food Bioscience & Technology, Korea University, Seoul 02841, South Korea.
| |
Collapse
|
|
5
|
Li WB, Li J, Yu W, Gao JH. Short-term efficacy of laparoscopic radical resection for colorectal cancer and risk of unplanned reoperation after surgery. World J Gastrointest Surg 2025; 17:102442. [DOI: 10.4240/wjgs.v17.i4.102442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 02/11/2025] [Accepted: 03/07/2025] [Indexed: 03/29/2025] Open
Abstract
BACKGROUND Surgery is the first choice of treatment for patients with colorectal cancer. Traditional open surgery imparts great damage to the body of the patient and can easily cause adverse stress reactions. With the continuous development of medical technology, laparoscopic minimally invasive surgery has shown great advantages for the treatment of patients with celiac disease.
AIM To investigate the short-term efficacy of laparoscopic radical surgery and traditional laparotomy for the treatment of colorectal cancer, and the differences in the risk analysis of unplanned reoperation after operation.
METHODS As the research subjects, this study selected 100 patients with colorectal cancer who received surgical treatment at the Yulin First Hospital from January 2018 to January 2022. Among them, 50 patients who underwent laparoscopic radical resection were selected as the research group and 50 patients who underwent traditional laparotomy were selected as the control group. Data pertaining to clinical indexes, gastrointestinal hormones, nutrition indexes, the levels of inflammatory factors, quality of life, Visual Analog Scale score, and the postoperative complications of the two groups of patients before and after treatment were collected, and the therapeutic effects in the two groups were analyzed and compared.
RESULTS Compared with the control group, perioperative bleeding, peristalsis recovery time, and hospital stays were significantly shorter in the research group. After surgery, the levels of gastrin (GAS) and motilin (MTL) were decreased in both groups, and the fluctuation range of GAS and MTL observed in the research group was significantly lower than that recorded in the control group. The hemoglobin (Hb) levels increased after surgery, and the level of Hb in the research group was significantly higher compared with the control group. After the operation, the expression levels of tumor necrosis factor-α, interleukin-6, and C-reactive protein and the total incidence of complications were significantly lower in the research group compared with the control group. One year after the operation, the quality of life of the two groups was greatly improved, with the quality of life in the research group being significantly better.
CONCLUSION Laparoscopy was effective for colorectal surgery by reducing the occurrence of complications and inflammatory stress reaction; moreover, the quality of life of patients was significantly improved, which warrants further promotion.
Collapse
Affiliation(s)
- Wen-Bin Li
- Department of General Surgery, Yulin First Hospital, Yulin 719000, Shaanxi Province, China
| | - Jiang Li
- Department of General Surgery, Yulin First Hospital, Yulin 719000, Shaanxi Province, China
| | - Wei Yu
- Department of General Surgery, Yulin First Hospital, Yulin 719000, Shaanxi Province, China
| | - Jian-Hua Gao
- Department of General Surgery, Yulin First Hospital, Yulin 719000, Shaanxi Province, China
| |
Collapse
|
|
6
|
Tian HP, Xiao ZX, Su BW, Li YX, Peng H, Meng CY. Impact of SLC16A8 on tumor microenvironment and angiogenesis in colorectal cancer: New therapeutic target insights. World J Gastrointest Oncol 2025; 17:99188. [DOI: 10.4251/wjgo.v17.i4.99188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 11/08/2024] [Accepted: 01/15/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND SLC16A8, a lactate efflux transporter, is upregulated in various cancers, but its effects on tumor microenvironments remain understudied. This research explores its role in colorectal cancer (CRC) and the impact on the associated microenvironment consisting of vascular endothelial cells.
AIM To explore the role in CRC and the impact on the associated microenvironment consisting of vascular endothelial cells.
METHODS Hypoxic conditions prompted examination of SLC16A8 expression, glycolysis, lactate efflux, and Warburg effect correlations in CRC cell lines. Co-culture with HUVEC allowed for endothelial-mesenchymal transition (EndMT) characterization, revealing lactate efflux's influence. Knockdown of SLC16A8 in CRC cells enabled relevant phenotype tests and tumorigenesis experiments, investigating tumor growth, blood vessel distribution, and signaling pathway alterations.
RESULTS SLC16A8 expression was significantly upregulated in CRC tissues compared to adjacent normal tissues and correlated with disease progression (P < 0.05). Under hypoxic conditions, HIF-1α induced SLC16A8 expression, leading to enhanced metabolic reprogramming and increased lactate production. siRNA-mediated SLC16A8 knockdown effectively reversed hypoxia-induced changes, including reduced glucose consumption and lactate production. Co-culture experiments revealed that SLC16A8 knockdown significantly inhibited hypoxia-induced EndMT in HUVEC cells. In vivo studies demonstrated that SLC16A8 knockdown suppressed tumor growth, reduced Ki67 expression, and decreased HIF-1α levels. Furthermore, SLC16A8 silencing led to decreased expression of key metabolic enzymes PKM2 and LDHA, indicating its role in glycolytic regulation.
CONCLUSION Our findings reveal that SLC16A8 functions as a critical mediator of hypoxia-induced metabolic reprogramming in CRC progression.
Collapse
Affiliation(s)
- Hong-Peng Tian
- Second Department of Gastrointestinal Surgery, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Zhong-Xiang Xiao
- Second Department of Gastrointestinal Surgery, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Bo-Wen Su
- Second Department of Gastrointestinal Surgery, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Yi-Xuan Li
- Department of Premarital and Prenatal Examination, Nanchong Shunqing District Maternal and Child Health Hospital, Nanchong 637000, Sichuan Province, China
| | - Hong Peng
- Department of Anorectal Surgery, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Chang-Yuan Meng
- Second Department of Gastrointestinal Surgery, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| |
Collapse
|
|
7
|
Zhang YR, Zhu HR, Li HR, Cheng YL, Yang SH, Sun SL, Wang Z. Trends in nanomedicine for colorectal cancer treatment: Bibliometric and visualization analysis (2010-2024). World J Gastrointest Oncol 2025; 17:102438. [DOI: 10.4251/wjgo.v17.i4.102438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 12/25/2024] [Accepted: 02/05/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Recently, numerous studies have reported the application of nanomedicines in colorectal cancer treatment. However, no systematic bibliometric analysis has been conducted to examine the potential and mechanisms of action of nanomedicine in this context. Such an analysis may provide a comprehensive overview of the current research landscape, identify emerging trends, and highlight key areas for future investigation.
AIM To describe the current global research landscape on the application of nanomedicine in colorectal cancer treatment.
METHODS The Web of Science Core Collection database was searched for literature published from January 1, 2010, to August 7, 2024, focusing on the application of nanomedicine in colorectal cancer treatment. Bibliometric analysis and visualization mapping of countries, institutions, authors, keywords, references of the relevant research literature were conducted using CiteSpace (6.2R6), VOSviewer (1.6.20), and bibliometrix (based on R 4.3.2).
RESULTS A total of 3598 articles were included, with a rapid increase in publication volume starting from 2010. China published the most papers on this topic, followed by the United States and India. The United States emerged as the central country in this field, and the Egyptian Knowledge Bank and Chinese Academy of Sciences were the institutions with the highest number of publications. The Chinese Academy of Sciences exhibited the highest centrality. The most prolific author was Zhang Y, whereas Siegel RL was the most cited author, and Li Y had the highest H-index. The International Journal of Nanomedicine had the most publications and Biomaterials received the most citations. Keyword co-occurrence analysis identified 11837 keywords grouped into 13 clusters with 15 high-frequency highlighted keywords. The top three keyword clusters were “0 colorectal cancer”, “1 drug delivery”, and “2 delivery”, with the top three keywords being “nanoparticles”, “colorectal cancer”, and “drug delivery”.
CONCLUSION Research on nanomedicine for colorectal cancer has surged since 2010, focusing on “nanoparticles” and “drug delivery”. Future studies should investigate nanomaterial stability and target-specific drug release.
Collapse
Affiliation(s)
- Yu-Ren Zhang
- Department of Oncology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hui-Rong Zhu
- Department of Oncology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hao-Ran Li
- Department of Oncology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yue-Lei Cheng
- Department of Oncology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Sun-Hu Yang
- Department of General Surgery, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
| | - Su-Ling Sun
- Department of General Surgery, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
| | - Zheng Wang
- Department of Internal Medicine, Shanghai Guanghua Hospital of Integrative Medicine, The Affiliated with Shanghai University of Traditional Chinese Medicine, Shanghai 200052, China
| |
Collapse
|
|
8
|
Lu XF, Zhang HW, Chang X, Guo YZ. F-box protein 22: A prognostic biomarker for colon cancer associated with immune infiltration and chemotherapy resistance. World J Gastrointest Oncol 2025; 17:102913. [DOI: 10.4251/wjgo.v17.i4.102913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 01/10/2025] [Accepted: 02/21/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Colon cancer represents a significant malignant neoplasm within the digestive system, characterized by a high incidence rate and substantial disease burden. The F-box protein 22 (FBXO22) plays a role in forming a specific type of ubiquitin ligase subunit, which is expressed abnormally in various malignant neoplasms and shows a notable relationship with prognosis in patients with cancer. Nevertheless, the function of FBXO22 in the context of colon cancer remains inadequately elucidated.
AIM To explore the role of FBXO22 in colon cancer by examining FBXO22 expression patterns and analyzing how the protein affects the prognosis in patients who have undergone surgery.
METHODS Samples of cancerous and nearby normal tissues from patients with colon cancer were gathered, along with pertinent clinical data. Expression levels of the FBXO22 gene in both cancerous and paracancerous tissues were assessed through immunohistochemistry. The median H score served as a criterion for categorizing FBXO22 gene expression into high and low levels in cancerous tissues, and the relationship between these expression levels and various pathologic characteristics of patients, such as age, sex, and clinical stage, was analyzed. Colon cancer cell lines HCT116 and DLD-1 were used and divided into three groups: A blank control group, a negative control group, and a si-FBXO22 group. FBXO22 gene mRNA and protein expression were measured 24 hours post-transfection using real-time fluorescence quantitative polymerase chain reaction and western blotting. The proliferation capabilities of the cells in each group were assessed using the Cell Counting Kit-8 assay and 5-ethynyl-2’-deoxyuridine assay, while cellular migration and invasion abilities were evaluated using scratch healing and Transwell assays. Various online platforms, including the Timer Immune Estimation Resource, were used to analyze pan-cancer expression, promoter methylation levels, and mutation frequencies of the FBXO22 gene in colon cancer patients. Additionally, the correlation between FBXO22 gene expression, patient prognosis, immune cell infiltration, and the expression of immune molecules in the colon cancer microenvironment was investigated. The relationship between FBXO22 gene expression and chemotherapy resistance, along with the potential mechanisms of action of the FBXO22 gene, were analyzed using The Cancer Genome Atlas dataset and the Genomics of Drug Sensitivity in Cancer drug training set via R software.
RESULTS Compared with normal colonic tissues, the FBXO22 gene was highly expressed in colon cancer tissues. Post-operative patients with colon cancer elevated FBXO22 reduced survival and exhibited resistance to various chemotherapeutic agents. FBXO22 expression suppresses the infiltration of anti-tumor immune cells. In vitro, FBXO22 knockdown inhibited the proliferation and migration of colon cancer cells.
CONCLUSION The FBXO22 gene is a biomarker of poor prognosis in patients with colon cancer and has potential as a target for immunotherapy and overcoming chemotherapy resistance.
Collapse
Affiliation(s)
- Xiao-Fei Lu
- Department of Clinical Medicine, Hebei University of Engineering, Handan 056002, Hebei Province, China
| | - Hong-Wei Zhang
- Department of Gastroenterology, Affiliated Hospital of Hebei Engineering University, Handan 056002, Hebei Province, China
| | - Xiao Chang
- Department of Gastroenterology, Affiliated Hospital of Hebei Engineering University, Handan 056002, Hebei Province, China
| | - Yong-Ze Guo
- Department of Gastroenterology, Affiliated Hospital of Hebei Engineering University, Handan 056002, Hebei Province, China
| |
Collapse
|
|
9
|
Zhao Z, Wu Y, Geng X, Yuan C, Yang G. Single-Cell Analysis Reveals Histone Deacetylation Factor Guide Intercellular Communication of Tumor Microenvironment that Contribute to Colorectal Cancer Progression and Immunotherapy. Biochem Genet 2025; 63:1862-1879. [PMID: 38637426 DOI: 10.1007/s10528-024-10730-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Accepted: 01/31/2024] [Indexed: 04/20/2024]
Abstract
In this study, single-cell RNA-seq data were collected to analyze the characteristics of Histone deacetylation factor (HDF). The tumor microenvironment (TME) cell clusters related to prognosis and immune response were identified by using CRC tissue transcriptome and immunotherapy cohorts from public repository. We explored the expression characteristics of HDF in stromal cells, macrophages, T lymphocytes, and B lymphocytes of the CRC single-cell dataset TME and further identified 4 to 6 cell subclusters using the expression profiles of HDF-associated genes, respectively. The regulatory role of HDF-associated genes on the CRC tumor microenvironment was explored by using single-cell trajectory analysis, and the cellular subtypes identified by biologically characterized genes were compared with those identified by HDF-associated genes. The interaction of HDF-associated gene-mediated microenvironmental cell subtypes and tumor epithelial cells were explored by using intercellular communication analysis, revealing the molecular regulatory mechanism of tumor epithelial cell heterogeneity. Based on the expression of feature genes mediated by HDF-related genes in the microenvironment T-cell subtypes, enrichment scoring was performed on the feature gene expression in the CRC tumor tissue transcriptome dataset. It was found that the feature gene scoring of microenvironment T-cell subtypes (HDF-TME score) has a certain predictive ability for the prognosis and immunotherapy benefits of CRC tumor patients, providing data support for precise immunotherapy in CRC tumors.
Collapse
Affiliation(s)
- Zihan Zhao
- Department of Gastroenterology, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, 15 Yuquan Road, Haidian District, Beijing, 100049, China
| | - Yarui Wu
- Department of Gastroenterology, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, 15 Yuquan Road, Haidian District, Beijing, 100049, China
| | - Xuhua Geng
- Department of Gastroenterology, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, 15 Yuquan Road, Haidian District, Beijing, 100049, China
| | - Congrui Yuan
- Department of Gastroenterology, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, 15 Yuquan Road, Haidian District, Beijing, 100049, China
| | - Guibin Yang
- Department of Gastroenterology, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, 15 Yuquan Road, Haidian District, Beijing, 100049, China.
| |
Collapse
|
|
10
|
Mohapatra B, Lavudi K, Kokkanti RR, Patnaik S. Regulation of NLRP3/TRIM family signaling in gut inflammation and colorectal cancer. Biochim Biophys Acta Rev Cancer 2025; 1880:189271. [PMID: 39864469 DOI: 10.1016/j.bbcan.2025.189271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 01/13/2025] [Accepted: 01/16/2025] [Indexed: 01/28/2025]
Abstract
CRC (Colorectal cancer) ranks among the most prevalent tumors in humans and remains a leading cause of cancer-related mortality worldwide. Numerous studies have highlighted the connection between inflammasome over-activation and the initiation and progression of CRC. The activation of the NLRP3 (NOD-like receptor family, pyrin domain containing 3) inflammasome is dependent on the nuclear NF-kβ (Nuclear Factor kappa-light-chain-enhancer of activated B cells) pathway, leading to the maturation and release of inflammatory cytokines such as IL-1ß (Interleukin 1 beta) and IL-18 (Interleukin 18). While inflammation is crucial for defense mechanisms and tissue repair, excessive information can pose significant risks. Mounting evidence suggests that overactivation of the inflammasome contributes to the pathogenesis of inflammatory diseases. Consequently, there is a concerted effort to tightly regulate inflammasome activity and mitigate excessive inflammatory responses, particularly in conditions such as IBD (Inflammatory Bowel Disease), which includes Ulcerative Colitis and Crohn's Disease. The tripartite motif (TRIM) protein family, characterized by a conserved structure and rapid evolutionary diversification, includes members with critical roles in ubiquitination and other regulatory functions. Their importance in modulating inflammatory responses is widely acknowledged. This article aims to investigate the interplay between TRIM proteins and the NLRP3 Inflammasome in CRC and gut inflammation, offering insights for future research endeavors and potential therapeutic strategies.
Collapse
Affiliation(s)
- Bibhashee Mohapatra
- School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT) Deemed to be University, Bhubaneswar, Odisha 751024, India
| | - Kousalya Lavudi
- Department of Radiation Oncology, College of Medicine, The Ohio State University, Columbus, OH 43210, United States; Comprehensive cancer center, The Ohio State University, Columbus, OH, United States
| | - Rekha Rani Kokkanti
- School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT) Deemed to be University, Bhubaneswar, Odisha 751024, India
| | - Srinivas Patnaik
- School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT) Deemed to be University, Bhubaneswar, Odisha 751024, India.
| |
Collapse
|
|
11
|
Xiong Y, Li J, Jin W, Sheng X, Peng H, Wang Z, Jia C, Zhuo L, Zhang Y, Huang J, Zhai M, Lyu B, Sun J, Zhou M. PCMR: a comprehensive precancerous molecular resource. Sci Data 2025; 12:551. [PMID: 40169679 DOI: 10.1038/s41597-025-04899-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Accepted: 03/25/2025] [Indexed: 04/03/2025] Open
Abstract
Early detection and intervention of precancerous lesions are crucial in reducing cancer morbidity and mortality. Comprehensive analysis of genomic, transcriptomic, proteomic and epigenomic alterations can provide insights into the early stages of carcinogenesis. However, the lacke of an integrated, well-curated data resource of molecular signatures limits our understanding of precancerous processes. Here, we introduce a comprehensive PreCancerous Molecular Resource (PCMR), which compiles 25,828 molecular profiles of precancerous samples paired with normal or malignant counterparts. These profiles cover precancerous lesions of 35 cancer types across 20 organs and tissues, derived from tissue samples, liquid biopsies, cell lines and organoids, with data from transcriptomics, proteomics and epigenomics. PCMR includes 62,566 precancer-gene associations derived from differential analysis and text-mining using the ChatGPT large language model. We examined PCMR dataset reliability and significance by the authoritative precancerous molecular signature, along with its biological and clinical relevance. Overall, PCMR will serve as a valuable resource for advancing precancer research and ultimately improving patient outcomes.
Collapse
Affiliation(s)
- Yichun Xiong
- School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, P. R. China
| | - Jiaqi Li
- School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, P. R. China
| | - Wang Jin
- School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, P. R. China
| | - Xiaoran Sheng
- School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, P. R. China
| | - Hui Peng
- School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, P. R. China
| | - Zhiyi Wang
- School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, P. R. China
| | - Caifeng Jia
- School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, P. R. China
| | - Lili Zhuo
- School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, P. R. China
| | - Yibo Zhang
- School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, P. R. China
| | - Jingzhe Huang
- School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, P. R. China
| | - Modi Zhai
- School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, P. R. China
| | - Beibei Lyu
- School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, P. R. China
| | - Jie Sun
- School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, P. R. China.
| | - Meng Zhou
- School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, P. R. China.
| |
Collapse
|
|
12
|
Ding Y, Yu Y. Therapeutic potential of flavonoids in gastrointestinal cancer: Focus on signaling pathways and improvement strategies (Review). Mol Med Rep 2025; 31:109. [PMID: 40017144 PMCID: PMC11884236 DOI: 10.3892/mmr.2025.13474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 01/30/2025] [Indexed: 03/01/2025] Open
Abstract
Flavonoids are a group of polyphenolic compounds distributed in vegetables, fruits and other plants, which have considerable antioxidant, anti‑tumor and anti‑inflammatory activities. Several types of gastrointestinal (GI) cancer are the most common malignant tumors in the world. A large number of studies have shown that flavonoids have inhibitory effects on cancer, and they are recognized as a class of potential anti‑tumor drugs. Therefore, the present review investigated the molecular mechanisms of flavonoids in the treatment of different types of GI cancer and summarized the drug delivery systems commonly used to improve their bioavailability. First, the classification of flavonoids and the therapeutic effects of various flavonoids on human diseases were briefly introduced. Then, to clarify the mechanism of action of flavonoids on different types of GI cancer in the human body, the metabolic process of flavonoids in the human body and the associated signaling pathways causing five common types of GI cancer were discussed, as well as the corresponding therapeutic targets of flavonoids. Finally, in clinical settings, flavonoids have poor water solubility, low permeability and inferior stability, which lead to low absorption efficiency in vivo. Therefore, the three most widely used drug delivery systems were summarized. Suggestions for improving the bioavailability of flavonoids and the focus of the next stage of research were also put forward.
Collapse
Affiliation(s)
- Ye Ding
- Henan Key Laboratory of Helicobacter Pylori and Microbiota and Gastrointestinal Cancer, Marshall Medical Research Center, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
- Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Yong Yu
- Henan Key Laboratory of Helicobacter Pylori and Microbiota and Gastrointestinal Cancer, Marshall Medical Research Center, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
- Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| |
Collapse
|
|
13
|
Song J, Zhu J, Jiang Y, Guo Y, Liu S, Qiao Y, Du Y, Li J. Advancements in immunotherapy for gastric cancer: Unveiling the potential of immune checkpoint inhibitors and emerging strategies. Biochim Biophys Acta Rev Cancer 2025; 1880:189277. [PMID: 39938663 DOI: 10.1016/j.bbcan.2025.189277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 01/08/2025] [Accepted: 02/04/2025] [Indexed: 02/14/2025]
Abstract
Gastric cancer (GC) is linked to high morbidity and mortality rates. Approximately two-thirds of GC patients are diagnosed at an advanced or metastatic stage. Conventional treatments for GC, including surgery, radiotherapy, and chemotherapy, offer limited prognostic improvement. Recently, immunotherapy has gained attention for its promising therapeutic effects in various tumors. Immunotherapy functions by activating and regulating the patient's immune cells to target and eliminate tumor cells, thereby reducing the tumor burden in the body. Among immunotherapies, immune checkpoint inhibitors (ICIs) are the most advanced. ICIs disrupt the inhibitory protein-small molecule (PD-L1, CTLA4, VISTA, TIM-3 and LAG3) interactions produced by immune cells, reactivating these cells to recognize and attack tumor cells. However, adverse reactions and resistance to ICIs hinder their further clinical and experimental development. Therefore, a comprehensive understanding of the advancements in ICIs for GC is crucial. This article discusses the latest developments in clinical trials of ICIs for GC and examines combination therapies involving ICIs (targeted therapy, chemotherapy, radiotherapy), alongside ongoing clinical trials. Additionally, the review investigates the tumor immune microenvironment and its role in non-responsiveness to ICIs, highlighting the function of tumor immune cells in ICI efficacy. Finally, the article explores the prospects and limitations of new immunotherapy-related technologies, such as tumor vaccines, nanotechnologies, and emerging therapeutic strategies, aiming to advance research into personalized and optimized immunotherapy for patients with locally advanced gastric cancer.
Collapse
Affiliation(s)
- Jiawei Song
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Air force Medical University, Xi'an 710038, China; Department of Experimental Surgery, Xijing Hospital, Xi'an 710038, China
| | - Jun Zhu
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Air force Medical University, Xi'an 710038, China
| | - Yu Jiang
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Air force Medical University, Xi'an 710038, China
| | - Yajie Guo
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Air force Medical University, Xi'an 710038, China
| | - Shuai Liu
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Air force Medical University, Xi'an 710038, China
| | - Yihuan Qiao
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Air force Medical University, Xi'an 710038, China
| | - Yongtao Du
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Air force Medical University, Xi'an 710038, China
| | - Jipeng Li
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Air force Medical University, Xi'an 710038, China; Department of Experimental Surgery, Xijing Hospital, Xi'an 710038, China.
| |
Collapse
|
|
14
|
Xie T, Guo J, Wang W. The Long Noncoding RNA Gall Bladder Cancer-Associated Suppressor of Pyruvate Carboxylase Inhibits the Proliferation, Migration, and Invasion of Colorectal Cancer Cells and Induces Their Apoptosis. Biochem Genet 2025; 63:1719-1733. [PMID: 38609669 DOI: 10.1007/s10528-024-10786-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Accepted: 03/15/2024] [Indexed: 04/14/2024]
Abstract
This study aimed to determine the role of the long noncoding RNA (lncRNA) gall bladder cancer-associated suppressor of pyruvate carboxylase (SOD2-1) in the progression of colorectal cancer (CRC). A total of 23 pairs of specimens, including CRC tissues and adjacent normal tissues, were collected, and the expression of lncRNA SOD2-1 (lnc-SOD2-1) was measured. lnc-SOD2-1 function was examined using HCT15 and HCT116 cells. A lnc-SOD2-1 overexpression vector was designed and transfected into both cell lines. MTS and colony formation assays were used to determine cell viability. Flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling assays were performed to measure apoptosis. Cell migration and invasion were evaluated using the Transwell assay. Migration and invasion markers were validated using quantitative reverse transcription-polymerase chain reaction and western blot analysis. The results indicated that the expression of lnc-SOD2-1 was downregulated in CRC tissues. lnc-SOD2-1 overexpression evidently decreased cell viability and led to the formation of fewer cell colonies. lnc-SOD2-1 overexpression induced ~ twofold higher apoptosis than the control group. lnc-SOD2-1 overexpression reduced the proportion of migratory and invasive cells to 50% and 75% of the control group, respectively. lnc-SOD2-1 overexpression significantly decreased the expression of matrix metalloproteinase-2 and -9. In conclusion, lnc-SOD2-1 may act as a tumor suppressor that inhibits the proliferation, migration, and invasion of CRC cells and induces their apoptosis.
Collapse
Affiliation(s)
- Tingting Xie
- Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jianian Guo
- Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Wei Wang
- Department of Thoracic Surgery, The Second Affiliated Hospital of Guangzhou Medical University, No.250 Changgang East Road, Haizhu District, Guangzhou, 510260, China.
| |
Collapse
|
|
15
|
Shi F, Li GJ, Liu Y, Zhou HM, Zhang Y, Wei SY, Zan BJ, Gao M, Chen FS, Li BX, Wang BQ, Dong MY, Du RL, Zhang XD. USP19 deficiency enhances T-cell-mediated antitumor immunity by promoting PD-L1 degradation in colorectal cancer. Pharmacol Res 2025; 214:107668. [PMID: 40020887 DOI: 10.1016/j.phrs.2025.107668] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 01/26/2025] [Accepted: 02/18/2025] [Indexed: 03/03/2025]
Abstract
Colorectal cancer (CRC) is characterized by a highly immunosuppressive tumor microenvironment, which limits the effectiveness of current immunotherapies. Identifying strategies to overcome this resistance is critical for improving treatment outcomes. In this study, we discovered that USP19 plays a pivotal role in regulating T-cell-mediated antitumor immunity through a CRISPR/Cas9 sgRNA library screen and co-culture assays with activated T cells. We demonstrated that USP19 deficiency significantly enhances the susceptibility to T cell-mediated cytotoxicity in CRC cells, organoids, and mouse models. Transcriptomic sequencing (RNA-seq) revealed activation of the PD-1 pathway in tumor with USP19-deficiency cells. Mechanistic investigations revealed that USP19 directly stabilizes PD-L1 by binding to its intracellular domain and preventing its degradation via K48-linked ubiquitination and proteasomal pathways. Clinically, USP19 expression was found to be significantly elevated in CRC tissues and was positively associated with PD-L1 levels, advanced tumor grade, poor differentiation, and TP53 mutations, highlighting its potential as a biomarker for aggressive CRC. Importantly, in vivo experiments demonstrated that targeting USP19, in combination with αPD-L1 therapy, synergistically suppressed CRC progression. This combination not only reduced PD-L1 levels but also enhanced CD8+ T-cell activation and GzmB infiltration, resulting in robust antitumor effects. These findings establish USP19 as a key driver of immune evasion in CRC and suggest that targeting USP19 could enhance the efficacy of immunotherapy, providing a promising new avenue for CRC treatment.
Collapse
Affiliation(s)
- Feng Shi
- National Health Commission Key Laboratory of Birth Defect Research and Prevention & MOE Key Lab of Rare Pediatric Diseases, Department of Cell Biology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang 421001, China
| | - Guang-Jing Li
- Key Laboratory of Research on Clinical Molecular Diagnosis for High Incidence Diseases in Western Guangxi of Guangxi Higher Education Institutions, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi 533000, China
| | - Yi Liu
- National Health Commission Key Laboratory of Birth Defect Research and Prevention & MOE Key Lab of Rare Pediatric Diseases, Department of Cell Biology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang 421001, China
| | - Hai-Meng Zhou
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China
| | - Yue Zhang
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China
| | - Si-Yi Wei
- National Health Commission Key Laboratory of Birth Defect Research and Prevention & MOE Key Lab of Rare Pediatric Diseases, Department of Cell Biology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang 421001, China
| | - Bo-Jun Zan
- Medical Laboratory College, Youjiang Medical University for Nationalities, Baise, Guangxi, China
| | - Meng Gao
- National Health Commission Key Laboratory of Birth Defect Research and Prevention & MOE Key Lab of Rare Pediatric Diseases, Department of Cell Biology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang 421001, China
| | - Fei-Shan Chen
- National Health Commission Key Laboratory of Birth Defect Research and Prevention & MOE Key Lab of Rare Pediatric Diseases, Department of Cell Biology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang 421001, China
| | - Bo-Xin Li
- National Health Commission Key Laboratory of Birth Defect Research and Prevention & MOE Key Lab of Rare Pediatric Diseases, Department of Cell Biology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang 421001, China
| | - Bai-Qi Wang
- National Health Commission Key Laboratory of Birth Defect Research and Prevention & MOE Key Lab of Rare Pediatric Diseases, Department of Cell Biology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang 421001, China
| | - Ming-You Dong
- National Health Commission Key Laboratory of Birth Defect Research and Prevention & MOE Key Lab of Rare Pediatric Diseases, Department of Cell Biology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang 421001, China.
| | - Run-Lei Du
- National Health Commission Key Laboratory of Birth Defect Research and Prevention & MOE Key Lab of Rare Pediatric Diseases, Department of Cell Biology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang 421001, China; Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China.
| | - Xiao-Dong Zhang
- National Health Commission Key Laboratory of Birth Defect Research and Prevention & MOE Key Lab of Rare Pediatric Diseases, Department of Cell Biology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang 421001, China.
| |
Collapse
|
|
16
|
Yan X, Wang Y, Ma A, Li H. The role of health economic evidence in clinical practice guidelines for colorectal cancer: a comparative analysis across countries. J Comp Eff Res 2025; 14:e240226. [PMID: 39969114 DOI: 10.57264/cer-2024-0226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/20/2025] Open
Abstract
Aim: Colorectal cancer (CRC) is among the most prevalent malignancies globally and causes massive resource consumption and economic burden. Health economic evidence (HEE) has been used in clinical practice guidelines (CPGs) for cancer to facilitate the rational allocation of health resources. However, in certain guideline development organizations, HEE is not yet utilized as a formal decision-making criterion. This study aimed to compare the discrepancies in the utilization of health economics as evidence in CRC CPGs across different countries and review specific features of economic evidence concerning the guidelines' applicability. Materials & methods: A systematic review was conducted using databases including Medline, Embase, CNKI, WanFang, and other guidelines databases to identify CPGs for CRC published in English or Chinese from January 2017 to September 2023. Data on the incorporation and application of HEE were extracted, and the method and quality of cost-effectiveness analysis (CEA) studies were evaluated. Descriptive analyses were used to summarize the results. Results: Out of 53 CPGs from 14 countries, most originated from the USA (n = 17 of 53 [32%]) and Canada (n = 9 of 53 [17%]). Sixty-eight percent (36/53) considered cost justification, and 57% (30/53) incorporated health economics studies as evidence. The included HEE cited in CPGs ranged from 1990 to 2021 and were not aligned with the countries in which the guidelines were issued. Among these CEA studies, 52% (26/50) were related to screening strategies, and 32% (16/50) pertained to treatment measures. The Markov model was the most frequently used (n = 27 of 50 [54%]). Based on the CHEQUE tool, the methodological quality of these CEA studies was inadequate in areas such as multiple data sources, approaches to select data sources, assessing the quality of data, and relevant equity or distribution. Conclusion: In summary, 57% of guidelines incorporated health economics studies as evidence, with a variation between different countries. The included HEE still had deficiencies in methodology and reporting quality. In the future, it is suggested that health economics research should use a standardized methodology and reporting approach to assist in clinical decision making.
Collapse
Affiliation(s)
- Xiaoyu Yan
- School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, Jiangsu, People's Republic of China
| | - Yue Wang
- School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, Jiangsu, People's Republic of China
| | - Aixia Ma
- School of International Pharmaceutical Business & Center for Pharmacoeconomics & Outcomes Research, China Pharmaceutical University, Nanjing, Jiangsu, People's Republic of China
| | - Hongchao Li
- School of International Pharmaceutical Business & Center for Pharmacoeconomics & Outcomes Research, China Pharmaceutical University, Nanjing, Jiangsu, People's Republic of China
| |
Collapse
|
|
17
|
Sood R, Badjatia T, Bhargava P. Mucinous rectal adenocarcinoma recurrence: A case report and literature review. Radiol Case Rep 2025; 20:2189-2193. [PMID: 39981160 PMCID: PMC11840533 DOI: 10.1016/j.radcr.2025.01.046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 01/04/2025] [Accepted: 01/09/2025] [Indexed: 02/22/2025] Open
Abstract
Mucinous rectal adenocarcinoma (MRA) is a relatively uncommon type of rectal cancer, accounting for only about 5%-10% of all adenocarcinomas of the rectum. Characterized by the presence of extracellular mucin constituting at least 50% of the tumor volume, MRA is associated with a poorer prognosis and more advanced tumor stage at presentation compared to nonmucinous rectal adenocarcinomas. We report a case of a 42-year-old male patient with no family history of colorectal cancer, who presented with chronic diarrhea and was diagnosed with T3N0 MRA. We highlight the multimodality imaging features of recurrent and metastatic disease specific to this subtype of rectal carcinoma.
Collapse
Affiliation(s)
- Riya Sood
- Department of Radiology, University of Texas Medical Branch, Galveston, TX, USA
| | - Trisha Badjatia
- Department of Radiology, University of Texas Medical Branch, Galveston, TX, USA
| | - Peeyush Bhargava
- Department of Radiology, University of Texas Medical Branch, Galveston, TX, USA
| |
Collapse
|
|
18
|
Liu T, Jiao S, Gao S, Shi Y. Optimal lymph node yield for long-term survival in elderly patients with right-sided colon cancer: a large population-based cohort study. BMC Cancer 2025; 25:590. [PMID: 40170177 DOI: 10.1186/s12885-025-13987-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 03/20/2025] [Indexed: 04/03/2025] Open
Abstract
BACKGROUND Although the recommended minimal lymph node yield (LNY) in colon cancer is 12, this standard remains controversial in elderly patients with right-sided colon cancer (RSCC) due to insufficient evidence. This study aims to clarify this issue by assessing the relationship between LNY and long-term survival in elderly patients with RSCC. METHODS Data from the SEER database (split into 7:3 training and testing sets) and patients from the colorectal surgery departments of two tertiary hospitals in China (validation set) were analyzed. Elderly patients with stages I-III RSCC undergoing resection were included. The correlation between LNY and overall survival (OS) was evaluated by a multivariate model and the application of the restricted cubic spline curve (RCS). The odds ratios (ORs) for stage migration and the hazard ratios (HRs) for OS with increased LNY were estimated using Locally Weighted Scatterplot Smoothing (LOWESS), with structural breakpoints identified using the Chow test. RESULTS The distribution of LNY was similar across the training (median: 18, IQR [14, 23]), testing (median: 18, IQR [14, 23]), and validation (median: 17, IQR [14, 20]) sets. Increasing LNY was associated with significantly improved OS in all datasets (Training set: HR = 0.983; Testing set: HR = 0.981; Validation set: HR = 0.944, all P < 0.001) after adjusting for confounders. Cut-point analysis identified an optimal LNY threshold of 18, validated across datasets, effectively discriminating survival probabilities. CONCLUSIONS A higher LNY is associated with improved survival. Our findings robustly support 18 LNYs as the optimal threshold for assessing the quality of lymph node dissection and prognosis stratification in elderly patients with RSCC.
Collapse
Affiliation(s)
- Tianyi Liu
- Department of Pathology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Shuai Jiao
- Department of Colorectal Surgery, Shanxi Province Cancer Hospital/Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Shan Gao
- Department of Pathology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Yan Shi
- Department of Pathology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
| |
Collapse
|
|
19
|
Fallon EA, Awiwi MO, Bhutiani N, Helmink B, Scally CP, Mansfield P, Fournier K, Vikram R, Uppal A, White MG. Peritoneal Cancer Index Correlates with Radiographic Assessment of Colorectal Carcinomatosis. Ann Surg Oncol 2025; 32:2923-2931. [PMID: 39730964 DOI: 10.1245/s10434-024-16737-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 12/10/2024] [Indexed: 12/29/2024]
Abstract
BACKGROUND The Peritoneal Cancer Index (PCI), calculated intraoperatively, has previously yielded mixed results when correlated with computed tomography. This study aimed to quantify variation in this scoring method comparing radiologists' and surgeons' radiologic PCI (rPCI) assessment. METHODS The rPCI of 104 patients treated at a single institution for peritoneal carcinomatosis was calculated by an abdominal radiologist and a surgeon. An additional 36-patient cohort was studied to compare preoperative rPCI with intraoperative gold standard PCI. Agreement was compared using kappa statistics. RESULTS The rPCI of the 104 patients studied ranged from 2 to 39 (median, 12; interquartile range [IQR], 6-23) by the radiologist's analysis and 2 to 37 (median, 9; IQR, 6-15) by the surgeon's analysis. There was good agreement for PCI cutoffs of 15 (77.48%; kappa, 0.40) and 20 (78.63%; kappa, 0.24). The 36-patient cohort undergoing surgical exploration showed a median rPCI of 4 (IQR, 2-5.75) and a median intraoperative PCI of 11 (IQR, 6-12), with a significant difference in score by method (p < 0.001, Wilcoxon signed-rank test). CONCLUSIONS For rPCI cutoffs greater than 15 and 20, the surgeon's and radiologist's rPCI showed strong concordance, denoting the interobserver reproducibility of rPCI. Moreover, concordance with intraoperative PCI translated to radiographic assessment. The rPCI consistently underestimated intraoperative PCI, suggesting that rPCI may be a useful conservative tool for assessing peritoneal burden. Although surgical exploration is needed to "rule in" patients as candidates for CRS, the authors suggest that rPCI can be used to "rule out" patients as CRS candidates based on institutional PCI cutoffs.
Collapse
Affiliation(s)
- Eleanor A Fallon
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Muhammad O Awiwi
- Department of Radiology, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Neal Bhutiani
- Department of Colon and Rectal Surgery, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - Beth Helmink
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Chris P Scally
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Paul Mansfield
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Keith Fournier
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Raghunandan Vikram
- Department of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Abhineet Uppal
- Department of Colon and Rectal Surgery, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - Michael G White
- Department of Colon and Rectal Surgery, The University of Texas MD Anderson Cancer Center, Houston, USA.
| |
Collapse
|
|
20
|
Wu Y, Yu Y, Li D, Dai Y, Wu J, Zhang Z, Pan H, Chen W, Li R, Hu L. CDH1 genetic variants and its aberrant expression are the risk factors for colorectal cancer metastasis. BMC Gastroenterol 2025; 25:214. [PMID: 40169954 DOI: 10.1186/s12876-025-03797-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Accepted: 03/18/2025] [Indexed: 04/03/2025] Open
Abstract
E-cadherin, encoded by the CDH1 gene, plays an essential role in epithelial cellular adhesion, and the loss of it has been reported to be associated with tumor progression and metastasis, potentially offer a glimpse in to the development of colorectal cancer. The present study aimed to explore effect of CDH1-160 polymorphism, CDH1 transcription and its protein E-cadherin expression on colorectal cancer, meanwhile uncovering the underlying mechanism. Specimens from cancer loci, adjacent cancer tissue, and distal normal tissue from colorectal cancer patients were collected for Hematoxylin-eosin staining to detect the histopathological change of colorectal mucosa. Direct sequencing and Quantitative Real-Time PCR were used to detect the CDH1 genotype and its mRNA expression, respectively. E-cadherin expression was detected using the ElivisionTM plus method. As a result, we found that the A allele of the CDH1-160 may be a protective gene against colorectal cancer, and the C > A polymorphism may regulate its transcription activity and expression of E-cadherin. The decrease of the CDH1 mRNA transcription level and the absence of E-cadherin on the cytomembrane may promote intestinal mucosal carcinogenesis and accelerate cancer cell metastasis. Deficiency of cytomembrane expression of E-cadherin protein may have some early warning signs for malignant lesions of the gut mucosa.
Collapse
Affiliation(s)
- Yunbo Wu
- Institute of Gastroenterology, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510000, China
| | - Ying Yu
- Institute of Gastroenterology, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510000, China
| | - Danyan Li
- Institute of Gastroenterology, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510000, China
| | - Yunkai Dai
- Institute of Gastroenterology, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510000, China
| | - Jianyu Wu
- First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510000, China
| | - Zijing Zhang
- First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510000, China
| | - Huaigeng Pan
- Institute of Gastroenterology, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510000, China
| | - Weijing Chen
- Institute of Gastroenterology, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510000, China
| | - Ruliu Li
- Institute of Gastroenterology, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510000, China
| | - Ling Hu
- Institute of Gastroenterology, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510000, China.
| |
Collapse
|
|
21
|
Yu K, Pu H, Zhang X, Yang Q, Wang W, Li W, Li Z. CLMP increases 5-fluorouracil sensitivity in colorectal cancer through the inhibition of autophagy. Tissue Cell 2025; 93:102771. [PMID: 39922002 DOI: 10.1016/j.tice.2025.102771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 01/06/2025] [Accepted: 01/27/2025] [Indexed: 02/10/2025]
Abstract
BACKGROUND We aimed to explore the biological function of CLMP in colorectal cancer (CRC) and to determine the effect of CLMP on 5-fluorouracil (5-FU) sensitivity in CRC. METHODS Sixteen pairs of CRC tissues and paracancerous tissues were collected. Immortalized intestinal epithelial cell lines and human CRC cell lines were purchased, and the cells were treated with DMSO and 5-FU. RTqPCR, western blotting, CCK8, colony formation, scratch, and Transwell assays were performed to determine the molecular mechanism of CLMP in the regulation of autophagy and sensitivity to 5-FU in CRC cells. RESULTS CLMP was expressed at low levels in CRC tissues. The upregulation of CLMP expression could inhibit cell proliferation, colony number, migration and invasion and increase the sensitivity of CRC cells to 5-FU. Mechanistic studies revealed that the overexpression of CLMP could block the activation of the PI3K/AKT signaling pathway, inhibit autophagy, and increase the chemosensitivity of CRC cells to 5-FU. CONCLUSION CLMP overexpression can reduce the level of autophagy and increase the sensitivity of CRC to 5-FU, providing a potential target for the treatment of CRC.
Collapse
Affiliation(s)
- Kun Yu
- Department of Colorectal Surgery, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan Hospital, Yunnan Cancer Hospital, Kunming, Yunnan 650118, China
| | - Hongjiang Pu
- Department of Oncology, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan Hospital, Yunnan Cancer Hospital, Kunming, Yunnan 650118, China
| | - Xuan Zhang
- Department of Colorectal Surgery, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan Hospital, Yunnan Cancer Hospital, Kunming, Yunnan 650118, China
| | - Quan Yang
- Department of Colorectal Surgery, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan Hospital, Yunnan Cancer Hospital, Kunming, Yunnan 650118, China
| | - Weimin Wang
- Department of Colorectal Surgery, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan Hospital, Yunnan Cancer Hospital, Kunming, Yunnan 650118, China
| | - Wenliang Li
- Department of Colorectal Surgery, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan Hospital, Yunnan Cancer Hospital, Kunming, Yunnan 650118, China.
| | - Ziyu Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing 100142, China; The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan Hospital, Kunming, Yunnan 650118, China.
| |
Collapse
|
|
22
|
Wu YT, Gao M, Cheng KY, Li L, Wang BQ, He YN, Zhang Y, Liu XY, Du RL, Li GQ, Liang YX, Zhang JF, Zhang XD, Liu Y. VRK2 promotes colorectal cancer growth and impedes immunotherapy and 5-FU treatment efficacy. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167729. [PMID: 39978443 DOI: 10.1016/j.bbadis.2025.167729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 12/31/2024] [Accepted: 02/13/2025] [Indexed: 02/22/2025]
Abstract
Vaccinia-Related Kinase 2 (VRK2), a member of the vaccinia virus-related protein kinase family, is crucial in regulating apoptosis and tumor cell growth signaling pathways. Despite its established roles in various cancers, investigations into its functions in colorectal cancer have been relatively limited. Utilizing The Cancer Genome Atlas and Genotype-Tissue Expression databases, this study assesses VRK2 expression across 33 cancer types, highlighting significant upregulation and diagnostic relevance, particularly in colorectal cancer, where it marks poor prognosis. VRK2's influence extends across multiple cancer-related signaling pathways, with focused experiments confirming its vital role in the E2F signaling pathway through transcriptomic sequencing and dual-luciferase reporter assays. Deletion of VRK2 markedly inhibits proliferation, cell cycle progression, migration, and tumorigenesis in colorectal cancer cells, whereas overexpression enhances these oncogenic traits. Additionally, VRK2 expression correlates with genomic instability and the tumor microenvironment, influencing antitumor immunity and response to immunotherapy. Importantly, our analysis reveals that VRK2 modulates the chemosensitivity of tumor cells, specifically enhancing resistance to the chemotherapeutic agent 5-FU. These findings underscore VRK2's multifaceted role in promoting colorectal cancer development and suggest its potential as a therapeutic target.
Collapse
Affiliation(s)
- Yu-Tong Wu
- National Health Commission Key Laboratory of Birth Defect Research and Prevention & MOE Key Lab of Rare Pediatric Diseases, Department of Cell Biology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang 421001, China
| | - Meng Gao
- National Health Commission Key Laboratory of Birth Defect Research and Prevention & MOE Key Lab of Rare Pediatric Diseases, Department of Cell Biology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang 421001, China
| | - Kun-Yang Cheng
- National Health Commission Key Laboratory of Birth Defect Research and Prevention & MOE Key Lab of Rare Pediatric Diseases, Department of Cell Biology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang 421001, China
| | - Le Li
- National Health Commission Key Laboratory of Birth Defect Research and Prevention & MOE Key Lab of Rare Pediatric Diseases, Department of Cell Biology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang 421001, China
| | - Bai-Qi Wang
- Department of Radiation Oncology, The Second Affiliated Hospital University of South China Clinical Research Center, For Prevention and Treatment of Breast & Thyroid Disease In Hunan Province, Hengyang, Hunan, China
| | - Ya-Nan He
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, Hubei, China
| | - Yue Zhang
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, Hubei, China
| | - Xue-Yi Liu
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, Hubei, China
| | - Run-Lei Du
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, Hubei, China
| | - Guo-Qing Li
- Hunan Provincial Key Laboratory of Basic and Clinical Pharmacological Research of Gastrointestinal Cancer, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China
| | - Yue-Xiu Liang
- Key Laboratory of Research on Clinical Molecular Diagnosis for High Incidence Diseases in Western Guangxi of Guangxi Higher Education Institutions & Department of Gynecology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Jian-Feng Zhang
- Xuancheng Institutes of Food and Drug Control, Xuancheng, China
| | - Xiao-Dong Zhang
- National Health Commission Key Laboratory of Birth Defect Research and Prevention & MOE Key Lab of Rare Pediatric Diseases, Department of Cell Biology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang 421001, China.
| | - Yi Liu
- National Health Commission Key Laboratory of Birth Defect Research and Prevention & MOE Key Lab of Rare Pediatric Diseases, Department of Cell Biology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang 421001, China.
| |
Collapse
|
|
23
|
Qiu Q, Ding Y, Guo X, Han J, Zhang J, Liu Y, She J, Chen Y. Extrachromosomal circular DNA as a novel biomarker for the progression of colorectal cancer. Mol Med 2025; 31:123. [PMID: 40165080 DOI: 10.1186/s10020-025-01164-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Accepted: 03/11/2025] [Indexed: 04/02/2025] Open
Abstract
BACKGROUND Extrachromosomal circular DNA (eccDNA) has potential in tumor diagnosis, particularly for improving diagnostic accuracy and early cancer detection; however, many challenges remain in its application to clinical practice. METHODS We conducted a Circle-Seq analysis on clinical samples at different stages of colorectal cancer progression to examine the dynamic changes of eccDNA during the progression of colorectal cancer. We used breakpoint-specific PCR to verify candidate eccDNAs identified by Circle-Seq. The results were further validated using the AOM/DSS-induced colorectal cancer model. RESULTS There was an increase in the abundance of eccDNA with the progression of colorectal cancer. The genes associated with these eccDNA molecules were primarily related to signaling pathways involved in tumor development and metastasis. Our analysis also revealed that eccDNA abundance positively correlates with gene expression, and eccDNA derived from specific genes has potential value for the early diagnosis of tumors. CONCLUSIONS This study revealed a connection between eccDNA and colorectal cancer progression and highlights the clinical potential of eccDNA for the early diagnosis of colorectal cancer.
Collapse
Affiliation(s)
- Quanpeng Qiu
- Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
- Department of High Talent, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Yi Ding
- Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
- Department of High Talent, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Xiaolong Guo
- Center for Gut Microbiome Research, Med-X Institute, the First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, Shaanxi, China
- Department of High Talent, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Jing Han
- Center for Gut Microbiome Research, Med-X Institute, the First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, Shaanxi, China
- Department of High Talent, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Jiaqi Zhang
- Center for Gut Microbiome Research, Med-X Institute, the First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, Shaanxi, China
- Department of High Talent, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Yaping Liu
- Department of High Talent, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Junjun She
- Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
- Center for Gut Microbiome Research, Med-X Institute, the First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, Shaanxi, China.
- Department of High Talent, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
| | - Yinnan Chen
- Center for Gut Microbiome Research, Med-X Institute, the First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, Shaanxi, China.
- Department of High Talent, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
- Hubei Province Key Laboratory of Precision Radiation Oncology, Wuhan, China.
| |
Collapse
|
|
24
|
Zhang Y, Wu D, Zhang Z, Ma J, Jiao S, Ma X, Li J, Meng Y, Zhao Z, Chen H, Jiang Z, Wang G, Liu H, Xi Y, Zhou H, Wang X, Guan X. Impact of lymph node metastasis on immune microenvironment and prognosis in colorectal cancer liver metastasis: insights from multiomics profiling. Br J Cancer 2025; 132:513-524. [PMID: 39753715 PMCID: PMC11920064 DOI: 10.1038/s41416-024-02921-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 11/15/2024] [Accepted: 11/26/2024] [Indexed: 02/19/2025] Open
Abstract
BACKGROUND This study aimed to investigate the prognostic impact of lymph node metastasis (LNM) on patients with colorectal cancer liver metastasis (CRLM) and elucidate the underlying immune mechanisms using multiomics profiling. METHODS We enrolled patients with CRLM from the US Surveillance, Epidemiology, and End Results (SEER) cohort and a multicenter Chinese cohort, integrating bulk RNA sequencing, single-cell RNA sequencing and proteomics data. The cancer-specific survival (CSS) and immune profiles of the tumor-draining lymph nodes (TDLNs), primary tumors and liver metastasis were compared between patients with and without LNM. Pathological evaluations were used to assess immune cell infiltration and histological features. RESULTS The CRLM patients with LNM had significantly shorter CSS than patients without LNM in two large cohorts. Our results showed that nonmetastatic TDLNs exhibited a greater abundance of immune cells, including CD4+ T cells, CD8+ T cells, and CD19+ B cells, whereas metastatic TDLNs were enriched with fibroblasts, endothelial cells, and macrophages. Immunohistochemical analysis confirmed elevated levels of CD3+ T cells, CD8+ T cells, and CD19+ B cells in nonmetastatic TDLNs. The presence of nonmetastatic TDLNs was associated with enhanced antitumor immune responses in primary tumors, characterized by a higher Klintrup-Makinen (KM) grade and the presence of tertiary lymphoid structures. Furthermore, liver metastasis in patients with nonmetastatic TDLNs were predominantly of the desmoplastic growth pattern (dHGP), while those with metastatic TDLNs were predominantly of the replacement growth pattern (rHGP). CONCLUSIONS This research highlights the adverse prognostic impact of LNM on patients with CRLM and reveals potential related mechanisms through multiomics analysis. Our research paves the way for further refinement of the AJCC TNM staging system for CRLM in clinical practice.
Collapse
Affiliation(s)
- Yueyang Zhang
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Deng Wu
- College of Biomedical Information and Engineering, Hainan Medical University, Haikou, China
| | - Zhen Zhang
- Department of Pathology, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
| | - Jian Ma
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shuai Jiao
- Department of Colorectal Surgery, Shanxi Province Cancer Hospital/Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
| | - Xiaolong Ma
- Department of Colorectal Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Jiangtao Li
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yongsheng Meng
- Department of Tumor Biobank, Shanxi Province Cancer Hospital/ Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/ Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
| | - Zhixun Zhao
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Haipeng Chen
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zheng Jiang
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Guiyu Wang
- Department of Colorectal Cancer Surgery, the Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, China
| | - Haiyi Liu
- Department of Colorectal Surgery, Shanxi Province Cancer Hospital/Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
| | - Yanfeng Xi
- Department of Pathology, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China.
| | - Haitao Zhou
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Xishan Wang
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
- Department of Colorectal Surgery, Shanxi Province Cancer Hospital/Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China.
| | - Xu Guan
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
- Department of Colorectal Surgery, Shanxi Province Cancer Hospital/Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China.
| |
Collapse
|
|
25
|
Liu J, Liang L, Gan P, Lin F, Dai Z, Chen Z, Xu Y, Yang Q, Cao M, Wang S, Gu Y, Yuan Z, Zhong Q, Hu D, Yao Y. Development of a Highly Efficient NIR-II Phototherapeutic Agent for Fluorescence Imaging-Guided Synergistic PTT/PDT/Chemotherapy of Colorectal Cancer. J Med Chem 2025. [PMID: 40168043 DOI: 10.1021/acs.jmedchem.5c00066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
NIR-II-triggered phototherapy presents a noninvasive, resistance-free alternative therapeutic approach with deeper tissue penetration and improved imaging of deep tumors. However, many NIR-II phototherapeutic agents suffer from low fluorescence quantum yields, poor photothermal conversion efficiency (PCE), and reduced efficacy due to the upregulation of heat shock protein HSP70. This study develops a small-molecule NIR-II phototherapeutic agent (IRF) with a high fluorescence quantum yield (17.4%), excellent PCE (96.8%) for photothermal therapy (PTT), and photodynamic therapy (PDT) activity. To decrease thermal resistance during phototherapy, IRF and evodiamine (EVO) were loaded onto hyaluronic acid (HA)-modified nanoparticles, creating a multifunctional nanoplatform termed EVO/IRF@HA NPs. EVO/IRF@HA NPs can actively target tumors for NIR-II fluorescence imaging via the HA moiety. Upon 980 nm laser irradiation, IRF increases the temperature and content of reactive oxygen species for synergistic PTT/PDT. Importantly, EVO effectively inhibits the overexpression of HSP70, enabling combined PTT/PDT/chemotherapy for effective colorectal cancer (CRC) treatment.
Collapse
Affiliation(s)
- Ji Liu
- State Key Laboratory of Natural Medicines, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, 639 Longmian Road, Jiangning District, Nanjing 211198, China
| | - Luyin Liang
- State Key Laboratory of Natural Medicines, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, 639 Longmian Road, Jiangning District, Nanjing 211198, China
| | - Ping Gan
- Department of Pharmacy, The Affiliated Taizhou Second People's Hospital of Yangzhou University, No.27 Jiankang Road, Jiangyan District, Taizhou 225500, China
| | - Fanjie Lin
- State Key Laboratory of Natural Medicines, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, 639 Longmian Road, Jiangning District, Nanjing 211198, China
| | - Zhiyue Dai
- State Key Laboratory of Natural Medicines, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, 639 Longmian Road, Jiangning District, Nanjing 211198, China
| | - Zhangjing Chen
- State Key Laboratory of Natural Medicines, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, 639 Longmian Road, Jiangning District, Nanjing 211198, China
| | - Yifan Xu
- State Key Laboratory of Natural Medicines, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, 639 Longmian Road, Jiangning District, Nanjing 211198, China
| | - Qiuxing Yang
- Department of Pharmacy, Affiliated Hospital 2 of Nantong University, No. 666, Shengli Road, Nantong 226001, China
| | - Mingyi Cao
- State Key Laboratory of Natural Medicines, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, 639 Longmian Road, Jiangning District, Nanjing 211198, China
| | - Shiya Wang
- State Key Laboratory of Natural Medicines, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, 639 Longmian Road, Jiangning District, Nanjing 211198, China
| | - Yueqing Gu
- State Key Laboratory of Natural Medicines, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, 639 Longmian Road, Jiangning District, Nanjing 211198, China
| | - Zhenwei Yuan
- State Key Laboratory of Natural Medicines, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, 639 Longmian Road, Jiangning District, Nanjing 211198, China
| | - Qifeng Zhong
- State Key Laboratory of Natural Medicines, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, 639 Longmian Road, Jiangning District, Nanjing 211198, China
| | - Dejun Hu
- State Key Laboratory of Natural Medicines, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, 639 Longmian Road, Jiangning District, Nanjing 211198, China
| | - Yongrong Yao
- State Key Laboratory of Natural Medicines, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, 639 Longmian Road, Jiangning District, Nanjing 211198, China
| |
Collapse
|
|
26
|
Zhang S, Lv J, Zhang J, Fan Z, Gu B, Fan B, Li C, Wang C, Zhang T. Benchmarking multi-omics integrative clustering methods for subtype identification in colorectal cancer. COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE 2025; 261:108603. [PMID: 39826483 DOI: 10.1016/j.cmpb.2025.108603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 11/27/2024] [Accepted: 01/12/2025] [Indexed: 01/22/2025]
Abstract
BACKGROUND AND OBJECTIVE Colorectal cancer (CRC) represents a heterogeneous malignancy that has concerned global burden of incidence and mortality. The traditional tumor-node-metastasis staging system has exhibited certain limitations. With the advancement of omics technologies, researchers are directing their focus on developing a more precise multi-omics molecular classification. Therefore, the utilization of unsupervised multi-omics integrative clustering methods in CRC, advocating for the establishment of a comprehensive benchmark with practical guidelines. METHODS In this study, we obtained CRC multi-omics data, encompassing DNA methylation, gene expression, and protein expression from the cancer genome atlas (TCGA)database. We then generated interrelated CRC multi-omics data with various structures based on realistic multi-omics correlations, and performed a comprehensive evaluation of eight representative methods categorized as early integration, intermediate integration, and late integration using complementary benchmarks for subtype classification accuracy. Lastly, we employed these methods to integrate real-world CRC multi-omics data, survival and differential analysis were used to highlight differences among newly identified multi-omics subtypes. RESULTS Through in-depth comparisons, we observed that similarity network fusion (SNF) exhibited exceptional performance in integrating multi-omics data derived from simulations. Additionally, SNF effectively distinguished CRC patients into five subgroups with the highest classification accuracy. Moreover, we found significant survival differences and molecular distinctions among SNF subtypes. CONCLUSIONS The findings consistently demonstrate that SNF outperforms other methods in CRC multi-omics integrative clustering. The significant survival differences and molecular distinctions among SNF subtypes provide novel insights into the multi-omics perspective on CRC heterogeneity with potential clinical treatment.
Collapse
Affiliation(s)
- Shuai Zhang
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Jiali Lv
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Jinglan Zhang
- School of Life Science, Shandong University, Qingdao, 266237, China
| | - Zhe Fan
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Bingbing Gu
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Bingbing Fan
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Chunxia Li
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Cheng Wang
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
| | - Tao Zhang
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China; Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, 300070, China.
| |
Collapse
|
|
27
|
Dong J, Zhao J, Wu Z, Liu J, Wang B, Qi X. The Predictive Value of Neutrophil Extracellular Trap-Related Risk Score in Prognosis and Immune Microenvironment of Colorectal Cancer Patients. Mol Biotechnol 2025; 67:1509-1525. [PMID: 38580851 DOI: 10.1007/s12033-024-01135-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 02/23/2024] [Indexed: 04/07/2024]
Abstract
Colorectal cancer (CRC) has brought great healthy burden for patients. Neutrophil extracellular traps (NETs) have been explored in several tumors, while it remains largely unclear in CRC. CRC-related data were downloaded from Cancer Genome Atlas and Gene Expression Omnibus databases. Then, a NET risk score was built after univariate Cox and LASSO Cox regression analysis. Prognostic value was evaluated via survival analysis, stratification analysis, and ROC analysis. The functional enrichment analysis was conducted basing on bulk and scRNA-seq data. The immune landscape difference was analyzed using CIBERSORT, XCell, and MCPcounter portals. NET risk score was built for CRC patients, basing on G0S2, HIST1H2BC, CRISPLD2, and IL17A. In TCGA-CRC and validation datasets, regardless of age or gender, high-risk CRC patients had significantly worse prognosis, besides higher NET risk score was mainly found in samples with MSI-H and advanced T, N, and M stages. Employing multiple databases, we noticed that M0 and M2 Macrophages infiltrated the most in high-risk CRC patients, besides M2 Macrophages and neutrophils showed positive correlation with NET risk score. A novel reliable prognostic NET risk score was developed for CRC patients, and high-risk patients had unfavorable prognosis with advanced disease status.
Collapse
Affiliation(s)
- Jiuxing Dong
- Department of Oncology, Hebei Petrochina Central Hospital, NO. 51 Xinkai Road, Langfang, 065000, Hebei, China
| | - Jia Zhao
- Department of Oncology, Hebei Petrochina Central Hospital, NO. 51 Xinkai Road, Langfang, 065000, Hebei, China
| | - Zhenming Wu
- Department of Oncology, Hebei Petrochina Central Hospital, NO. 51 Xinkai Road, Langfang, 065000, Hebei, China
| | - Jun Liu
- Department of Oncology, Hebei Petrochina Central Hospital, NO. 51 Xinkai Road, Langfang, 065000, Hebei, China
| | - Baoxin Wang
- Department of Oncology, Hebei Petrochina Central Hospital, NO. 51 Xinkai Road, Langfang, 065000, Hebei, China
| | - Xiuheng Qi
- Department of Oncology, Hebei Petrochina Central Hospital, NO. 51 Xinkai Road, Langfang, 065000, Hebei, China.
| |
Collapse
|
|
28
|
Ma M, Chu J, Zhuo C, Xiong X, Gu W, Li H, Xu M, Huang D. Prognostic implications and therapeutic opportunities related to CAF subtypes in CMS4 colorectal cancer: insights from single-cell and bulk transcriptomics. Apoptosis 2025; 30:826-841. [PMID: 39755821 DOI: 10.1007/s10495-024-02063-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/17/2024] [Indexed: 01/06/2025]
Abstract
Cancer-associated fibroblasts (CAFs) significantly influence tumor progression and therapeutic resistance in colorectal cancer (CRC). However, the distributions and functions of CAF subpopulations vary across the four consensus molecular subtypes (CMSs) of CRC. This study performed single-cell RNA and bulk RNA sequencing and revealed that myofibroblast-like CAFs (myCAFs), tumor-like CAFs (tCAFs), inflammatory CAFs (iCAFs), CXCL14+CAFs, and MT+CAFs are notably enriched in CMS4 compared with other CMSs of CRC. Multiplex immunohistochemistry was used to validate the distribution of CAF subtypes in patients with different CMSs. Prognosis-related CAF subtypes were identified, leading to the selection of four key genes (COL3A1, COL1A2, GEM, and TMEM47). Through machine learning, we developed a CAF poor-prognosis gene (CAFPRG) model to predict outcomes of patients with CMS4. High levels of CAFPRGs were identified as independent poor-risk factors for prognosis (p < 0.001). Tumors with elevated CAFPRGs exhibited increased infiltration of immune-suppressive cells and resistance to chemotherapy. The expression of these key genes was confirmed to be significantly higher in CAFs than in normal fibroblasts (NFs). Therefore, CAFPRGs may be valuable for precisely predicting patient survival and may present potential therapeutic opportunities for CMS4 CRC.
Collapse
Affiliation(s)
- Mengke Ma
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Fudan University Shanghai Medical College, Shanghai, China
| | - Jin Chu
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Fudan University Shanghai Medical College, Shanghai, China
| | - Changhua Zhuo
- Department of Colorectal Surgery, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, China
| | - Xin Xiong
- Department of Oncology, Fudan University Shanghai Medical College, Shanghai, China
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Wenchao Gu
- Department of Artificial Intelligence Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hansheng Li
- School of Information Science and Technology, Northwest University, Xi'an, China
| | - Midie Xu
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Fudan University Shanghai Medical College, Shanghai, China.
| | - Dan Huang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Fudan University Shanghai Medical College, Shanghai, China.
| |
Collapse
|
|
29
|
Chen F, Chen J, Zhou L, Hu X, Huang X, Lin S. A Water-Soluble Small-Molecule Fluorescent Probe for Selective Imaging of Colorectal Cancer with High Biosafety. J Fluoresc 2025:10.1007/s10895-025-04267-1. [PMID: 40163173 DOI: 10.1007/s10895-025-04267-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Accepted: 03/18/2025] [Indexed: 04/02/2025]
Abstract
Early diagnosis of colorectal cancer (CRC), a malignant tumor with high incidence and mortality rates worldwide, can significantly reduce both its incidence and mortality. Among cancer diagnostic methods, tumor fluorescence imaging provides a non-invasive approach, eliminating the need for tissue biopsy and minimizing patient discomfort. In this study, we identified a water-soluble quinolinium molecular fluorescent probe (CYI), which exhibits a dose-dependent quantum yield in PBS solution, reaching 5.96% at a concentration of 20 µM. The results demonstrated that CYI selectively enters CRC cells and maintains stable fluorescence intensity within them by specifically targeting the mitochondria and lysosomes, leading to probe accumulation and enhanced intracellular fluorescence. Importantly, toxicity assays at both the cellular and animal levels confirmed that CYI is highly biocompatible at fluorescence imaging doses, with no toxic effects observed in normal colorectal cells or organisms. This study identifies CYI as a water-soluble molecular fluorescent probe with a high biosafety profile, excellent imaging stability, and preferential uptake by CRC cells, demonstrating strong potential for early CRC screening and in vivo monitoring.
Collapse
Affiliation(s)
- Fang Chen
- The Wenzhou Third Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou People's Hospital, Wenzhou Maternal and Child Health Care Hospital, Wenzhou, China
| | - Jian Chen
- The First People's Hospital of Linping, Hangzhou, China
| | - Lu Zhou
- The Wenzhou Third Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou People's Hospital, Wenzhou Maternal and Child Health Care Hospital, Wenzhou, China
| | - Xianqing Hu
- The Wenzhou Third Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou People's Hospital, Wenzhou Maternal and Child Health Care Hospital, Wenzhou, China
| | - Xiaohui Huang
- The Wenzhou Third Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou People's Hospital, Wenzhou Maternal and Child Health Care Hospital, Wenzhou, China
| | - Shangqin Lin
- The Wenzhou Third Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou People's Hospital, Wenzhou Maternal and Child Health Care Hospital, Wenzhou, China.
| |
Collapse
|
|
30
|
Chen Y, Huang J, Fan Y, Huang L, Cai X. Understanding the cellular and molecular heterogeneity in colorectal cancer through the use of single-cell RNA sequencing. Transl Oncol 2025; 55:102374. [PMID: 40163910 DOI: 10.1016/j.tranon.2025.102374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2025] [Revised: 03/08/2025] [Accepted: 03/18/2025] [Indexed: 04/02/2025] Open
Abstract
The very prevalent nature, genetic variability, and intricate tumor microenvironment (TUME) of colorectal cancer (COREC) are its defining features. In order to better understand the molecular and cellular make-up of COREC, this work used single-cell RNA sequencing (SRNAS) to isolate and characterize important cell types as well as their interactions within the TUME. Our analysis of 51,204 cells yielded six distinct types: epithelial, fibroblast, endothelial, T&NK, B, and myeloid. C3 B cells were shown to be the most active in immunological regulation, according to chemokine signaling study, which was one of seven clusters of B cells that were thoroughly subtyped. The examination of copy number variation (CONUV) revealed a great deal of genetic variability, especially in epithelial cells. We traced the activity of three key transcription factor clusters (M1, M2, and M3) across all B cell subtypes using transcription factor analysis. We created a predictive model that correctly sorts patients according to survival results by using marker genes from C3 B cells. In addition, the relationship between genetic changes and the immune system was better understood by tumor mutational burden (TUMUB) and immune infiltration studies. Our research sheds light on the genetic complexity and cellular variety of COREC, which in turn opens up new possibilities for targeted treatments and individualized approaches to patient care.
Collapse
Affiliation(s)
| | - Jian Huang
- Wenzhou Central Hospital, Wenzhou, China
| | - Yufang Fan
- Wenzhou Central Hospital, Wenzhou, China
| | | | | |
Collapse
|
|
31
|
Xu S, Tang Y, Tong J. Dexmedetomidine alleviates the pro-tumor activity of perioperative stress in tumor-bearing mice: an alternative approach of psycho-physiological intervention. World J Surg Oncol 2025; 23:103. [PMID: 40156037 PMCID: PMC11951540 DOI: 10.1186/s12957-025-03665-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 01/19/2025] [Indexed: 04/01/2025] Open
Abstract
BACKGROUND The immediate perioperative period (IPP) usually is highly stressful and has significant effects on the postoperative recurrence/metastasis of tumors. Effective methods for limiting the impact of the IPP on postoperative recurrence/metastasis of tumors remain scarce. We aimed to determine the effects of dexmedetomidine (DEX) treatment during the IPP on postoperative recurrence/metastasis of tumors and the stress response. MATERIALS AND METHODS The clinical perioperative setting was mimicked via tumor resection and perioperative restraint stress in tumor-bearing mice with or without DEX during the IPP. The stress response was assessed using stress hormone and interleukin (IL)-6 levels in peripheral blood. Tumor cell growth was measured via in vivo bioluminescent imaging, cell viability assay, wound-healing assay, and Western blotting. RESULTS In tumor-bearing mice, DEX during the IPP limited the growth of implanted tumor cells and stress response in a dose-dependent manner. The serum from mice without DEX promoted cultured tumor cell growth, which was alleviated by beta-adrenergic receptor blocker propranolol or IL-6 antibody. Relative to the serum from mice without DEX, the serum from mice with DEX had lower stress hormone and IL-6 levels, as well as weaker effects on tumor growth promotion. Dexmedetomidine supplementation during culture had no significant effects on tumor cells. CONCLUSIONS Dexmedetomidine alleviates the pro-tumor activity of perioperative stress in abdominal tumors.
Collapse
Affiliation(s)
- Shanqing Xu
- Department of Anaesthesiology, Third Xiangya Hospital, Central South University, Changsha, China
- Hunan Province Key Laboratory of Brain Homeostasis, Third Xiangya Hospital, Central South University, Changsha, China
| | - Yongzhong Tang
- Department of Anaesthesiology, Third Xiangya Hospital, Central South University, Changsha, China
- Center of Clinical Pharmacology, Central South University, Changsha, China
| | - Jianbin Tong
- Department of Anaesthesiology, Third Xiangya Hospital, Central South University, Changsha, China.
- Hunan Province Key Laboratory of Brain Homeostasis, Third Xiangya Hospital, Central South University, Changsha, China.
- Department of Anesthesiology, Third Xiangya Hospital, 138 Tongzipo Road, Yuelu District, Changsha, Hunan, 410013, P.R. China.
| |
Collapse
|
|
32
|
Isah AD, Wang X, Shaibu Z, Yuan X, Dang SC. Systematic review and meta-analysis comparing extraperitoneal and transperitoneal routes of colostomy-related complications. World J Gastrointest Surg 2025; 17:98947. [PMID: 40162385 PMCID: PMC11948114 DOI: 10.4240/wjgs.v17.i3.98947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 12/10/2024] [Accepted: 01/17/2025] [Indexed: 02/24/2025] Open
Abstract
BACKGROUND Complications associated with stomas-including parastomal hernia (PSH), prolapse, mucocutaneous separation, and stoma retraction-provide considerable postoperative challenges for colostomy patients. Selecting between extraperitoneal colostomy (EPC) and transperitoneal colostomy (TPC) pathways is therefore essential for mitigating these complications. AIM To analyze the existing data regarding the efficacy of EPC compared to TPC in reducing stoma-related complications post-colostomy. METHODS PubMed, Google Scholar, EMBASE, MEDLINE, and the Cochrane Library were adopted to uncover pertinent papers in which EPC and TPC approaches were compared. We then conducted a meta-analysis using RevMan 5.4.1. RESULTS Both laparoscopic (Lap) and open approaches showed a reduced incidence of PSH in EPC relative to TPC (P < 0.00001 and P = 0.02 respectively). In addition, Lap EPC depicted a lesser incidence of prolapse, mucocutaneous separation, and stoma retraction (P = 0.007, P = 0.03, and P = 0.01, respectively) compared to Lap TPC. However, EPC and TPC did not differ with respect to operation time, blood loss, edema, ischemia, necrosis, or infection after the LAP approach. CONCLUSION The extraperitoneal approach may provide benefits in minimizing some stoma-related problems such as PSH, prolapse, mucocutaneous separation, and stoma retraction after colostomy surgery.
Collapse
Affiliation(s)
- Adamu D Isah
- Department of Gastrointestinal Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, Jiangsu Province, China
- Department of Radiation Oncology, Institute of Oncology, Affiliated Hospital, Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
| | - Xu Wang
- Department of Radiation Oncology, Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
| | - Zakari Shaibu
- School of Medicine, Jiangsu University, Zhenjiang 212013, Jiangsu Province, China
| | - Xiao Yuan
- Department of Radiation Oncology, Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
| | - Sheng-Chun Dang
- Department of General Surgery, The Affiliated Hospital of Jiangsu University, Zhenjiang 212001, Jiangsu Province, China
| |
Collapse
|
|
33
|
Wang Y, Chen B, Yu J. A machine learning-based model for predicting survival in patients with Rectosigmoid Cancer. PLoS One 2025; 20:e0319248. [PMID: 40132000 PMCID: PMC11936176 DOI: 10.1371/journal.pone.0319248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Accepted: 01/30/2025] [Indexed: 03/27/2025] Open
Abstract
BACKGROUND The unique anatomical characteristics and blood supply of the rectosigmoid junction confer particular significance to its physiological functions and clinical surgeries. However, research on the prognosis of rectosigmoid junction cancer (RSC) is scarce, and reliable clinical prediction models are lacking. METHODS This retrospective study included 524 patients diagnosed with RSC who were admitted to the Department of Gastrointestinal and Colorectal Surgery at the First Hospital of Jilin University between January 1, 2017, and June 1, 2019. Univariate and multivariate Cox regression analyses were conducted in this study to identify independent risk factors impacting the survival of RSC patients. Subsequently, models were constructed using six different machine learning algorithms. Finally, the discrimination, calibration, and clinical applicability of each model were evaluated to determine the optimal model. RESULTS Through univariate and multivariate Cox regression analyses, we identified seven independent risk factors associated with the survival of RSC patients: age (HR = 1.9, 95% CI: 1.3-2.8, P = 0.001), gender (HR = 0.6, 95% CI: 0.4-0.9, P = 0.013), diabetes (HR = 2.0, 95% CI: 1.3-3.1, P = 0.002), tumor differentiation (HR = 2.1, 95% CI: 1.4-3.1, P < 0.001), tumor N stage (HR = 2.02, 95% CI: 1.2-3.4, P = 0.009), distant metastasis (HR = 4.2, 95% CI: 2.7-6.7, P < 0.001), and anastomotic leakage (HR = 2.4, 95% CI: 1.1-5.3, P = 0.034). After evaluating each model, the prediction model based on XGBoost was determined to be the optimal model, with AUC of 0.7856, 0.8484, and 0.796 at 1, 3, and 5 years. It also had the lowest Brier scores at all time points, and decision curve analysis (DCA) demonstrated the best clinical decision benefits compared to other models. CONCLUSION We developed a prediction model based on the optimal machine learning, XGBoost, which can assist clinical decision-making and potentially extend the survival of patients with rectosigmoid junction cancer.
Collapse
Affiliation(s)
- Yifei Wang
- Department of Gastric and Colorectal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, China
| | - Bingbing Chen
- Department of Gastric and Colorectal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, China
| | - Jinhai Yu
- Department of Gastric and Colorectal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, China
| |
Collapse
|
|
34
|
Wang Z, Qiao X, Xue K, Chen Q, Li A. PTOV1 interacts with ZNF449 to promote colorectal cancer development. Commun Biol 2025; 8:489. [PMID: 40133702 PMCID: PMC11937480 DOI: 10.1038/s42003-025-07930-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Accepted: 03/12/2025] [Indexed: 03/27/2025] Open
Abstract
PTOV1 is recognized to have a significant role in various human cancers, including prostate cancer. However, it remains unclear what its clinical significance and biological role are in colorectal cancer (CRC). TCGA, NCBI/GEO, and Kaplan-Meier plot database mining provided important clues into the function and clinical importance of PTOV1 in CRC. Western blotting, immunohistochemistry, and immunofluorescence were utilized to discover PTOV1 protein levels in CRC cell lines and tissues. To explore the involvement of PTOV1 in the development of CRC and the underlying mechanisms, several in-vitro and in-vivo studies were executed, such as CCK-8 assays, colony formation, transwell assays, qRT-PCR, Co-IP, GST pull-down, immunostaining, and mouse xenograft assays. It was shown that PTOV1 expression level was upregulated in the tissues and cells of human CRC. PTOV1 high-expression level was associated with short survival. ZNF449 interacted with PTOV1 and accelerated CRC development in vitro and in vivo. Through Co-IP and GST pull-down studies, the physical interaction of PTOV1/ZNF449 was demonstrated. Furthermore, PTOV1 directly bound ZNF449, and this complex synergistically promoted the transcription of MYC. In addition, the PTOV1/ZNF449 interaction was disrupted by the TAT- PTOV1 (125-283 aa) protein leading to inhibit the CRC development in a xenografted mouse model. According to these findings, PTOV1 has an essential role in CRC progression, and PTOV1/ZNF449 interaction could be a possible therapeutic target for CRC.
Collapse
Affiliation(s)
- Zhiyong Wang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xinwei Qiao
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Kaming Xue
- Department of Traditional Chinese Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Qianzhi Chen
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
| | - Anshu Li
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
| |
Collapse
|
|
35
|
Zhou J, Liu Y, Yang F, Wang Y, Liu Y, Ming W, Guo S, Zhou D, He L, Zhong X. Health-promoting lifestyle among Chinese patients with colorectal polyps: a cross-sectional study. Sci Rep 2025; 15:10150. [PMID: 40128541 PMCID: PMC11933256 DOI: 10.1038/s41598-025-90352-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Accepted: 02/12/2025] [Indexed: 03/26/2025] Open
Abstract
This study aims to investigate the level of health-promoting lifestyles and its influencing factors in Chinese patients with colorectal polyps. A total of 169 colorectal polyps patients from three tertiary care hospitals in Nanchong and Deyang, China, were recruited. Data were collected using the Impact of Health-Promoting Lifestyle Profile-II (HPLP-IIR), Colorectal Cancer Knowledge Questionnaire, Colorectal Cancer Health Belief Scale, the Chinese version of the Health Information Literacy Self-Rating Scale, and a demographic questionnaire. Factors influencing health-promoting lifestyles in patients with colorectal polyps were analyzed using multiple linear regression analysis. The mean HPLP-IIR score was 96.02 ± 14.42, indicating a moderate level of health promotion. Multiple linear regression analysis revealed that the total score of health information literacy, colorectal cancer knowledge and health beliefs were significantly associated with the total score of health promotion lifestyle in Chinese patients with colorectal polyps (P < 0.001), explaining 36.1% of the total variance. The health-promoting lifestyle of colorectal polyp patients was at an intermediate level. Health information literacy, colorectal cancer health knowledge, and colorectal cancer health beliefs were identified as key factors influencing their health-promoting lifestyles. Efforts should focus on improving health information literacy, increasing colorectal cancer health knowledge, and promoting positive health beliefs to establish a better health-promoting lifestyle.
Collapse
Affiliation(s)
- Jingru Zhou
- Department of Nursing, Deyang People's Hospital, Deyang, Sichuan, China
| | - Yanjun Liu
- Department of Infection, Mianzhu People's Hospital, Mianzhu, Sichuan, China
| | - Fang Yang
- Department of Nursing, Deyang People's Hospital, Deyang, Sichuan, China
| | - Yanfen Wang
- Department of Nursing, Deyang People's Hospital, Deyang, Sichuan, China
| | - Yan Liu
- Department of Nursing, Deyang People's Hospital, Deyang, Sichuan, China
| | - Wenwen Ming
- Department of Nursing, Deyang People's Hospital, Deyang, Sichuan, China
| | - Sisi Guo
- Department of Nursing, Deyang People's Hospital, Deyang, Sichuan, China
| | - Dan Zhou
- Department of Nursing, Deyang People's Hospital, Deyang, Sichuan, China
| | - Lin He
- Department of Nursing, Deyang People's Hospital, Deyang, Sichuan, China.
| | - Xiaoli Zhong
- Department of Nursing, Deyang People's Hospital, Deyang, Sichuan, China.
| |
Collapse
|
|
36
|
Zhai F, Yun B, Ming J, Yu T, Li B, Liu X, Wang X, Chen ZH, Song C, Zhao M, Li W, Liu Z, Liang A, Li J, Zhang F. Non-Invasive Diagnosis of Early Colorectal Cancerization via Amplified Sensing of MicroRNA-21 in NIR-II Window. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2025:e2501378. [PMID: 40123304 DOI: 10.1002/adma.202501378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 03/04/2025] [Indexed: 03/25/2025]
Abstract
Accurate, sensitive, and in situ visualization of aberrant expression level of low-abundant biomolecules is crucial for early colorectal cancer (CRC) detection ahead of tumor morphology change. However, the clinical used colonoscopy and biopsy methods are invasive and lack of sensitivity at early-stage of cancerization. Here, an amplified sensing strategy is developed in the second near-infrared long-wavelength subregion (NIR-II-L, 1500-1900 nm) by integrating DNAzyme-triggered signal amplification technology and lanthanide-dye hybrid system. In the early-stage of CRC, the overexpressed biomarker microRNA-21 initiates the NIR-II-L luminescence ratiometric signal amplification of the CRCsensor. The high sensitivity with a limit of detection (LOD) of 1.26 pm allows non-invasive visualization of orthotopic colorectal cancerization via rectal administration, which achieves early and accurate in situ diagnosis at 2 weeks ahead of the in vitro histological results. This innovative approach offers a promising tool for early diagnosis and long-term monitoring of carcinogenesis progression, with potential applications in other cancer-related biomarkers.
Collapse
Affiliation(s)
- Fuheng Zhai
- Department of Oncology, Huadong Hospital, Fudan University, Shanghai, 200040, P. R. China
- Department of Chemistry, State Key Laboratory of Molecular Engineering of Polymers, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials and iChem, Fudan University, Shanghai, 200433, P. R. China
| | - Baofeng Yun
- Department of Chemistry, State Key Laboratory of Molecular Engineering of Polymers, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials and iChem, Fudan University, Shanghai, 200433, P. R. China
| | - Jiang Ming
- Department of Chemistry, State Key Laboratory of Molecular Engineering of Polymers, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials and iChem, Fudan University, Shanghai, 200433, P. R. China
| | - Tianyu Yu
- Department of Oncology, Huadong Hospital, Fudan University, Shanghai, 200040, P. R. China
| | - Benhao Li
- Department of Chemistry, State Key Laboratory of Molecular Engineering of Polymers, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials and iChem, Fudan University, Shanghai, 200433, P. R. China
| | - Xiao Liu
- Department of Chemistry, State Key Laboratory of Molecular Engineering of Polymers, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials and iChem, Fudan University, Shanghai, 200433, P. R. China
| | - Xusheng Wang
- Department of Chemistry, State Key Laboratory of Molecular Engineering of Polymers, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials and iChem, Fudan University, Shanghai, 200433, P. R. China
| | - Zi-Han Chen
- Department of Chemistry, State Key Laboratory of Molecular Engineering of Polymers, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials and iChem, Fudan University, Shanghai, 200433, P. R. China
| | - Changfeng Song
- Department of Oncology, Huadong Hospital, Fudan University, Shanghai, 200040, P. R. China
| | - Mengyao Zhao
- Department of Chemistry, State Key Laboratory of Molecular Engineering of Polymers, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials and iChem, Fudan University, Shanghai, 200433, P. R. China
| | - Wenlin Li
- Department of Cell Biology, Naval Medical University, Shanghai, 200433, P. R. China
| | - Zhebin Liu
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200433, P. R. China
| | - Aibin Liang
- Department of Hematology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, P. R. China
| | - Jiyu Li
- Department of Oncology, Huadong Hospital, Fudan University, Shanghai, 200040, P. R. China
- Department of Oncology, Pudong Hospital, Fudan University, Shanghai, 201399, P. R. China
| | - Fan Zhang
- Department of Oncology, Huadong Hospital, Fudan University, Shanghai, 200040, P. R. China
- Department of Chemistry, State Key Laboratory of Molecular Engineering of Polymers, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials and iChem, Fudan University, Shanghai, 200433, P. R. China
- Department of Hematology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, P. R. China
| |
Collapse
|
|
37
|
Li L, Chen M, Reis RL, Kundu SC, Xiao B, Shi X. Advancements of nanoscale drug formulations for combination treatment of colorectal cancer. Int J Pharm 2025; 674:125508. [PMID: 40132771 DOI: 10.1016/j.ijpharm.2025.125508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 03/10/2025] [Accepted: 03/21/2025] [Indexed: 03/27/2025]
Abstract
Combination chemotherapy is widely utilized in treating colorectal cancer (CRC), particularly for patients who are ineligible for surgery or those with metastatic CRC (mCRC). While this therapeutic method has demonstrated efficacy in managing CRC and mCRC, its broader clinical application is limited due to the unique physical properties, mechanisms of action, and pharmacokinetics of different chemotherapeutic drugs. Consequently, achieving satisfactory treatment outcomes proves to be challenging. Nanotechnology has given rise to innovative drug systems that are precise, controllable, and highly efficient in drug delivery. These nanoscale drug delivery systems can integrate the advantageous aspects of various therapeutic modalities, including chemotherapy, gene therapy, and immunotherapy. This review aims to explain the application of nano-drug delivery system in the treatment of colorectal cancer. Through its unique physical/chemical properties and biological functions, it can solve the limitations of traditional therapy and achieve more accurate, efficient and safe treatment. The advantages/disadvantages, physical and chemical characteristics of various drug delivery systems are described in detail, and suggestions on selecting reasonable NDDSs according to different drug combination methods are given to achieve the best therapeutic effect. This review paper presents an exhaustive summary of the diverse range of drugs utilized in chemotherapy, in addition to outlining strategies for effectively integrating chemotherapy with other treatment modalities. Furthermore, it delves into the principle of selecting carriers for various drug combinations.
Collapse
Affiliation(s)
- Liqi Li
- Department of General Surgery, Xinqiao Hospital, Army Medical University, Chongqing 400037, China
| | - Maohua Chen
- Department of Pharmacy, Xinqiao Hospital, Army Medical University, Chongqing 400037, China
| | - Rui L Reis
- 3Bs Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetic, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Barco, Guimarães 4805-017, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga, Guimarães 4800-058, Portugal
| | - Subhas C Kundu
- 3Bs Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetic, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Barco, Guimarães 4805-017, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga, Guimarães 4800-058, Portugal
| | - Bo Xiao
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610054, China.
| | - Xiaoxiao Shi
- State Key Laboratory of Resource Insects, College of Sericulture, Textile, and Biomass Sciences, Southwest University, Beibei, Chongqing 400715, China.
| |
Collapse
|
|
38
|
Zhou B, Song Y, Chen C, Chen X, Tao T. Preoperative Prediction of Sarcopenia in Patients Scheduled for Gastric and Colorectal Cancer Surgery. J Gastrointest Cancer 2025; 56:82. [PMID: 40116976 DOI: 10.1007/s12029-025-01206-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/14/2025] [Indexed: 03/23/2025]
Abstract
INTRODUCTION Sarcopenia negatively impacts surgical outcomes in gastrointestinal cancer patients, yet practical preoperative screening tools are lacking. The CRP/ALB ratio, a novel biomarker of systemic inflammation and nutritional status, may enhance sarcopenia prediction but remains underexplored in surgical oncology. This study aims to identify the predictors for preoperative sarcopenia prediction in gastric and colorectal cancer patients. METHODS This retrospective study analyzed 145 patients undergoing curative surgery (2019-2021). Sarcopenia was defined by sex-specific CT-measured L3 skeletal muscle index (cutoffs, male ≤ 40.8 cm2/m2; female ≤ 34.9 cm2/m2). Multivariable logistic regression identified predictors, with model performance assessed via ROC analysis and Cohen's Kappa. RESULTS The cohort (median age 64 years; 73.8% male) comprised 66 gastric (45.5%) and 79 colorectal (54.5%) cancer patients, with 29 (20%) diagnosed with sarcopenia. Sarcopenic patients exhibited a higher NRS 2002 score (P < 0.001), lower PNI score (P < 0.05), and higher CRP/ALB ratio (P < 0.05). Multivariate logistic regression analysis results showed that CRP/ALB ratio (OR = 3.084, 95% CI 1.071-8.882, P = 0.037), age (OR = 1.074, 95% CI 1.021-1.130, P = 0.006), and BMI (OR = 0.667, 95% CI 0.542-0.820, P = 0.000) were associated with the increased risk of sarcopenia. The combined model achieved superior discrimination (AUC = 0.854, 95% CI 0.770-0.937), yielding 75.86% sensitivity and 84.82% specificity at optimal cutoff value - 1.0340, and a Cohen's Kappa coefficient of 0.542 when compared to CT results. CONCLUSION The CRP/ALB ratio combined with BMI and age is utilized as a convenient and effective tool for preoperative sarcopenia screening. This model-driven approach provides robust strategies to facilitate preoperative interventions, optimize perioperative care, and enhance long-term oncological outcomes for patients undergoing gastric and colorectal cancer surgery.
Collapse
Affiliation(s)
- Beijia Zhou
- Department of Clinical Nutrition, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Yanjun Song
- Department of General Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Chen Chen
- Department of Clinical Nutrition, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Xiaotian Chen
- Department of Clinical Nutrition, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Tingting Tao
- Department of General Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.
| |
Collapse
|
|
39
|
Saadh MJ, Allela OQB, Kareem RA, Baldaniya L, Ballal S, Vashishth R, Parmar M, Sameer HN, Hamad AK, Athab ZH, Adil M. Prognostic gene expression profile of colorectal cancer. Gene 2025:149433. [PMID: 40122415 DOI: 10.1016/j.gene.2025.149433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 02/26/2025] [Accepted: 03/18/2025] [Indexed: 03/25/2025]
Abstract
Colorectal cancer is a major global health burden, with significant heterogeneity in clinical outcomes among patients. Identifying robust prognostic gene expression signatures can help stratify patients, guide treatment decisions, and improve clinical management. This review provides an overview of current prognostic gene expression profiles in colorectal cancer research. We have synthesized evidence from numerous published studies investigating the association between tumor gene expression patterns and patient survival outcomes. The reviewed literature reveals several promising gene signatures that have demonstrated the ability to predict disease-free survival and overall survival in CRC patients, independent of standard clinicopathological risk factors. These genes are crucial in fundamental biological processes, including cell cycle control, epithelial-mesenchymal transition, and immune regulation. The implementation of prognostic gene expression tests in clinical practice holds great potential for enabling more personalized management strategies for colorectal cancer.
Collapse
Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman 11831, Jordan.
| | | | | | - Lalji Baldaniya
- Marwadi University Research Center, Department of Pharmacy, Faculty of Health Sciences, Marwadi University, Rajkot 360003 Gujarat, India.
| | - Suhas Ballal
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India.
| | - Raghav Vashishth
- Department of Surgery, National Institute of Medical Sciences, NIMS University Rajasthan, Jaipur, India.
| | - Manisha Parmar
- Chandigarh Pharmacy College, Chandigarh Group of Colleges-Jhanjeri, Mohali, Punjab, India.
| | - Hayder Naji Sameer
- Collage of Pharmacy, National University of Science and Technology, Dhi Qar 64001, Iraq.
| | | | - Zainab H Athab
- Department of Pharmacy, Al-Zahrawi University College, Karbala, Iraq.
| | | |
Collapse
|
|
40
|
Qi W, Zhou R, Qiu Q, Cui J. Relationship between core symptoms, function, and quality of life in colorectal cancer patients: a network analysis. Qual Life Res 2025:10.1007/s11136-025-03946-7. [PMID: 40106132 DOI: 10.1007/s11136-025-03946-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/11/2025] [Indexed: 03/22/2025]
Abstract
PURPOSE To identify core symptoms in patients with colorectal cancer and investigate how these symptoms correlate with functional status and quality of life (QoL). METHODS This study included patients over 18 years of age who underwent therapeutic surgery for colorectal cancer with or without a stoma. The European Organization for Research and Treatment of Cancer - Quality of Life Questionnaire Core 30 (EORTC-QLQ C30) and Colorectal Cancer Module (EORTC-QLQ CR29) were used. Data analysis involved constructing networks using the qgraph package in R, identifying core symptoms based on strength centrality, and assessing centrality stability using the bootnet package. RESULTS The study included 511 patients: 321 without a stoma and 190 with a stoma. The QoL score for both groups were 55.06 and 55.09, showing no significant difference (p= 0.991). Fatigue and pain are common core symptoms in colorectal cancer surgery patients, whereas appetite loss (rs = 0.37) is specific to those without a stoma and body image concerns (rs = 1.06) are central issues for stoma patients. Notably, despite its prevalence and severity, anxiety was not a core symptom in either group of patients. In the QoL network, emotional functioning served as an intermediary link between QoL and core symptoms in patients without a stoma, whereas QoL was directly associated with core symptoms in patients with a stoma. CONCLUSION Improving quality of life requires distinct clinical pathways depending on whether the patient has a stoma, necessitating individualized symptom management strategies in the early postoperative period.
Collapse
Affiliation(s)
- Wenqian Qi
- Department of Nursing, Naval Medical University, 800 Xiangyin Rd, Yangpu District, Shanghai, China
| | - Ruzhen Zhou
- Department of Colorectal Surgery, First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Qun Qiu
- Department of Colorectal Surgery, First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Jing Cui
- Department of Nursing, Naval Medical University, 800 Xiangyin Rd, Yangpu District, Shanghai, China.
| |
Collapse
|
|
41
|
Wang Y, Dong A, Man J, Chen H, Shen W, Wang L, Yang H, Hu L, Yang K. TREM2 scFv-Engineering Escherichia coli Displaying Modulation of Macrophages to Boost Cancer Radio-Immunotherapy. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2025:e2417920. [PMID: 40103438 DOI: 10.1002/adma.202417920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 02/10/2025] [Indexed: 03/20/2025]
Abstract
Preoperative neoadjuvant radio-chemotherapy is a cornerstone in the treatment of low rectal cancer, yet its effectiveness can be limited by the insensitivity of some patients, profoundly impacting their quality of life. Through preliminary research, it is found that TREM2+ macrophages play a pivotal role in the non-responsiveness to immunotherapy. To address this challenge, a novel ionizing radiation-responsive delivery system is developed for the precise expression of anti-TREM2 single-chain antibody fragments (scFv) using an engineered probiotic, Escherichia coli Nissle 1917 (EcN), to modulate immunotherapy. The released anti-TREM2 scFv can be precisely targeted and delivered to the tumor site via the engineered EcN outer membrane vesicles (OMVs), thereby reversing the immunosuppressive tumor microenvironment and enhancing tumor therapeutic efficiency when used in combination with the αPD-L1 immune checkpoint inhibitor. Additionally, these engineered bacteria can be further modified to enhance the intestinal colonization capabilities through oral administration, thereby regulating the gut microbiota and its metabolic byproducts. Consequently, the ionizing radiation-responsive drug delivery system based on the engineered bacteria not only introduces a promising new therapeutic option for low rectal cancer but also showcases the potential to finely tune immune responses within the intricate tumor microenvironment, paving the way for innovative strategies in tumor radio-immunotherapy.
Collapse
Affiliation(s)
- Yifan Wang
- Department of Pathology at the First Affiliated Hospital, State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection & School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Cancer Institute, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, 215123, China
| | - Anqi Dong
- Department of Pathology at the First Affiliated Hospital, State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection & School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Cancer Institute, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, 215123, China
| | - Jianping Man
- Department of Pathology at the First Affiliated Hospital, State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection & School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Cancer Institute, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, 215123, China
| | - Hua Chen
- Department of Pathology at the First Affiliated Hospital, State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection & School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Cancer Institute, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, 215123, China
| | - Wenhao Shen
- Department of Pathology at the First Affiliated Hospital, State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection & School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Cancer Institute, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, 215123, China
| | - Lei Wang
- Department of Pathology at the First Affiliated Hospital, State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection & School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Cancer Institute, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, 215123, China
| | - Hongli Yang
- Department of Pathology at the First Affiliated Hospital, State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection & School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Cancer Institute, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, 215123, China
| | - Lin Hu
- Department of Pathology at the First Affiliated Hospital, State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection & School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Cancer Institute, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, 215123, China
| | - Kai Yang
- Department of Pathology at the First Affiliated Hospital, State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection & School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Cancer Institute, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, 215123, China
| |
Collapse
|
|
42
|
Karousi P, Kontos CK, Nikou ST, Carell T, Sideris DC, Scorilas A. Discovery of circular transcripts of the human BCL2-like 12 (BCL2L12) apoptosis-related gene, using targeted nanopore sequencing, provides new insights into circular RNA biology. Funct Integr Genomics 2025; 25:66. [PMID: 40106061 PMCID: PMC11923030 DOI: 10.1007/s10142-025-01578-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Revised: 03/05/2025] [Accepted: 03/11/2025] [Indexed: 03/22/2025]
Abstract
Circular RNAs (circRNAs) constitute an RNA type formed by back-splicing. BCL2-like 12 (BCL2L12) is an apoptosis-related gene comprising 7 exons. In this study, we used targeted nanopore sequencing to identify circular BCL2L12 transcripts in human colorectal cancer cells and investigated the effect of circRNA silencing on mRNA expression of the parental gene. In brief, nanopore sequencing following nested PCR amplification of cDNAs of BCL2L12 circRNAs from 7 colorectal cancer cell lines unraveled 46 BCL2L12 circRNAs, most of which described for the first time. Interestingly, 40 novel circRNAs are likely to form via back-splicing between non-canonical back-splice sites residing in highly similar regions of the primary transcripts. All back-splice junctions were validated using next-generation sequencing (NGS) after circRNA enrichment. Surprisingly, 2 novel circRNAs also comprised a poly(A) tract after BCL2L12 exon 7; this poly(A) tract was back-spliced to exon 1, in both cases. Furthermore, the selective silencing of a BCL2L12 circRNA resulted in a subsequent decrease of BCL2L12 mRNA levels in HCT 116 cells, thus providing evidence of parental gene expression regulation by circRNAs. In conclusion, our study led to the discovery of many circular transcripts from a single human gene and provided new insights into circRNA biogenesis and mode of action.
Collapse
Affiliation(s)
- Paraskevi Karousi
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Christos K Kontos
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece.
| | - Stavroula T Nikou
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Thomas Carell
- Department for Chemistry, Institute for Chemical Epigenetics, Ludwig Maximilian University of Munich, Munich, Germany
| | - Diamantis C Sideris
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Andreas Scorilas
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
| |
Collapse
|
|
43
|
Babigumira R, Veierød MB, Larsen IK, Berge LAM, Shala NK, Marjerrison N, Samuelsen SO, Bråtveit M, Kirkeleit J, Nordby KC, Hosgood HD, Demers PA, Vermeulen R, Kromhout H, Engel LS, Nilsen TIL, Silverman DT, Friesen MC, Rothman N, Lan Q, Grimsrud TK, Stenehjem JS. Benzene exposure and risk of colorectal cancer by anatomical subsite in the Norwegian offshore petroleum workers cohort. ENVIRONMENTAL RESEARCH 2025; 276:121407. [PMID: 40118315 DOI: 10.1016/j.envres.2025.121407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 03/13/2025] [Accepted: 03/14/2025] [Indexed: 03/23/2025]
Abstract
OBJECTIVE To investigate the association between low levels of benzene exposure (≤0.879 parts per million [ppm]-years) and risk of colorectal cancer (CRC) including its anatomical subsites. METHODS Among 25,347 male workers in the Norwegian Offshore Petroleum Workers (NOPW) cohort with offshore work history (1965-1998), 455 CRC cases were diagnosed 1999-2021. We compared these with a subcohort (n = 2031) drawn from the full cohort. Work histories were linked to a previously developed industry-specific benzene job-exposure matrix (JEM). Cox regression for case-cohort analyses was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for CRC, adjusted for age, body mass index, smoking, alcohol intake, red/processed meat intake, and physical activity. RESULTS Risks of CRC increased with increasing benzene exposure. For all CRC, the HRs (95% CI) for the most exposed [quartile 4] vs. the unexposed were 1.32 (0.96 to 1.81, [0.177-0.879 ppm-years]; p-trend = 0.085) for cumulative, 1.52 (1.11 to 2.07, [17-34 years]; p-trend = 0.032) for duration, and 1.56 (1.15 to 2.12, [0.015-0.046 ppm]; p-trend = 0.005) for average intensity of benzene exposure. For right-sided colon cancer, the association was most evident for exposure duration (HR = 2.25 (1.33 to 3.80), quartile 4 [17-34 years] vs. unexposed; p-trend = 0.007). Sensitivity analyses showed consistent associations. CONCLUSION This study found positive exposure-response associations between low-level benzene exposure and CRC risk in offshore petroleum workers. These findings add to emerging evidence that benzene can be associated with solid tumours including lung and bladder, which potentially has important occupational and public health implications.
Collapse
Affiliation(s)
- Ronnie Babigumira
- Department of Research, Cancer Registry of Norway, Norwegian Institute of Public Health, Oslo, 0304, Norway; Oslo Centre for Biostatistics and Epidemiology, Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, 0317, Oslo, Norway.
| | - Marit B Veierød
- Oslo Centre for Biostatistics and Epidemiology, Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, 0317, Oslo, Norway
| | - Inger K Larsen
- Department of Registration, Cancer Registry of Norway, Norwegian Institute of Public Health, Oslo, 0304, Norway
| | - Leon A M Berge
- Department of Research, Cancer Registry of Norway, Norwegian Institute of Public Health, Oslo, 0304, Norway; Oslo Centre for Biostatistics and Epidemiology, Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, 0317, Oslo, Norway
| | - Nita K Shala
- Department of Research, Cancer Registry of Norway, Norwegian Institute of Public Health, Oslo, 0304, Norway; Oslo Centre for Biostatistics and Epidemiology, Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, 0317, Oslo, Norway
| | - Niki Marjerrison
- Department of Research, Cancer Registry of Norway, Norwegian Institute of Public Health, Oslo, 0304, Norway; Oslo Centre for Biostatistics and Epidemiology, Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, 0317, Oslo, Norway
| | - Sven O Samuelsen
- Department of Mathematics, University of Oslo, Oslo, 0316, Norway
| | - Magne Bråtveit
- Department of Global Public Health and Primary Care, University of Bergen, Bergen, 5020, Norway
| | - Jorunn Kirkeleit
- Department of Global Public Health and Primary Care, University of Bergen, Bergen, 5020, Norway; Department of Occupational Medicine and Epidemiology, National Institute of Occupational Health, Oslo, 0304, Norway
| | - Karl-Christian Nordby
- Department of Occupational Medicine and Epidemiology, National Institute of Occupational Health, Oslo, 0304, Norway
| | - H Dean Hosgood
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, 10461, NY, USA
| | - Paul A Demers
- Occupational Cancer Research Centre, Ontario Health, Toronto, M5G 2L3, Ontario, Canada
| | - Roel Vermeulen
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, 3584, the Netherlands; Institute of Risk Assessment Sciences, Utrecht University, Utrecht, 3584, the Netherlands
| | - Hans Kromhout
- Institute of Risk Assessment Sciences, Utrecht University, Utrecht, 3584, the Netherlands
| | - Lawrence S Engel
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, 27599-7435, NC, USA
| | - Tom I L Nilsen
- Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim, 7491, Norway; Clinic of Anesthesia and Intensive Care, St Olav's Hospital, Trondheim University Hospital, Trondheim, 7030, Norway
| | - Debra T Silverman
- Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, 20892, MD, USA
| | - Melissa C Friesen
- Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, 20892, MD, USA
| | - Nathaniel Rothman
- Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, 20892, MD, USA
| | - Qing Lan
- Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, 20892, MD, USA
| | - Tom K Grimsrud
- Department of Research, Cancer Registry of Norway, Norwegian Institute of Public Health, Oslo, 0304, Norway
| | - Jo S Stenehjem
- Department of Research, Cancer Registry of Norway, Norwegian Institute of Public Health, Oslo, 0304, Norway; Oslo Centre for Biostatistics and Epidemiology, Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, 0317, Oslo, Norway
| |
Collapse
|
|
44
|
Zhou Y, Tao Q, Luo C, Chen J, Chen G, Sun J. Epacadostat Overcomes Cetuximab Resistance in Colorectal Cancer by Targeting IDO-Mediated Tryptophan Metabolism. Cancer Sci 2025. [PMID: 40103010 DOI: 10.1111/cas.70057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2025] [Revised: 03/06/2025] [Accepted: 03/12/2025] [Indexed: 03/20/2025] Open
Abstract
Primary or acquired mutations in RAS/RAF genes resulting in cetuximab resistance have limited its clinical application in colorectal cancer (CRC) patients. The mechanism of this resistance remains unclear. RNA sequencing from cetuximab-sensitive and -resistant specimens revealed an activation of the tryptophan pathway and elevation of IDO1 and IDO2 in cetuximab-resistant CRC patients. In vitro, in vivo, and clinical specimens confirmed the upregulation of IDO1and IDO2 and the Kyn/Trp after cetuximab treatment. Additionally, the IDO inhibitor, epacadostat, could effectively inhibit the migration and proliferation of cetuximab-resistant CRC cells while promoting apoptosis. Compared to epacadostat monotherapy, the combination of cetuximab and epacadostat showed a stronger synergistic anti-tumor effect. Furthermore, in vivo experiments confirmed that combination therapy effectively suppressed tumor growth. Mechanistically, KEGG pathway analysis revealed the activation of the IFN-γ pathway in cetuximab-resistant CRC tissues. Luciferase reporter assays confirmed the transcriptional activity of IDO1 following cetuximab treatment. Silencing IFN-γ then suppressed the upregulation induced by cetuximab. Moreover, we observed that the combination reduced the concentration of the tryptophan metabolite kynurenine, promoted the infiltration of CD8+ T lymphocytes, and enhanced the polarization of M1 macrophages within the tumor microenvironment, thereby exerting potent anti-tumor immune effects. Overall, our results confirm the remarkable therapeutic efficacy of combining cetuximab with epacadostat in cetuximab-resistant CRC. Our findings may provide a novel target for overcoming cetuximab resistance in CRC.
Collapse
Affiliation(s)
- Yimin Zhou
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Qiongyan Tao
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chubin Luo
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
| | - Jinsong Chen
- Department of Clinical Medicine, Shaoguan University, Shaoguan, Guangdong, China
| | - Genwen Chen
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jianyong Sun
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China
| |
Collapse
|
|
45
|
Gleaves X, Tan JKH, Peh CH, Koh WL, Lau J, Lieske B, Cheong WK, Chan DKH, Tan KK. Risk factors for non-clinical prolonged lengths of stay after elective colorectal surgery. Sci Rep 2025; 15:9184. [PMID: 40097477 PMCID: PMC11914062 DOI: 10.1038/s41598-025-93013-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 03/04/2025] [Indexed: 03/19/2025] Open
Abstract
Identification of reasons and causative factors for prolonged lengths of stay (LOS) after elective colorectal surgery in patients with uneventful postoperative recovery. A prospectively maintained database of colorectal cancer (CRC) patients between 2019 and 2021 was reviewed. Peri-operative parameters were evaluated to identify risk factors for prolonged LOS. Uneventful postoperative recovery was defined as Clavien-Dindo (CD) Complication Grade 0. 181 patients had uneventful postoperative recovery. 30 (16.7%) patients had delayed discharge, the underlying reasons were ongoing physiotherapy assessment for discharge (N = 11), caregiver training for stoma/drain (N = 6), family/patient confidence and or pending community placement for continuation of postoperative rehabilitation (N = 14). Factors such as pre-operative status of activity of daily living (ADL) and community ambulance, stoma creation, and high dependency (HD) ward admission were independently associated with delayed discharge. Multiple factors accounted for delayed discharge in in patients after elective surgery for CRC. Pre-operative identification and intervention to some of these factors might pave the way to reduce the overall length of hospitalization.
Collapse
Affiliation(s)
- Xuan Gleaves
- University Surgical Cluster, National University Hospital, Singapore, Singapore
| | - Jarrod Kah Hwee Tan
- University Surgical Cluster, National University Hospital, Singapore, Singapore
| | - Cherie Hui Peh
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Wei-Ling Koh
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jerrald Lau
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore
| | - Bettina Lieske
- University Surgical Cluster, National University Hospital, Singapore, Singapore
| | - Wai Kit Cheong
- University Surgical Cluster, National University Hospital, Singapore, Singapore
| | - Dedrick Kok Hong Chan
- University Surgical Cluster, National University Hospital, Singapore, Singapore
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Ker Kan Tan
- University Surgical Cluster, National University Hospital, Singapore, Singapore.
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.
| |
Collapse
|
|
46
|
Shi L, Wang H, Sun Y, Xu N, Pei A, Zhang N. Development and validation of a disulfidptosis-related prognostic model for colorectal cancer using multi-omics analysis. Discov Oncol 2025; 16:338. [PMID: 40095116 PMCID: PMC11914417 DOI: 10.1007/s12672-025-02055-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Accepted: 03/04/2025] [Indexed: 03/19/2025] Open
Abstract
This study aims to integrate multi-omic and clinical data concerning disulfidptosis-related genes (DRGs) to facilitate molecular typing and prognosis in colorectal cancer (CRC). Public databases provided CRC transcriptome and clinical data, enabling differential expression, genomic analyses, pathway enrichment, survival analysis, and subtyping based on the expression levels of 15 DRGs identified in published studies. Differentially expressed genes (DEGs) between subtypes were identified to create a disulfidptosis prognostic model using LASSO and Cox regression analyses. This model was evaluated by comparing risk scores, survival curves, cellular infiltration, and drug sensitivity between high- and low-risk groups. Analyses revealed differential expression, mutations, and copy number variations (CNV) in DRGs in CRC. Survival analysis demonstrated significant prognostic differences among DRG expression subtypes. GSVA and ssGSEA highlighted DRGs' regulatory roles in CRC. DEGs identified between DRG expression subtypes led to the classification into subtypes A and B. A disulfidptosis prognostic model, including genes VSIG4, SCG2, INHBB, DDC, CXCL13, KLK10, CXCL10, and CCL11A, was developed to stratify patients into high- and low-risk groups. This model displayed strong predictive capability (AUC = 0.700) and calibration. The risk score was also strongly associated with immune cell infiltration, stromal cell score, and stem cell index in the CRC tumor microenvironment. Drug sensitivity analysis indicated that high-risk samples were more responsive to most medications. We established a robust disulfidptosis prognostic model for CRC through comprehensive multi-omics analysis. Our findings provide valuable insights into the role of DRGs in CRC progression and disease management, presenting an important resource for further research.
Collapse
Affiliation(s)
- Lei Shi
- Gastroenterology Department & Endoscopic Center, The First Bethune Hospital of Jilin University, 1 Xinmin Street, Changchun City, 130021, China
| | - Huimei Wang
- Gastroenterology Department & Endoscopic Center, The First Bethune Hospital of Jilin University, 1 Xinmin Street, Changchun City, 130021, China
| | - Yongxiao Sun
- Gastroenterology Department & Endoscopic Center, The First Bethune Hospital of Jilin University, 1 Xinmin Street, Changchun City, 130021, China
| | - Na Xu
- Gastroenterology Department & Endoscopic Center, The First Bethune Hospital of Jilin University, 1 Xinmin Street, Changchun City, 130021, China
| | - Aiyue Pei
- Gastroenterology Department & Endoscopic Center, The First Bethune Hospital of Jilin University, 1 Xinmin Street, Changchun City, 130021, China.
| | - Nan Zhang
- Gastroenterology Department & Endoscopic Center, The First Bethune Hospital of Jilin University, 1 Xinmin Street, Changchun City, 130021, China.
| |
Collapse
|
|
47
|
Zhang H, Zhang N, Yang X, Wang C, Yang Q, Luo J, Ye T. BRAF mutation cancer, colorectal cancer, tumor associated lymph node structure and immune microenvironment study: MAPK protein kinase molecular action and SIRPG-CD47 protein signaling pathway. Int J Biol Macromol 2025; 307:142191. [PMID: 40101830 DOI: 10.1016/j.ijbiomac.2025.142191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 03/11/2025] [Accepted: 03/15/2025] [Indexed: 03/20/2025]
Abstract
BRAF mutation affects the biological characteristics and microenvironment of the tumor during the development of colorectal cancer. Tumor-associated lymph nodes are the key sites of immune response. This study aimed to systematically evaluate the impact of BRAF gene mutations on the remodeling of the CRC immune microenvironment, with a particular focus on their effects on the maturation and function of TLS·In this study, clinical samples of CRC patients were collected, and immune cell subsets were analyzed by single-cell RNA sequencing, and pseudo-temporal locus analysis and spatial transcriptome analysis were performed to explore intercellular communication and functional enrichment analysis. The distribution and maturity of TLS were evaluated by immunohistochemistry and multiple fluorescence staining techniques, and statistical analysis was performed.The results showed that BRAF mutation significantly affected the number and maturity of lymphatic structures infiltrated by tumors, and was negatively correlated with patient prognosis. BRAF mutations lead to alterations in T cell subsets, particularly the dual role of CD4+ CXCL13 cells in TLS maturation. B-cell subpopulation analysis revealed functional deficits in CRC patients with BRAF mutations, which further drove the remodeling of the tumor immune microenvironment.
Collapse
Affiliation(s)
- Hao Zhang
- Department of Oncology, Minhang Hospital, Fudan University, Shanghai 201199, China
| | - Nenglin Zhang
- Department of Gastroenterology, First Affiliated Hospital of Anhui University of Science and Technology, , Huainan 232007, China
| | - Xiaodi Yang
- Department of Oncology, Minhang Hospital, Fudan University, Shanghai 201199, China
| | - Chen Wang
- Department of Oncology, Minhang Hospital, Fudan University, Shanghai 201199, China
| | - Qinghui Yang
- Department of Oncology, Minhang Hospital, Fudan University, Shanghai 201199, China
| | - Jing Luo
- Department of Oncology, Minhang Hospital, Fudan University, Shanghai 201199, China; Key Laboratory of Whole-period Monitoring and Precise Intervention of Digestive Cancer (SMHC), Minhang Hospital & AHS, Fudan University, Shanghai 201199, China.
| | - Tao Ye
- Department of Oncology, Minhang Hospital, Fudan University, Shanghai 201199, China; Key Laboratory of Whole-period Monitoring and Precise Intervention of Digestive Cancer (SMHC), Minhang Hospital & AHS, Fudan University, Shanghai 201199, China.
| |
Collapse
|
|
48
|
Qin K, Luo JY, Zeng DT, Huang WY, Li B, Li Q, Zhan YT, He RQ, Huang WJ, Chen G, Chen ZY, Chi BT, Tang YX, Tang RX, Li H. Kinesin family member 14 expression and its clinical implications in colorectal cancer. World J Gastrointest Oncol 2025; 17:102696. [PMID: 40092935 PMCID: PMC11866231 DOI: 10.4251/wjgo.v17.i3.102696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 11/22/2024] [Accepted: 12/25/2024] [Indexed: 02/14/2025] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is the third most common cancer globally, causing over 900000 deaths annually. Risk factors include aging, diet, obesity, sedentary lifestyle, tobacco use, genetic predisposition, and inflammatory bowel disease. Despite current treatments, survival rates for advanced CRC remain low, highlighting the need for better therapeutic strategies. AIM To evaluate both the clinical significance and the pathological implications of the Kinesin family member 14 (KIF14) expression within CRC specimens. Additionally, this study aims to investigate the interaction between nitidine chloride (NC) and KIF14, considering their potential as therapeutic targets. METHODS The expression of the KIF14 protein in CRC was analyzed using immunohistochemical staining. The integration of multicenter high-throughput data facilitated the calculation of the standardized mean difference (SMD) for KIF14 mRNA levels. The assessment of clinical and pathological impact was enhanced by analyzing combined receiver operating characteristic curves, along with measures of sensitivity, specificity, and likelihood ratios. Additionally, clustered regularly interspaced short palindromic repeats knockout screening for cell growth and single-cell sequencing were employed to validate the significance of KIF14 expression in CRC. Survival analysis established the prognostic value of KIF14 in CRC. The molecular mechanism of NC against CRC was elucidated through whole-genome sequencing and enrichment analysis, and molecular docking was utilized to explore the targeting affinity between NC and KIF14. RESULTS KIF14 was highly expressed in 208 CRC patients. Data from 17 platforms involving 2436 CRC samples and 1320 noncancerous colorectal tissue controls indicated that KIF14 expression was significantly higher in CRC samples, with an SMD of 1.92 (95%CI: 1.49-2.35). The area under the curve was 0.94 (95%CI: 0.92-0.96), with a sensitivity of 0.85 (95%CI: 0.78-0.90) and a specificity of 0.90 (95%CI: 0.85-0.93). The positive and negative likelihood ratios were 8.38 (95%CI: 5.39-13.02) and 0.17 (95%CI: 0.11-0.26), respectively. At the single-cell level, significant overexpression of KIF14 was observed in CRC cells (P < 0.001), with 35 CRC cell lines dependent on KIF14 for growth. The K-M plots demonstrated that KIF14 possesses prognostic value in CRC patients within the GSE71187 and GSE103679 datasets (P < 0.05). Binding energy calculations indicated that KIF14 is a potential target for NC (binding energy: 10.3 kcal/mol). CONCLUSION KIF14 promotes the growth of CRC cells and acts as an oncogenic factor, potentially serving as a therapeutic target for NC in the treatment of CRC.
Collapse
Affiliation(s)
- Kai Qin
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Jia-Yuan Luo
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Da-Tong Zeng
- Department of Pathology, Redcross Hospital of Yulin City, Yulin 537000, Guangxi Zhuang Autonomous Region, China
| | - Wan-Ying Huang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Bin Li
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Qi Li
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Yan-Ting Zhan
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Rong-Quan He
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Wei-Jian Huang
- Department of Pathology, Redcross Hospital of Yulin City, Yulin 537000, Guangxi Zhuang Autonomous Region, China
| | - Gang Chen
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Zu-Yuan Chen
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Bang-Teng Chi
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Yu-Xing Tang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Rui-Xue Tang
- Department of Pathology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250000, Shandong Province, China
| | - Hui Li
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| |
Collapse
|
|
49
|
Demarchis L, Chiloiro S, Giampietro A, De Marinis L, Bianchi A, Fleseriu M, Pontecorvi A. Cancer screening in patients with acromegaly: a plea for a personalized approach and international registries. Rev Endocr Metab Disord 2025:10.1007/s11154-025-09957-6. [PMID: 40088375 DOI: 10.1007/s11154-025-09957-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/25/2025] [Indexed: 03/17/2025]
Abstract
Acromegaly is a rare condition, and often diagnosis is delayed by several years, for most patients. Acromegaly is characterized by short and long-term respiratory, cardiovascular and metabolic comorbidities, with possible impact on mortality. In the last two decades, life expectancy has progressively increased in part due to a reduction in biochemically active disease, multidisciplinary treatment approaches and a reduction in complications, and the availability of new drugs. Of note, a leading cause of mortality, cardiovascular comorbidity, has been replaced by cancer(s). As such, neoplasms more frequently observed (colon, thyroid, breast, prostate, and stomach) in patients with acromegaly are receiving increased attention. Chronic exposure to increased growth hormone serum levels may contribute to an increase in the occurrence and progression of cancers. Various efforts have been made to determine the pathogenetic mechanisms involved. However, there are no clear medical-related societal agreement(s) in relation to screening methods or timing regarding neoplasm(s) diagnosis in patients with acromegaly. Additionally, independent and dependent risk factor data in patients with acromegaly is lacking. International/national registries could help lay the groundwork to better study the impact of cancer(s) in patients with acromegaly and subsequently lead to and validate the most appropriate diagnostic and therapeutic path forward.
Collapse
Affiliation(s)
- Luigi Demarchis
- Dipartimento Di Medicina Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- Dipartimento Di Medicina Interna, Endocrinologia E Diabetologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Sabrina Chiloiro
- Dipartimento Di Medicina Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy.
- Dipartimento Di Medicina Interna, Endocrinologia E Diabetologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy.
| | - Antonella Giampietro
- Dipartimento Di Medicina Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- Dipartimento Di Medicina Interna, Endocrinologia E Diabetologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Laura De Marinis
- Dipartimento Di Medicina Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- Dipartimento Di Medicina Interna, Endocrinologia E Diabetologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Antonio Bianchi
- Dipartimento Di Medicina Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- Dipartimento Di Medicina Interna, Endocrinologia E Diabetologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Maria Fleseriu
- Pituitary Center, and Departments of Medicine, and Neurological Surgery, Oregon Health & Science University, Portland, OR, USA
| | - Alfredo Pontecorvi
- Dipartimento Di Medicina Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- Dipartimento Di Medicina Interna, Endocrinologia E Diabetologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| |
Collapse
|
|
50
|
Ao X, Zhou X, Liu J, Wu Q, Yang Y, Liu Y, Hao W, Li L, Wang K, Li Z. Insect medicines for colorectal cancer: A review of mechanisms, preclinical evidence, and future prospects. Medicine (Baltimore) 2025; 104:e41873. [PMID: 40101066 PMCID: PMC11922444 DOI: 10.1097/md.0000000000041873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/20/2025] Open
Abstract
Colorectal cancer is recognized as the third most prevalent malignant tumor globally. The recommended treatment modalities, including surgery, radiotherapy, and chemotherapy, are frequently associated with severe side effects and high recurrence rates. Cancer experts are actively engaged in a global pursuit of safer and more efficacious treatment strategies for colorectal cancer (CRC). Insect medicine, a unique subset of traditional Chinese medicine, is characterized by their broad spectrum of therapeutic effects, which include antibacterial, anticoagulant, antithrombotic, and sedative actions. Insects are enriched with proteins, peptides, and amino acids. These compounds exhibit pharmacological activities, including anti-tumor effects, inhibition of cancer cell proliferation, induction of apoptosis in cancer cells, anti-inflammatory properties, and immunomodulation. Recent studies have revealed that certain traditional Chinese insect medicines, such as Bombyx Batryticatus, Tubiechong, and Aspongopus chinensis Dalls, demonstrate outstanding therapeutic efficacy in the treatment of CRC. The anti-CRC actions of these insect medicines are potentially mediated through mechanisms involving the Hedgehog and Wnt/β-catenin signaling pathways, as well as immunomodulatory effects. Consequently, these insect medicines are proposed as a potential strategy for CRC treatment.
Collapse
Affiliation(s)
- Xinyi Ao
- Department of Spleen and Stomach Diseases, the Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China
- The Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Digestive System Diseases of Luzhou City, the Affiliated Traditional Medicine Hospital, Southwest Medical University, Luzhou, China
| | - Xin Zhou
- Department of Spleen and Stomach Diseases, the Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China
- The Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Digestive System Diseases of Luzhou City, the Affiliated Traditional Medicine Hospital, Southwest Medical University, Luzhou, China
| | - Jianqin Liu
- Department of Spleen and Stomach Diseases, the Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China
- The Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Digestive System Diseases of Luzhou City, the Affiliated Traditional Medicine Hospital, Southwest Medical University, Luzhou, China
| | - Qian Wu
- Department of Spleen and Stomach Diseases, the Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China
- The Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Digestive System Diseases of Luzhou City, the Affiliated Traditional Medicine Hospital, Southwest Medical University, Luzhou, China
| | - Yanlin Yang
- Department of Spleen and Stomach Diseases, the Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China
- The Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Digestive System Diseases of Luzhou City, the Affiliated Traditional Medicine Hospital, Southwest Medical University, Luzhou, China
| | - Yali Liu
- Department of Spleen and Stomach Diseases, the Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China
- The Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Digestive System Diseases of Luzhou City, the Affiliated Traditional Medicine Hospital, Southwest Medical University, Luzhou, China
| | - Weian Hao
- Department of Spleen and Stomach Diseases, the Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China
- The Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Digestive System Diseases of Luzhou City, the Affiliated Traditional Medicine Hospital, Southwest Medical University, Luzhou, China
| | - Li Li
- Department of Spleen and Stomach Diseases, the Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China
- The Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Digestive System Diseases of Luzhou City, the Affiliated Traditional Medicine Hospital, Southwest Medical University, Luzhou, China
| | - Kaixuan Wang
- Department of Spleen and Stomach Diseases, the Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Zhi Li
- Department of Spleen and Stomach Diseases, the Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China
- The Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Digestive System Diseases of Luzhou City, the Affiliated Traditional Medicine Hospital, Southwest Medical University, Luzhou, China
| |
Collapse
|