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Chen D, Wang W, Chen X, Liang N, Li J, Ding W, Zhang H, Yang Z, Zhao H, Liu Z. Plant-derived extracts or compounds for Helicobacter-associated gastritis: a systematic review of their anti-Helicobacter activity and anti-inflammatory effect in animal experiments. Chin Med 2025; 20:53. [PMID: 40264171 DOI: 10.1186/s13020-025-01093-2] [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: 06/21/2024] [Accepted: 03/10/2025] [Indexed: 04/24/2025] Open
Abstract
BACKGROUND Helicobacter infection, which is the leading cause of gastritis and stomach cancer, has become common worldwide. Almost all Helicobacter-infected patients have chronic active gastritis, also known as Helicobacter-associated gastritis (HAG). However, the eradication rate of Helicobacter is decreasing due to the poor efficacy of current medications, which causes infection to recur, inflammation to persist, and stomach cancer to develop. Natural components have robust antibacterial activity and anti-inflammatory capacity, as confirmed by many studies of alternative natural medicines. PURPOSE This article aimed to conduct a comprehensive search and meta-analysis to evaluate the efficacy of anti-Helicobacter and anti-inflammatory activities of plant-derived extracts or compounds that can treat HAG in animal experiments. We intended to provide detailed preclinical-research foundation including plant and compound information, as well as the mechanisms by which these plant-derived substances inhibit the progression of Helicobacter infection, gastritis and neoplasms for future study. METHODS The systematic review is aligned with the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, and the protocol was registered in PROSPERO (CRD42024527889). An extensive search was performed across multiple databases, including PubMed, Scopus, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), the Chinese Scientific Journal database (VIP), the Wanfang database, and the China biomedical literature service system (SinoMed), up until November 2023. Meta-analysis on Review Manager software (RevMan 5.4) estimating anti-Helicobacter and anti-inflammatory activity was performed. We used the Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) risk of bias tool to evaluate the risk of bias of each study included. RESULTS Our study encompassed 61 researches, comprised 36 extracts and 37 compounds improving HAG by inhibiting Helicobacter infection, the inflammatory response, oxidative stress, and regulating apoptosis and proliferation. Sixteen families especially Asteraceae, Fabaceae and Rosaceae and nine classes including Terpenoids, Alkaloids, Phenols, and Flavonoids may be promising directions for valuable new drugs. The Meta-analyse demonstrated the plant-base substance treatments possess significant anti-Helicobacter and anti-inflammation activity comparing to control groups. The included plants and compounds confirmed that signaling pathways NF-κB, JAK2/STAT3, MAPK, TLR4/MyD88, PI3K/AKT, NLRP3/Caspase-1 and NRF2/HO-1 play a key role in the progression of HAG. CONCLUSION Plant-derived extracts or compounds actively improve HAG by modulating relevant mechanisms and signaling pathways, particularly through the anti-Helicobacter and inflammatory regulation ways. Further researches to apply these treatments in humans are needed, which will provide direction for the future development of therapeutic drugs to increase eradication rate and alleviate gastritis.
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Affiliation(s)
- Danni Chen
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 Bei San Huan Dong Lu, Chaoyang District, Beijing, 100029, China
| | - Wenlai Wang
- Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, No. 16 Nanxiaojie, Dongzhimen Nei, Dongcheng District, Beijing, 100700, China
| | - Xiangyun Chen
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 Bei San Huan Dong Lu, Chaoyang District, Beijing, 100029, China
| | - Ning Liang
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Jiawang Li
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 Bei San Huan Dong Lu, Chaoyang District, Beijing, 100029, China
| | - Wei Ding
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 Bei San Huan Dong Lu, Chaoyang District, Beijing, 100029, China
| | - Hongrui Zhang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, No. 5 Haiyuncang, Dongcheng District, Beijing, 100700, China
- Institute for Brain Disorders, Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Zhen Yang
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 Bei San Huan Dong Lu, Chaoyang District, Beijing, 100029, China.
| | - Hongxia Zhao
- Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, No. 16 Nanxiaojie, Dongzhimen Nei, Dongcheng District, Beijing, 100700, China.
| | - Zhenhong Liu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, No. 5 Haiyuncang, Dongcheng District, Beijing, 100700, China.
- Institute for Brain Disorders, Beijing University of Chinese Medicine, Beijing, 100700, China.
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Dehuo Y, Ying W, Lin C. Regulation of the MAPK/ERK Pathway by miRNA-27b in Gastric Cancer: Diagnostic Implications and Therapeutic Potential of Aloin. Asia Pac J Clin Oncol 2025. [PMID: 40240889 DOI: 10.1111/ajco.14171] [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: 01/31/2025] [Revised: 03/09/2025] [Accepted: 04/02/2025] [Indexed: 04/18/2025]
Abstract
BACKGROUND Globally, gastric cancer (GC) ranks as the fourth most deadly and fifth most prevalent kind of cancer. Appropriate treatment methods, precise etiology, and molecular processes of GC are still unclear. METHODS In silico and quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR)-based expression of miRNA-27b was quantified in GC cell lines (AGS, MKN-28, MKN-45, NCI-N87, SNU-1), and ROC curve analysis was done to evaluate their diagnostic efficiency. In silico target prediction through miRDB and TargetScan followed by in vitro validation was done using luciferase assays. Expression analysis of MAPK/ERK target genes including GRB2, SOS1, KRAS, BRAF, MAP2K1, and MAPK1 was done using qRT-PCR and Western blot analysis, followed by ROC curve analysis to evaluate their diagnostic efficiency. GC cell lines were treated with Aloin (ALO), followed by cell viability, wound healing, and apoptosis assays. Furthermore, the expression of MAPK/ERK pathway genes in GC cell lines was evaluated by qRT-PCR following ALO treatment. RESULTS The in silico analysis identified specific binding sites for miRNA-27b within the 3'UTRs of key components in the MAPK/ERK signaling pathway, including GRB2, SOS1, KRAS, BRAF, MAP2K1, and MAPK1. Luciferase reporter assays confirmed the direct interaction of miRNA-27b with these target genes, showing significantly reduced luciferase activity in cells transfected with wild-type 3'UTRs compared to controls. Expression analysis revealed that miRNA-27b was significantly downregulated in GC patients and cell lines when compared to normal controls. The downregulation of miRNA-27b was further validated through qRT-PCR in a variety of GC cell lines. ROC curve analysis demonstrated an AUC of 100 for miRNA-27b, suggesting its strong potential as a diagnostic biomarker for GC. In contrast, the expression of MAPK/ERK pathway genes was significantly upregulated in GC cell lines, with ROC analysis revealing high diagnostic accuracy for several genes, including GRB2, SOS1, and KRAS. Protein expression analysis via Western blot confirmed the upregulation of these pathway components in GC cells. Further investigation into the effects of ALO treatment showed a dose-dependent reduction in cell viability, migration, and colony formation in GC cell lines. ALO treatment also induced apoptosis, as evidenced by the upregulation of apoptotic markers and the downregulation of the anti-apoptotic molecule Bcl-2. CONCLUSION MiRNA-27b and MAPK/ERK pathway genes (GRB2, SOS1, KRAS, BRAF, MAP2K1, and MAPK1) could serve as efficient diagnostic, prognostic, and therapeutic targets for GC patients. Furthermore, this study's findings shed light on ALO's anti-tumor capabilities by demonstrating that it inhibits GC cell migration and proliferation while restoring the expression status of MAPK/ERK pathway genes.
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Affiliation(s)
- Yang Dehuo
- Jinhua Maternal and Child Health Care Hospital, Jinhua, China
| | - Wang Ying
- Jinhua Maternal and Child Health Care Hospital, Jinhua, China
| | - Cao Lin
- Jinhua Maternal and Child Health Care Hospital, Jinhua, China
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Li F, Cai C, Wang F, Zhang N, Zhao Q, Chen Y, Cui X, Wang S, Zhang W, Liu D, Cai Y, Jin J. 20(S)-ginsenoside Rg3 suppresses gastric cancer cell proliferation by inhibiting E2F-DP dimerization. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 141:156740. [PMID: 40252583 DOI: 10.1016/j.phymed.2025.156740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Revised: 03/24/2025] [Accepted: 04/07/2025] [Indexed: 04/21/2025]
Abstract
BACKGROUND Gastric cancer (GC) is a common and aggressive malignancy, with treatment options often limited by drug resistance and the adverse effects of targeted therapies and immunotherapy. Ginsenoside Rg3, a bioactive compound derived from ginseng, has shown promise in inhibiting the growth of various tumor types, including GC. However, the molecular mechanisms underlying its therapeutic effects against GC remain insufficiently understood. OBJECTIVE This study aimed to elucidate the molecular mechanisms underlying the anti-cancer effects of ginsenoside Rg3 against GC. METHODS To explore the molecular mechanisms underlying Rg3's anti-GC effects, RNA sequencing (RNA-Seq) was conducted to identify potential Rg3-regulated targets. The interaction between Rg3 and E2F was analyzed using several approaches, including the cellular thermal shift assay (CETSA), Rg3-PEGA pull-down, Rg3 pull-down protein mass spectrometry, and 3D molecular docking. Additionally, quantitative reverse transcription PCR (qRT-PCR), co-transfection followed by immunoprecipitation, Western blotting, flow cytometry, Annexin V-FITC staining, Hoechst staining, and luciferase reporter assays were employed to elucidate the molecular effects of Rg3. The inhibitory effect of Rg3 on GC proliferation was assessed through colony formation assays in vitro and tumor xenograft experiments in C57BL/6 mice in vivo. RESULTS Rg3-mediated gene expression profiling in GC cells revealed several transcription factors, including E2F, and biological processes potentially influenced by Rg3. Consistent with these findings, Rg3 suppressed E2F expression and impeded GC cell proliferation by inducing G1/S cell cycle arrest, reducing cell growth both in vitro and in vivo, enhancing apoptosis, and inhibiting CDC6 transactivation. CETSA and Rg3 pull-down assays confirmed an interaction between Rg3 and E2F. Additionally, 3D molecular docking analysis demonstrated that Rg3 binds with high affinity to E2F at the heterodimeric domain via hydrogen bonding, potentially disrupting E2F-DP heterodimer formation and subsequently inhibiting cell cycle gene expression. In agreement with this, Rg3-treated GC cells exhibited reduced expression of cyclin D1, CDK4, cyclin A, CDK1, and CDK2. Moreover, Rg3 activated the tumor suppressors p53 and p21, further inhibiting RB phosphorylation by suppressing cyclin/CDK activity, thereby blocking transcription of G1/S transition-related genes. CONCLUSION This study provides the first evidence that Rg3 directly binds to E2F proteins, disrupting E2F-DP heterodimer formation and inhibiting the transcription of E2F-DP-regulated target genes. Furthermore, Rg3 activates the p53-p21 pathway while suppressing the cyclin/CDK-RB signaling pathway, effectively inhibiting cancer cell proliferation. These findings highlight a potential therapeutic strategy for developing small molecules structurally similar to Rg3 to target tumors with high E2F expression.
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Affiliation(s)
- Fuqiang Li
- School of Life Sciences, Jilin University, 2699 Qianjin Street, Chaoyang District, Changchun, Jilin 130012, China; School of Pharmacy, Changchun University of Chinese Medicine, Boshuo Road, Jingyue Development Zone, Changchun, Jilin 130117, China
| | - Chengyu Cai
- School of Life Sciences, Jilin University, 2699 Qianjin Street, Chaoyang District, Changchun, Jilin 130012, China
| | - Fei Wang
- School of Life Sciences, Jilin University, 2699 Qianjin Street, Chaoyang District, Changchun, Jilin 130012, China
| | - Na Zhang
- School of Life Sciences, Jilin University, 2699 Qianjin Street, Chaoyang District, Changchun, Jilin 130012, China
| | - Qingzhi Zhao
- School of Life Sciences, Jilin University, 2699 Qianjin Street, Chaoyang District, Changchun, Jilin 130012, China
| | - Yuyang Chen
- School of Life Sciences, Jilin University, 2699 Qianjin Street, Chaoyang District, Changchun, Jilin 130012, China
| | - Xueli Cui
- School of Life Sciences, Jilin University, 2699 Qianjin Street, Chaoyang District, Changchun, Jilin 130012, China
| | - Siyang Wang
- School of Life Sciences, Jilin University, 2699 Qianjin Street, Chaoyang District, Changchun, Jilin 130012, China
| | - Wenjie Zhang
- School of Life Sciences, Jilin University, 2699 Qianjin Street, Chaoyang District, Changchun, Jilin 130012, China
| | - Da Liu
- School of Pharmacy, Changchun University of Chinese Medicine, Boshuo Road, Jingyue Development Zone, Changchun, Jilin 130117, China.
| | - Yong Cai
- School of Life Sciences, Jilin University, 2699 Qianjin Street, Chaoyang District, Changchun, Jilin 130012, China.
| | - Jingji Jin
- School of Life Sciences, Jilin University, 2699 Qianjin Street, Chaoyang District, Changchun, Jilin 130012, China.
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Wang C, Qiu Y, Zheng X, Chen S, He C. MOSPD1 facilitates fatty acid metabolism and gastric cancer progression by promoting the MAPK pathway. Tissue Cell 2025; 93:102752. [PMID: 39864210 DOI: 10.1016/j.tice.2025.102752] [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: 08/22/2024] [Revised: 01/02/2025] [Accepted: 01/15/2025] [Indexed: 01/28/2025]
Abstract
BACKGROUND Motile sperm domain containing 1 (MOSPD1) is overexpressed in colorectal, prostate, and breast cancers, but its role in gastric cancer (GC) progression remains unclear. METHODS The effect of MOSPD1 was evaluated using cell viability, colony formation, wound healing, and Transwell assays. Triglyceride and lipid levels were measured in GC cells. Western blotting was used to examine protein expression. A mouse model of subcutaneous tumor xenotransplantation was used to evaluate the effects of MOSPD1 knockdown on GC cells. RESULTS MOSPD1 expression in GC tissues and cells was higher than in normal tissues and cells. MOSPD1 knockdown decreased the proliferation, migration, and invasion of GC cells and the growth of subcutaneous tumors. MOSPD1 overexpression increased the proliferation, migration, and invasion of GC cells. Levels of triglyceride, lipid, and fatty acid synthesis-related enzymes (ACLY, ACC1, and FASN) were downregulated in MOSPD1 knockdown cells and upregulated in MOSPD1 overexpressed cells. MOSPD1 knockdown inhibited the phosphorylation of ERK, JNK, and P38 in GC cells and subcutaneous tumors. MOSPD1 overexpression promoted the phosphorylation of ERK, JNK, and P38 in GC cells. CONCLUSIONS High MOSPD1 expression facilitates fatty acid metabolism and GC progression by activating the MAPK pathway. Thus, MOSPD1 may be a potential therapeutic target for GC.
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Affiliation(s)
- Chengliang Wang
- Department of Gastrointestinal Surgery, The Affiliated Taian City Central Hospital of Qingdao University, Tai'an, Shandong 271000, China
| | - Yunping Qiu
- Department of Gastrointestinal Surgery, The Affiliated Taian City Central Hospital of Qingdao University, Tai'an, Shandong 271000, China
| | - Xiao Zheng
- Department of Gastrointestinal Surgery, The Affiliated Taian City Central Hospital of Qingdao University, Tai'an, Shandong 271000, China
| | - Shuhui Chen
- Department of Gastrointestinal Surgery, The Affiliated Taian City Central Hospital of Qingdao University, Tai'an, Shandong 271000, China
| | - Chao He
- Department of Gastrointestinal Surgery, The Affiliated Taian City Central Hospital of Qingdao University, Tai'an, Shandong 271000, China.
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Wang Y, Sun X, Ren M, Ma F, Zhao R, Zhu X, Xu Y, Cao N, Chen Y, Pan Y, Zhao A. Integrative network pharmacology, transcriptomics, and proteomics reveal the material basis and mechanism of the Shen Qing Weichang Formula against gastric cancer. Chin Med 2025; 20:42. [PMID: 40155922 PMCID: PMC11954191 DOI: 10.1186/s13020-025-01091-4] [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: 11/19/2024] [Accepted: 03/05/2025] [Indexed: 04/01/2025] Open
Abstract
BACKGROUND Gastric cancer (GC) is a common malignancy with poor prognosis and lack of efficient therapeutic methods. Shen Qing Weichang Formula (SQWCF) is a patented traditional herbal prescription for GC, but its efficacy and underlying mechanism remains to be clarified. PURPOSE To explore the efficacy and potential mechanism of SQWCF in treating GC. METHODS A subcutaneous transplantation tumor model of human GC was established for assessing SQWCF's efficacy and safety. A comprehensive strategy integrating mass spectrometry, network pharmacology, omics analysis, and bioinformatic methods was adopted to explore the core components, key targets, and potential mechanism of SQWCF in treating GC. Molecular docking, immunohistochemistry, quantitative real-time PCR, and western blot were applied to validation. RESULTS In the mouse model of GC, SQWCF effectively suppressed the GC growth without evident toxicity and enhanced the therapeutic efficacy of paclitaxel. Network pharmacology and molecular docking based on mass spectrometry showed that key targets (CASP3, TP53, Bcl-2, and AKT1) and core active components (Calycosin, Glycitein, Liquiritigenin, Hesperetin, and Eriodictyol) involved in the anti-GC effect of SQWCF had stable binding affinity, of which AKT1 ranked the top in the affinity. Validation based on network pharmacology and omics analysis confirmed that PI3K-AKT and MAPK signaling pathways, as well as downstream apoptosis pathway, explained the therapeutic effects of SQWCF on GC. In addition, family with sequence similarity 81 member A (FAM81A) was identified as a novel biomarker of GC that was aberrantly highly expressed in GC and associated with poor prognosis by bioinformatic analysis, and was an effector target of SQWCF at both mRNA and protein levels. CONCLUSION This study uncovers a synergistic multi-component, multi-target, and multi-pathway regulatory mechanism of SQWCF in treating GC comprehensively, emphasizing its potential for therapeutic use and providing new insights into GC treatment.
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Affiliation(s)
- Yi Wang
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, South Wanping Rd. 725, Shanghai, 200032, China
| | - Xiaoyu Sun
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, South Wanping Rd. 725, Shanghai, 200032, China
| | - Mingming Ren
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, South Wanping Rd. 725, Shanghai, 200032, China
| | - Fangqi Ma
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, South Wanping Rd. 725, Shanghai, 200032, China
| | - Ruohan Zhao
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, South Wanping Rd. 725, Shanghai, 200032, China
| | - Xiaohong Zhu
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, South Wanping Rd. 725, Shanghai, 200032, China
| | - Yan Xu
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, South Wanping Rd. 725, Shanghai, 200032, China
| | - Nida Cao
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, South Wanping Rd. 725, Shanghai, 200032, China
| | - Yuanyuan Chen
- Cancer Institute of Traditional Chinese Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, South Wanping Rd. 725, Shanghai, 200032, China
| | - Yongfu Pan
- Cancer Institute of Traditional Chinese Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, South Wanping Rd. 725, Shanghai, 200032, China.
| | - Aiguang Zhao
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, South Wanping Rd. 725, Shanghai, 200032, China.
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Jiang X, Li X, Li Y, Zhang Y, Gu X, Zong W, Shen X, Ju S. Systematic assessment of serum i-tRF-AsnGTT in gastric cancer: a potential clinical biomarker. Carcinogenesis 2025; 46:bgae044. [PMID: 39023209 DOI: 10.1093/carcin/bgae044] [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: 04/25/2024] [Revised: 06/07/2024] [Accepted: 07/17/2024] [Indexed: 07/20/2024] Open
Abstract
Since gastric cancer (GC) shows no apparent signs in its early stages, most patients are diagnosed later with a poor prognosis. We therefore seek more sensitive and specific GC biomarkers. Small RNAs formed from tRNAs represent a novel class of non-coding RNAs that are highly abundant in bodily fluids and essential to biological metabolism. This study explores the potential of i-tRF-AsnGTT in gastric cancer diagnostics. To begin with, we sequenced i-tRF-AsnGTT using high-throughput methods. i-tRF-AsnGTT expression levels in GC were determined using real-time fluorescence polymerase chain reaction. Agarose gel electrophoresis, Sanger sequencing, and repeated freezing and thawing were performed to verify molecular properties. A correlation was found between clinical and pathological parameters and i-tRF-AsnGTT expression levels through the χ2 test, and receiver operating characteristic was used to analyze its diagnostic value in GC. In serum, i-tRF-AsnGTT has a low and stable expression level. It can differentiate between patients with gastric cancer and gastritis and healthy donors with better diagnostic efficacy. In combination with clinicopathological parameters, i-tRF-AsnGTT correlates with tumor differentiation; infiltration depth of tumors; tumor, node, metastasis stage; lymph node metastases; and neural/vascular invasion. Serum i-tRF-AsnGTT expression is low in GC patients. Serum from postoperative patients shows increased i-tRF-AsnGTT expression levels. Potentially, this could be used as a biomarker to help diagnose gastric cancer and monitor its prognosis.
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Affiliation(s)
- Xiaodan Jiang
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, China
| | - Xun Li
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, China
| | - Yang Li
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, China
| | - Yu Zhang
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, China
| | - Xinliang Gu
- General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China
| | - Wei Zong
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Xianjuan Shen
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Shaoqing Ju
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
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Yun H, Dong F, Wei X, Yan X, Zhang R, Zhang X, Wang Y. Role and value of the tumor microenvironment in the progression and treatment resistance of gastric cancer (Review). Oncol Rep 2025; 53:14. [PMID: 39611496 PMCID: PMC11622107 DOI: 10.3892/or.2024.8847] [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: 08/08/2024] [Accepted: 10/08/2024] [Indexed: 11/30/2024] Open
Abstract
Gastric cancer (GC) is characterized by a complex and heterogeneous tumor microenvironment (TME) that significantly influences disease progression and treatment outcomes. The tumor stroma, which is composed of a variety of cell types such as cancer‑associated fibroblasts, immune cells and vascular components, displays significant spatial and temporal diversity. These stromal elements engage in dynamic crosstalk with cancer cells, shaping their proliferative, invasive and metastatic potential. Furthermore, the TME is instrumental in facilitating resistance to traditional chemotherapy, specific treatments and immunotherapy strategies. Understanding the underlying mechanisms by which the GC microenvironment evolves and supports tumor growth and therapeutic resistance is critical for developing effective treatment strategies. The present review explores the latest progress in understanding the intricate interactions between cancer cells and their immediate environment in GC, highlighting the implications for disease pathogenesis and therapeutic interventions.
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Affiliation(s)
- Heng Yun
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, Gansu 730900, P.R. China
| | - Fangde Dong
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, Gansu 730900, P.R. China
| | - Xiaoqin Wei
- Department of Pain, The Second People's Hospital of Baiyin, Baiyin, Gansu 730900, P.R. China
| | - Xinyong Yan
- Department of Proctology, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, Gansu 730900, P.R. China
| | - Ronglong Zhang
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, Gansu 730900, P.R. China
| | - Xiuyu Zhang
- Department of Gastroenterology, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, Gansu 730900, P.R. China
| | - Yulin Wang
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, Gansu 730900, P.R. China
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Yuan W, Shi Y, Dai S, Deng M, Zhu K, Xu Y, Chen Z, Xu Z, Zhang T, Liang S. The role of MAPK pathway in gastric cancer: unveiling molecular crosstalk and therapeutic prospects. J Transl Med 2024; 22:1142. [PMID: 39719645 PMCID: PMC11667996 DOI: 10.1186/s12967-024-05998-8] [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: 09/22/2024] [Accepted: 12/15/2024] [Indexed: 12/26/2024] Open
Abstract
Gastric cancer remains a significant health burden globally, especially prevalent in Asian and European regions. Despite a notable decline in incidence in the United States and Western Europe over recent decades, the disease's persistence underscores the urgency for advanced research in its pathogenesis and treatment strategies. Central to this pursuit is the exploration of the mitogen-activated protein kinase (MAPK) pathway, a pivotal cellular mechanism implicated in the complex processes of gastric cancer development, including cellular proliferation, invasion, migration, and metastasis. The MAPK or extracellular signal-regulated kinase pathway serves as a crucial conduit for transmitting extracellular signals to elicit intracellular responses, with its signaling cascades subject to alterations due to genetic and epigenetic variations across various diseases, prominently cancer. This review delves into the intricate role of the MAPK signaling pathway in the pathogenesis of gastric cancer, drawing upon the most recent and critical studies that shed light on MAPK pathway alterations as a gateway to the disease. It highlights the pathway's involvement in Helicobacter pylori-mediated gastric carcinogenesis and the tumorigenic processes induced by the Epstein-Barr virus, showcasing the substantial influence of miRNAs and lncRNAs in modulating gastric cancer's biological properties through their interaction with the MAPK pathway. Furthermore, the review extends into the therapeutic arena, discussing the promising impacts of herbal medicines, MAPK pathway inhibitors, and immunosuppressants on mitigating gastric cancer's progression. Through an exhaustive examination of the MAPK pathway's multifaceted role in gastric cancer, from molecular crosstalks to therapeutic prospects, this review aspires to contribute to the ongoing efforts in understanding and combating this global health challenge, paving the way for novel therapeutic interventions and improved patient outcomes.
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Affiliation(s)
- Weiwei Yuan
- Department of Thyroid Surgery, Baoshan Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201999, China
| | - Yin Shi
- Department of Internal Medicine, Yiwu Maternity and Children Hospital, Yiwu, Zhejiang, China
| | - Shiping Dai
- Department of General Surgery, Wuwei City People's Hospital, No.256, West Street, Wuwei, 238300, China
| | - Mao Deng
- Department of General Surgery, Wuwei City People's Hospital, No.256, West Street, Wuwei, 238300, China
| | - Kai Zhu
- Department of General Surgery, Wuwei City People's Hospital, No.256, West Street, Wuwei, 238300, China
| | - Yuanmin Xu
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Zhangming Chen
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Zhou Xu
- Department of Thyroid Surgery, Baoshan Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201999, China.
| | - Tianlong Zhang
- Department of Critical Care Medicine, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China.
| | - Song Liang
- Department of General Surgery, The Lu'an Affiliated Hospital of Anhui Medical University, Lu'an People's Hospital, Lu'an, 237000, China.
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Heo YJ, Ahn S, Kang SY, Kim H, Min BH, Kim KM. Distinct genomic, transcriptomic, and immune profiles for tumor and non-tumor mucosal regions in early gastric cancer. Pathol Res Pract 2024; 266:155768. [PMID: 39719794 DOI: 10.1016/j.prp.2024.155768] [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: 11/03/2024] [Revised: 12/02/2024] [Accepted: 12/11/2024] [Indexed: 12/26/2024]
Abstract
In early gastric cancer, local recurrence develops after endoscopic resection by field cancerization. Understanding the nature of cancer-prone environments is important to establish effective strategies to prevent recurrence. We hypothesized that the molecular/immune profiles in non-tumor (cancer-prone) tissue differ according to the relative distance from the gastric tumor. For this purpose, we performed whole-exome and transcriptome sequencing of 16 early gastric cancer samples with paired non-tumor mucosa 1 cm (N1) and 3 cm (N3) away from the tumor. The whole exome sequencing revealed mutations in both the tumor and non-tumor mucosa. TTN was the most frequently altered gene in tumors (31 %) and was the second most frequently altered gene in N1 (25 %) samples; however, the mutation rate was significantly lower in N3 (12 %) samples (P = 0.0046). Moreover, the expression levels of TTN mRNA were higher in tumors than in the N1 and N3 samples and were significantly associated with TTN mutations (P = 0.04). TP53 mutations were mainly observed in tumors (50 %) and in 6.3 % of N1, with no mutation detected in N3 samples. Transcriptome sequencing revealed that the expression of the epithelial-mesenchymal transition signature, mesenchymal signature, and proliferation signature was increased in tumors, whereas programmed death-ligand 1 expression was decreased in the non-tumor mucosa. In the tumor, although the numbers of M0/M1 macrophages, neutrophils, and eosinophils increased, plasma cell numbers were markedly decreased compared to non-tumor mucosa. In conclusion, non-tumor mucosa at 1 cm and 3 cm from the tumor harbored different genomic, transcriptomic, and immune cell profiles. The non-tumor mucosa closer to the tumor (1 cm) exhibited similar genomic and transcriptomic features. These findings can offer clinical guidance for acquiring a safe horizontal margin in endoscopic resection for early gastric cancer.
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Affiliation(s)
- You Jeong Heo
- The Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Samsung Medical Center, Sungkyunkwan University School of Medicine and Neocella Inc., Seoul, Republic of Korea
| | - Soomin Ahn
- Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - So Young Kang
- Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Hyunjin Kim
- Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; Seegene Medical Foundation, Seoul, Republic of Korea
| | - Byung-Hoon Min
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
| | - Kyoung-Mee Kim
- Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; Center of Companion Diagnostics, Samsung Medical Center, Seoul, Republic of Korea.
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10
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Lu P, Xia M, Li J, Qi H, Wang H, Mao R. XRCC1 is linked to poor prognosis in adenocarcinoma of the esophagogastric junction after radiotherapy: transcriptome and alternative splicing events analysis. Clin Transl Oncol 2024:10.1007/s12094-024-03773-1. [PMID: 39527358 DOI: 10.1007/s12094-024-03773-1] [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: 05/14/2024] [Accepted: 10/18/2024] [Indexed: 11/16/2024]
Abstract
PURPOSE This study aimed to (i) investigate the relationship between X-ray repair cross-complementing protein 1 gene (XRCC1) and prognosis in patients with adenocarcinoma of the esophagogastric junction (AEG), and (ii) analyze the roles of XRCC1 in human gastric adenocarcinoma (AGS) cells following X-ray radiation. METHODS A total of 46 AEG patients were enrolled and examined for XRCC1 protein by immunohistochemistry. XRCC1 was knocked down in AGS cells by transfection, and AGS cells were subsequently exposed to 6 Gy of X-ray radiation. XRCC1 mRNA and protein expression was examined via quantitative real-time PCR (qRT-PCR) and Western blot analysis. The apoptosis of AGS cells was examined by flow cytometer. RNA-sequencing technology was used to identified differentially expressed genes and alternative splicing events following XRCC1 knockdown and radiation exposure. RESULTS XRCC1 positivity was strongly associated with distant metastasis, pathological tumor-node-metastasis (pTNM) classification, and radiotherapy resistance in AEG patients. A significant difference in progression-free survival was observed between AEG patients with low and high XRCC1 protein expression. The knockdown of XRCC1 notably exacerbated the effects of X-ray radiation on apoptosis in AGS cells. Additionally, X-ray radiation modified the expression of genes related to apoptosis and immune response in XRCC1-knockdown AGS cells. Furthermore, the generation of splice variants was influenced by XRCC1 knockdown in AGS cells. CONCLUSION XRCC1 may serve as a key oncogene that elucidates the role of alternative splicing events in the progression of AEG following X-ray treatment.
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Affiliation(s)
- Pengfei Lu
- Cancer Center, The First Affiliated Hospital of Xinjiang Medical University, No. 137 Liyushan Road, Urumqi, 830054, Xinjiang, China
| | - Min Xia
- Cancer Center, The First Affiliated Hospital of Xinjiang Medical University, No. 137 Liyushan Road, Urumqi, 830054, Xinjiang, China
| | - Juan Li
- Department of Infectious Diseases, The First People's Hospital of Urumqi, Urumqi, 830000, China
| | - Hongzhi Qi
- Cancer Center, The First Affiliated Hospital of Xinjiang Medical University, No. 137 Liyushan Road, Urumqi, 830054, Xinjiang, China
| | - Hui Wang
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, Xinjiang, China.
| | - Rui Mao
- Cancer Center, The First Affiliated Hospital of Xinjiang Medical University, No. 137 Liyushan Road, Urumqi, 830054, Xinjiang, China.
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Tobias J, Maglakelidze M, Andrić Z, Ryspayeva D, Bulat I, Nikolić I, Petrović Z, Chawla T, Nagarkar R, Garner-Spitzer E, Zielinski CC, Chong LMO, Nixon B, Ede NJ, Yavrom S, Kundi M, Wiedermann U. Phase II Trial of HER-Vaxx, a B-cell Peptide-Based Vaccine, in HER2-Overexpressing Advanced Gastric Cancer Patients Under Platinum-Based Chemotherapy (HERIZON). Clin Cancer Res 2024; 30:4044-4054. [PMID: 39028916 PMCID: PMC11393538 DOI: 10.1158/1078-0432.ccr-24-0742] [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: 03/14/2024] [Revised: 05/01/2024] [Accepted: 07/17/2024] [Indexed: 07/21/2024]
Abstract
PURPOSE A multicenter, randomized, open-label, phase II study (HERIZON; NCT02795988) was conducted to evaluate the clinical and immunologic efficacy of HER-Vaxx (IMU-131), a B-cell, peptide-based vaccine targeting HER2 overexpressed in 6% to 30% of gastroesophageal adenocarcinomas (GEA). PATIENTS AND METHODS Patients (n = 36) with GEA were treated with standard-of-care chemotherapy (n = 17) or HER-Vaxx plus chemotherapy (n = 19), using the recommended phase 2 dose for the vaccine. Overall survival (OS; primary endpoint), safety, progression-free survival (PFS), clinical response (secondary endpoints), and vaccine-induced HER2-specific antibody levels in serum and correlation with tumor response rates (exploratory endpoints) were investigated. RESULTS A 40% OS benefit [HR, 0.60; median OS, 13.9 months; 80% confidence interval (CI), 7.52-14.32] for patients treated with HER-Vaxx plus chemotherapy compared with OS of 8.31 months (80% CI, 6.01-9.59) in patients that received chemotherapy alone. A 20% PFS difference was obtained for the vaccination arm (HR, 0.80; 80% CI, 0.47, 1.38). No additional toxicity due to HER-Vaxx was observed. The vaccine-induced high levels of HER2-specific total IgG and IgG1 antibodies (P < 0.001 vs. controls) that significantly correlated with tumor reduction (IgG, P = 0.001; IgG1, P = 0.016), had a significant capacity in inhibiting phosphorylation of the intracellular HER2-signaling pathways, mediated antibody-dependent cellular cytotoxicity, and decreased immunosuppressive FOXP3+ regulatory T cells. CONCLUSIONS HER-Vaxx plus standard chemotherapy exhibits an excellent safety profile and improves OS. Furthermore, vaccine-induced immune response was significantly associated with reduced tumor size compared with standard-of-care chemotherapy. The presented vaccination approach may substitute for treatment with trastuzumab, upon unavailability or toxicity, based on further evidence of equivalent treatment efficacy.
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Affiliation(s)
| | | | - Zoran Andrić
- Clinical Hospital Center Bezanijska Kosa, Belgrade, Serbia.
| | | | - Iurie Bulat
- ARENSIA Exploratory Medicine Research Unit, Institute of Oncology, Chisinau, Republic of Moldova.
| | - Ivan Nikolić
- Oncology Institute of Vojvodina, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia.
| | | | | | | | | | - Christoph C. Zielinski
- Central European Cancer Center, Wiener Privatklinik, Central European Cooperative Oncology Group (CECOG), Vienna, Australia.
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12
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Yao J, Ma F, Shi D, Da M. ZFP1 is a biomarker related to poor prognosis and immunity in gastric cancer. Sci Rep 2024; 14:21233. [PMID: 39261568 PMCID: PMC11390720 DOI: 10.1038/s41598-024-72387-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: 04/12/2024] [Accepted: 09/06/2024] [Indexed: 09/13/2024] Open
Abstract
We aimed to determine the prognostic significance of ZFP1 in gastric cancer (GC), its role in the immune microenvironment, and its potential as a therapeutic target using data from The Cancer Genome Atlas (TCGA) database. ZFP1 overexpression was closely associated with tumour T stage and histological grade. Patients with GC and high ZFP1 expression had poor outcomes. Lower ZFP1 expression was associated with longer symptom-free intervals and disease-specific survival. Subgroup analyses of T3 and T4, N0, N1, and M0 patients showed that overall survival (OS), disease-specific survival, and progression-free interval (PFI) were worse in those with high ZFP1 expression. ZFP1 expression in GC was moderately to strongly positively correlated with the infiltration levels of effector central memory T cells and T helper cells and negatively correlated with Th17 cells and NK CD56bright cells. The lncRNA-miRNA-ZFP1 axis was predicted using a public database. CCK8, colony formation, and wound healing assays were conducted to investigate whether ZFP1 promoted the proliferation and migration of GC cells. Our study suggests that ZFP1 plays a key role in the prognosis, immune response, and progression of GC and is a significant factor in the diagnosis and treatment of this disease.
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Affiliation(s)
- Jibin Yao
- The First School of Clinical Medicine, Lanzhou University, No.204 Donggang West Road, Lanzhou, 730000, People's Republic of China
- Department of Surgical Oncology, Gansu Province Hospital, Lanzhou, People's Republic of China
| | - Fubin Ma
- Department of Surgery, Ningxia Medical University, Yinchuan, People's Republic of China
| | - Donghai Shi
- The First School of Clinical Medicine, Gansu University of Chinese Medicine, Lanzhou, People's Republic of China
| | - Mingxu Da
- The First School of Clinical Medicine, Lanzhou University, No.204 Donggang West Road, Lanzhou, 730000, People's Republic of China.
- Department of Surgical Oncology, Gansu Province Hospital, Lanzhou, People's Republic of China.
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Elimam H, Abdel Mageed SS, Hatawsh A, Moussa R, Radwan AF, Elfar N, Alhamshry NAA, Abd-Elmawla MA, Mohammed OA, Zaki MB, Doghish AS. Unraveling the influence of LncRNA in gastric cancer pathogenesis: a comprehensive review focus on signaling pathways interplay. Med Oncol 2024; 41:218. [PMID: 39103705 DOI: 10.1007/s12032-024-02455-w] [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: 05/12/2024] [Accepted: 07/16/2024] [Indexed: 08/07/2024]
Abstract
Gastric cancers (GCs) are among the most common and fatal malignancies in the world. Despite our increasing understanding of the molecular mechanisms underlying GC, further biomarkers are still needed for more in-depth examination, focused prognosis, and treatment. GC is one among the long non-coding RNAs, or lncRNAs, that have emerged as key regulators of the pathophysiology of cancer. This comprehensive review focuses on the diverse functions of long noncoding RNAs (lncRNAs) in the development of GC and their interactions with important intracellular signaling pathways. LncRNAs affect GC-related carcinogenic signaling cascades including pathways for EGFR, PI3K/AKT/mTOR, p53, Wnt/β-catenin, JAK/STAT, Hedgehog, NF-κB, and hypoxia-inducible factor. Dysregulated long non-coding RNA (lncRNA) expression has been associated with multiple characteristics of cancer, such as extended growth, apoptosis resistance, enhanced invasion and metastasis, angiogenesis, and therapy resistance. For instance, lncRNAs such as HOTAIR, MALAT1, and H19 promote the development of GC via altering these pathways. Beyond their main roles, GC lncRNAs exhibit potential as diagnostic and prognostic biomarkers. The overview discusses CRISPR/Cas9 genome-modifying methods, antisense oligonucleotides, small molecules, and RNA interference as potential therapeutic approaches to regulate the expression of long noncoding RNAs (lncRNAs). An in-depth discussion of the intricate functions that lncRNAs play in the development of the majority of stomach malignancies is provided in this review. It provides the groundwork for future translational research in lncRNA-based whole processes toward GC by highlighting their carcinogenic effects, regulatory roles in significant signaling cascades, and practical scientific uses as biomarkers and therapeutic targets.
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Affiliation(s)
- Hanan Elimam
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, 32897, Egypt.
| | - Sherif S Abdel Mageed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Abdulrahman Hatawsh
- Biotechnology School, Nile University, 26th of July Corridor, Sheikh Zayed City, 12588, Giza, Egypt
| | - Rewan Moussa
- Faculty of Medicine, Helwan University, Cairo, 11795, Egypt
| | - Abdullah F Radwan
- Department of Biochemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, 11829, Cairo, Egypt
| | - Nourhan Elfar
- School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, New Administrative Capital, 11578, Cairo, Egypt
- Egyptian Drug Authority (EDA), Ministry of Health and Population, Cairo, 11567, Egypt
| | - Nora A A Alhamshry
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, 32897, Egypt
| | - Mai A Abd-Elmawla
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Osama A Mohammed
- Department of Pharmacology, College of Medicine, University of Bisha, 61922, Bisha, Saudi Arabia
| | - Mohamed Bakr Zaki
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, 32897, Egypt
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt.
- Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231, Cairo, Egypt.
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14
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Zeng Z, Zhu Q. Progress and prospects of biomarker-based targeted therapy and immune checkpoint inhibitors in advanced gastric cancer. Front Oncol 2024; 14:1382183. [PMID: 38947886 PMCID: PMC11211377 DOI: 10.3389/fonc.2024.1382183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Accepted: 05/24/2024] [Indexed: 07/02/2024] Open
Abstract
Gastric cancer and gastroesophageal junction cancer represent the leading cause of tumor-related death worldwide. Although advances in immunotherapy and molecular targeted therapy have expanded treatment options, they have not significantly altered the prognosis for patients with unresectable or metastatic gastric cancer. A minority of patients, particularly those with PD-L1-positive, HER-2-positive, or MSI-high tumors, may benefit more from immune checkpoint inhibitors and/or HER-2-directed therapies in advanced stages. However, for those lacking specific targets and unique molecular features, conventional chemotherapy remains the only recommended effective and durable regimen. In this review, we summarize the roles of various signaling pathways and further investigate the available targets. Then, the current results of phase II/III clinical trials in advanced gastric cancer, along with the superiorities and limitations of the existing biomarkers, are specifically discussed. Finally, we will offer our insights in precision treatment pattern when encountering the substantial challenges.
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Affiliation(s)
| | - Qing Zhu
- Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, China
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15
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Wang L, Gong WH. Predictive model using four ferroptosis-related genes accurately predicts gastric cancer prognosis. World J Gastrointest Oncol 2024; 16:2018-2037. [PMID: 38764813 PMCID: PMC11099433 DOI: 10.4251/wjgo.v16.i5.2018] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Revised: 01/31/2024] [Accepted: 03/08/2024] [Indexed: 05/09/2024] Open
Abstract
BACKGROUND Gastric cancer (GC) is a common malignancy of the digestive system. According to global 2018 cancer data, GC has the fifth-highest incidence and the third-highest fatality rate among malignant tumors. More than 60% of GC are linked to infection with Helicobacter pylori (H. pylori), a gram-negative, active, microaerophilic, and helical bacterium. This parasite induces GC by producing toxic factors, such as cytotoxin-related gene A, vacuolar cytotoxin A, and outer membrane proteins. Ferroptosis, or iron-dependent programmed cell death, has been linked to GC, although there has been little research on the link between H. pylori infection-related GC and ferroptosis. AIM To identify coregulated differentially expressed genes among ferroptosis-related genes (FRGs) in GC patients and develop a ferroptosis-related prognostic model with discrimination ability. METHODS Gene expression profiles of GC patients and those with H. pylori-associated GC were obtained from The Cancer Genome Atlas and Gene Expression Omnibus (GEO) databases. The FRGs were acquired from the FerrDb database. A ferroptosis-related gene prognostic index (FRGPI) was created using least absolute shrinkage and selection operator-Cox regression. The predictive ability of the FRGPI was validated in the GEO cohort. Finally, we verified the expression of the hub genes and the activity of the ferroptosis inducer FIN56 in GC cell lines and tissues. RESULTS Four hub genes were identified (NOX4, MTCH1, GABARAPL2, and SLC2A3) and shown to accurately predict GC and H. pylori-associated GC. The FRGPI based on the hub genes could independently predict GC patient survival; GC patients in the high-risk group had considerably worse overall survival than did those in the low-risk group. The FRGPI was a significant predictor of GC prognosis and was strongly correlated with disease progression. Moreover, the gene expression levels of common immune checkpoint proteins dramatically increased in the high-risk subgroup of the FRGPI cohort. The hub genes were also confirmed to be highly overexpressed in GC cell lines and tissues and were found to be primarily localized at the cell membrane. The ferroptosis inducer FIN56 inhibited GC cell proliferation in a dose-dependent manner. CONCLUSION In this study, we developed a predictive model based on four FRGs that can accurately predict the prognosis of GC patients and the efficacy of immunotherapy in this population.
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Affiliation(s)
- Li Wang
- Department of Emergency, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Wei-Hua Gong
- Department of Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou 310052, Zhejiang Province, China
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16
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Gu Y, Chen G, Ning X. Homeobox Protein BarH-like 1 Promotes Gastric Cancer Progression by Activating Coiled-Coil Domain-Containing Protein 178. Dig Dis Sci 2024; 69:1182-1199. [PMID: 38358459 DOI: 10.1007/s10620-024-08312-0] [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: 09/27/2023] [Accepted: 01/22/2024] [Indexed: 02/16/2024]
Abstract
BACKGROUND Coiled-coil domain-containing protein 178 (CCDC178) has been revealed to exert metastasis-promoting properties in hepatocellular carcinoma, whereas its function in gastric cancer (GC) has not been fully understood. AIMS We evaluated its role in GC and the molecular mechanism. METHODS The differentially expressed genes in datasets related to GC metastasis were intersected with survival-related genes in GC, followed by prognostic significance prediction. Loss- and gain-of-function assays were conducted to examine the involvement of CCDC178, Homeobox protein BarH-like 1 (BARX1), and the extracellular signal-regulated kinase (ERK) pathway in GC cell malignant phenotype and the polarization of tumor-associated macrophages (TAM). The corresponding functions were verified in the in vivo animal experiment. RESULTS High CCDC178 expression predicted a poor prognosis for GC patients, and CCDC178 correlated significantly with macrophage infiltration in GC tissues. CCDC178 activated the ERK pathway in GC. Silencing of CCDC178 reduced the colony formation, migratory and invasive potential of GC cells, and the M2-like polarization of TAM, which was reversed by TBHQ (an ERK activator). BARX1 bound to the promoter region of CCDC178, thus inducing its transcriptional level. Silencing of BARX1 suppressed the M2-type polarization of TAM in vitro and in vivo, and CCDC178 mitigated the repressing role of BARX1 knockdown. CONCLUSIONS BARX1 activates the transcription of CCDC178 to induce the ERK pathway, thereby supporting macrophage recruitment and M2-like polarization in GC.
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Affiliation(s)
- Yue Gu
- Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, No. 37, Yiyuan Street, Nangang District, 150001, Harbin, Heilongjiang, People's Republic of China.
| | - Gang Chen
- Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, No. 37, Yiyuan Street, Nangang District, 150001, Harbin, Heilongjiang, People's Republic of China
| | - Xinwei Ning
- Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, No. 37, Yiyuan Street, Nangang District, 150001, Harbin, Heilongjiang, People's Republic of China
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Yang J, Shu G, Chen T, Dong A, Dong C, Li W, Sun X, Zhou Y, Li D, Zhou J. ESM1 Interacts with c-Met to Promote Gastric Cancer Peritoneal Metastasis by Inducing Angiogenesis. Cancers (Basel) 2023; 16:194. [PMID: 38201620 PMCID: PMC10778290 DOI: 10.3390/cancers16010194] [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: 12/04/2023] [Revised: 12/22/2023] [Accepted: 12/27/2023] [Indexed: 01/12/2024] Open
Abstract
The peritoneum is the most common metastatic site of advanced gastric cancer and is associated with extremely poor prognosis. Endothelial-specific molecule 1 (ESM1) was found to be significantly associated with gastric cancer peritoneal metastasis (GCPM); however, the biological functions and molecular mechanisms of ESM1 in regulating GCPM remain unclear. Herein, we demonstrated that ESM1 expression was significantly upregulated in gastric cancer tissues and positively correlated with platelet endothelial cell adhesion molecule-1 (CD31) levels. Moreover, clinical validation, in in vitro and in vivo experiments, confirmed that ESM1 promoted gastric cancer angiogenesis, eventually promoting gastric cancer peritoneal metastasis. Mechanistically, ESM1 promoted tumor angiogenesis by binding to c-Met on the vascular endothelial cell membrane. In addition, our results confirmed that ESM1 upregulated VEGFA, HIF1α, and MMP9 expression and induced angiogenesis by activating the MAPK/ERK pathway. In conclusion, our findings identified the role of ESM1 in gastric cancer angiogenesis and GCPM, thus providing insights into the diagnosis and treatment of advanced gastric cancer.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Dongbao Li
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006, China; (J.Y.); (G.S.); (T.C.); (A.D.); (C.D.); (W.L.); (X.S.); (Y.Z.)
| | - Jin Zhou
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006, China; (J.Y.); (G.S.); (T.C.); (A.D.); (C.D.); (W.L.); (X.S.); (Y.Z.)
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Cheng W, Liao Y, Xie Y, Wang Q, Li L, Chen Y, Zhao Y, Zhou J. Helicobacter pylori-induced fibroblast-derived Serpin E1 promotes gastric cancer growth and peritoneal dissemination through p38 MAPK/VEGFA-mediated angiogenesis. Cancer Cell Int 2023; 23:326. [PMID: 38104099 PMCID: PMC10725580 DOI: 10.1186/s12935-023-03177-1] [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: 09/04/2023] [Accepted: 12/07/2023] [Indexed: 12/19/2023] Open
Abstract
BACKGROUND Fibroblasts, especially cancer-associated fibroblasts (CAFs), represent the predominant stromal cell population in the tumor microenvironment and have an important function in tumorigenesis by interacting with tumor cells. However, their interaction remains elusive in an inflammatory tumor microenvironment induced by Helicobacter pylori (H. pylori). METHODS The expression of Serpin family E member 1 (Serpin E1) was measured in fibroblasts with or without H. pylori infection, and primary gastric cancer (GC) cells. Serpin E1 knockdown and overexpression fibroblasts were generated using Serpin E1 siRNA or lentivirus carrying Serpin E1. Co-culture models of fibroblasts and GC cells or human umbilical vein endothelial cells (HUVECs) were established with direct contact or the Transwell system. In vitro functional experiments and in vivo tumorigenesis assay were employed to study the malignant behaviors of GC cells interacting with fibroblasts. ELISA was used for quantifying the levels of Serpin E1 and VEGFA in the culture supernatant. The tube formation capacity of HUVECs was assessed using a tube formation assay. Recombinant human Serpin E1 (recSerpin E1), anti-Serpin E1 antibody, and a MAPK pathway inhibitor were utilized to treat HUVECs for elucidating the underlying molecular mechanisms. RESULTS Serpin E1 was predominantly expressed in gastric CAFs. H. pylori infection significantly enhanced the expression and secretion of Serpin E1 by CAFs. Both fibroblast-derived Serpin E1 and recSerpin E1 enhanced the growth, invasion, and migration of GC cells, along with increased VEGFA expression and tube formation in HUVECs. Furthermore, the co-inoculation of GC cells and fibroblasts overexpressing Serpin E1 triggered the expression of Serpin E1 in cancer cells, which facilitated together xenograft tumor growth and peritoneal dissemination of GC cells in nude mice, with an increased expression of Ki67, Serpin E1, CD31 and/or VEGFA. These processes may be mediated by Serpin E1-induced migration and p38 MAPK/VEGFA-mediated angiogenesis of HUVECs. CONCLUSION H. pylori infection induces Serpin E1 expression in fibroblasts, subsequently triggering its expression in GC cells through their interaction. Serpin E1 derived from these cells promotes the migration and p38 MAPK/VEGFA-mediated angiogenesis of HUVECs, thereby facilitating GC growth and peritoneal metastasis. Targeting Serpin E1 signaling is a potential therapy strategy for H. pylori-induced GC.
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Affiliation(s)
- Wei Cheng
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang, China
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Yonghui Liao
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang, China
- Prenatal Diagnosis Center of Qianxinan People's Hospital, Xingyi, China
| | - Yuan Xie
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang, China
| | - Qinrong Wang
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang, China
| | - Leilei Li
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang, China
| | - Yuanjia Chen
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang, China
| | - Yan Zhao
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang, China.
| | - Jianjiang Zhou
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang, China.
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Liao Y, Gui Y, Li Q, An J, Wang D. The signaling pathways and targets of natural products from traditional Chinese medicine treating gastric cancer provide new candidate therapeutic strategies. Biochim Biophys Acta Rev Cancer 2023; 1878:188998. [PMID: 37858623 DOI: 10.1016/j.bbcan.2023.188998] [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: 07/24/2023] [Revised: 09/26/2023] [Accepted: 10/08/2023] [Indexed: 10/21/2023]
Abstract
Gastric cancer (GC) is one of the severe malignancies with high incidence and mortality, especially in Eastern Asian countries. Significant advancements have been made in diagnosing and treating GC over the past few decades, resulting in tremendous improvements in patient survival. In recent years, traditional Chinese medicine (TCM) has garnered considerable attention as an alternative therapeutic approach for GC due to its multicomponent and multitarget characteristics. Consequently, natural products found in TCM have attracted researchers' attention, as growing evidence suggests that these natural products can impede GC progression by regulating various biological processes. Nevertheless, their molecular mechanisms are not systematically uncovered. Here, we review the major signaling pathways involved in GC development. Additionally, clinical GC samples were analyzed. Moreover, the anti-GC effects of natural products, their underlying mechanisms and potential targets were summarized. These summaries are intended to facilitate further relevant research, and accelerate the clinical applications of natural products in GC treatment.
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Affiliation(s)
- Yile Liao
- School of Basic Medical Sciences, State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yu Gui
- Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan 610041, China
| | - Qingzhou Li
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Jun An
- School of Basic Medical Sciences, State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Dong Wang
- School of Basic Medical Sciences, State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
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20
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Cao Y, Xiao J, Sheng N, Qu Y, Wang Z, Sun C, Mu X, Huang Z, Li X. X-LDA: An interpretable and knowledge-informed heterogeneous graph learning framework for LncRNA-disease association prediction. Comput Biol Med 2023; 167:107634. [PMID: 39491920 DOI: 10.1016/j.compbiomed.2023.107634] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 10/06/2023] [Accepted: 10/23/2023] [Indexed: 11/05/2024]
Abstract
The identification of disease-related long noncoding RNAs (lncRNAs) is beneficial to unravel the intricacies of gene expression regulation and epigenetic signatures. Computational methods provide a cost-effective means to explore lncRNA-disease associations (LDAs). However, these methods often lack interpretability, leaving their predictions less convincing to biological and medical researchers. We propose an interpretable and knowledge-informed heterogeneous graph learning framework based on graph patch convolution and integrated gradients to predict LDAs and provides intuitive explanations for its predictions, called X-LDA. The heterogeneous graph is the foundation of the predictions of LDAs, we construct the knowledge-informed heterogeneous graph including LDAs drawn from biological experiments, lncRNA similarities rooted in gene sequences, disease similarities constructed based on disease categorizations. To integrate diverse biological premises and facilitate interpretability, we define nine distinct graph patch types, which encapsulate essential topological relationships within lncRNA-disease node pairs. X-LDA is designed to employ parameter sharing and multi-convolution kernels to grasp common and multiple perspectives of the graph patches, respectively. This approach culminates in the fusion of various semantic information into context embeddings. These post-hoc explanations hinge on graph patch features and integrated gradients, shedding light on the underlying factors driving predictions. Cross validation experiment on the dataset curated from databases and literatures demonstrates that the superior performance of X-LDA in comparison to nine state-of-the-art methods of three categories. X-LDA achieves a larger average area under the receiver operating curve 0.9891 (by at least 6.68%), and a larger average area under the precision-recall curve 0.7907 (by at least 23.2%) than competitive methods. The results of our well-designed ablation and interpretability experiments and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis demonstrate X-LDA's robustness, learnability, predictability, and interpretability. The applicability of X-LDA is also demonstrated through a case study involving the investigation of associated lncRNAs in prostate cancer, colorectal cancer, and breast cancer.
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Affiliation(s)
- Yangkun Cao
- School of Artificial Intelligence, Jilin University, Changchun, 130012, China
| | - Jun Xiao
- College of Computer Science and Technology, Jilin University, Changchun, 130012, China
| | - Nan Sheng
- College of Computer Science and Technology, Jilin University, Changchun, 130012, China
| | - Yinwei Qu
- College of Computer Science and Technology, Jilin University, Changchun, 130012, China
| | - Zhihang Wang
- College of Computer Science and Technology, Jilin University, Changchun, 130012, China
| | - Chang Sun
- College of Computer Science, Nankai University, Tianjin, 300071, China
| | - Xuechen Mu
- School of Mathematics, Jilin University, Changchun, 130012, China
| | - Zhenyu Huang
- College of Computer Science and Technology, Jilin University, Changchun, 130012, China.
| | - Xuan Li
- College of Computer Science and Technology, Jilin University, Changchun, 130012, China.
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21
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Xu M, Lin J, Yang S, Yao J, Chen M, Feng J, Zhang L, Zhou L, Zhang J, Qin Q. Epstein-Barr virus-encoded miR-BART11-3p modulates the DUSP6-MAPK axis to promote gastric cancer cell proliferation and metastasis. J Virol 2023; 97:e0088123. [PMID: 37681959 PMCID: PMC10537804 DOI: 10.1128/jvi.00881-23] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 07/02/2023] [Indexed: 09/09/2023] Open
Abstract
Epstein-Barr virus (EBV)-encoded miRNAs within the BamHI-A rightward transcript (BART) region are abundantly expressed in EBV-associated gastric cancer (EBVaGC), suggesting that they play roles in tumorigenesis. However, how these viral miRNAs contribute to the development of EBVaGC remains largely obscure. In this study, we found that EBV-encoded miR-BART11-3p targets 3' -UTR of dual-specificity phosphatase 6 (DUSP6) mRNA to upregulate ERK phosphorylation and downregulate JNK and p38 phosphorylation. By doing so, miR-BART11-3p promotes gastric cancer (GC) cell proliferation, migration, and invasion in vitro, and facilitates tumor growth in vivo. Restoration of DUSP6 expression reverses the tumor-promoting activity of miR-BART11-3p in AGS GC cells. Consistently, knockdown of DUSP6 ablates the antitumor effects of miR-BART11-3p inhibitors in EBV-positive GC cells. Furthermore, blocking ERK phosphorylation with trametinib inhibited the proliferation, migration, and invasion of miR-BART11-3p-expressing AGS cells. Administration of a miR-BART11-3p antagomir reduced the growth of EBV-positive xenograft tumors. Together, these findings reveal a novel mechanism by which EBV dysregulates MAPK pathways through an EBV-encoded microRNA to promote the development and progression of EBVaGC, which may be harnessed to develop new therapeutics to treat EBVaGC. IMPORTANCE The Epstein-Barr virus (EBV) is the first human tumor virus found to encode miRNAs, which within the BART region have been detected abundantly in EBV-associated gastric cancer (EBVaGC) and play various roles in promoting tumorigenesis. In our study, we observed that EBV-miR-BART11-3p promotes cell proliferation and induces migration and invasion in GC. Interestingly, we showed that miR-BART11-3p upregulates p-ERK and downregulates p-JNK and p-p38 by directly targeting 3'-UTR of dual-specificity phosphatase 6 (DUSP6). Restoration of DUSP6 rescues the effects generated by miR-BART11-3p in GC cells, and blocking ERK phosphorylation with Trametinib augments JNK and p38 phosphorylation and inhibits the effects of miR-BART11-3p-expressing AGS cells, suggesting that miR-BART11-3p promotes cell proliferation, migration, and invasion by modulating DUSP6-MAPK axis in EBVaGC. The findings presented in this study provide new mechanisms into the tumorigenesis in EBVaGC and new avenues for the development of therapeutic strategies to combat EBVaGC targeting miR-BART11-3p or phospho-ERK.
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Affiliation(s)
- Mingqian Xu
- Laboratory of Human Virology and Oncology, Shantou University Medical College, Shantou, Guangdong Province, China
| | - Jiarui Lin
- Department of Gastrointestinal Surgery, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Shuaibing Yang
- Laboratory of Human Virology and Oncology, Shantou University Medical College, Shantou, Guangdong Province, China
| | - Jiahu Yao
- Laboratory of Human Virology and Oncology, Shantou University Medical College, Shantou, Guangdong Province, China
| | - Meiyang Chen
- Laboratory of Human Virology and Oncology, Shantou University Medical College, Shantou, Guangdong Province, China
| | - Jinfu Feng
- Laboratory of Human Virology and Oncology, Shantou University Medical College, Shantou, Guangdong Province, China
| | - Liang Zhang
- Laboratory of Human Virology and Oncology, Shantou University Medical College, Shantou, Guangdong Province, China
| | - Li Zhou
- Department of Gynecologic Oncology, Cancer Hospital of Shantou University Medical College, Shantou, China
| | - Junjie Zhang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, State Key Laboratory of Virology, Medical Research Institute, Wuhan University, Wuhan, China
- Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China
| | - Qingsong Qin
- Laboratory of Human Virology and Oncology, Shantou University Medical College, Shantou, Guangdong Province, China
- International Science and Technology Collaboration Center for Emerging Infectious Diseases, Shantou University Medical College, Shantou, Guangdong, China
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22
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Fukuoka S, Koga Y, Yamauchi M, Koganemaru S, Yasunaga M, Shitara K, Doi T, Yoshino T, Kuronita T, Elenbaas B, Wahra P, Zhang H, Crowley L, Jenkins MH, Clark A, Kojima T. p70S6K/Akt dual inhibitor DIACC3010 is efficacious in preclinical models of gastric cancer alone and in combination with trastuzumab. Sci Rep 2023; 13:16017. [PMID: 37749105 PMCID: PMC10520030 DOI: 10.1038/s41598-023-40612-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 08/14/2023] [Indexed: 09/27/2023] Open
Abstract
The PI3K-Akt-mTOR (PAM) pathway is implicated in tumor progression in many tumor types, including metastatic gastric cancer (GC). The initial promise of PAM inhibitors has been unrealized in the clinic, presumably due, in part, to the up-regulation of Akt signaling that occurs when the pathway is inhibited. Here we present that DIACC3010 (formerly M2698), an inhibitor of two nodes in the PAM pathway, p70S6K and Akt 1/3, blocks the pathway in in vitro and in vivo preclinical models of GC while providing a mechanism that inhibits signaling from subsequent Akt up-regulation. Utilizing GC cell lines and xenograft models, we identified potential markers of DIACC3010-sensitivity in Her2-negative tumors, i.e., PIK3CA mutations, low basal pERK, and a group of differentially expressed genes (DEGs). The combination of DIACC3010 and trastuzumab was evaluated in Her2-positive cell lines and models. Potential biomarkers for the synergistic efficacy of the combination of DIACC3010 + trastuzumab also included DEGs as well as a lack of up-regulation of pERK. Of 27 GC patient-derived xenograft (PDX) models tested in BALB/c nu/nu mice, 59% were sensitive to DIACC3010 + trastuzumab. Of the 21 HER2-negative PDX models, DIACC3010 significantly inhibited the growth of 38%. Altogether, these results provide a path forward to validate the potential biomarkers of DIACC3010 sensitivity in GC and support clinical evaluation of DIACC3010 monotherapy and combination with trastuzumab in patients with HER2- negative and positive advanced GCs, respectively.
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Affiliation(s)
- Shota Fukuoka
- Division of Experimental Therapeutics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Yoshikatsu Koga
- Division of Developmental Therapeutics, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center Hospital, Kashiwa, Japan
| | - Mayumi Yamauchi
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Shigehiro Koganemaru
- Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan
| | - Masahiro Yasunaga
- Division of Developmental Therapeutics, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center Hospital, Kashiwa, Japan
| | - Kohei Shitara
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Toshihiko Doi
- Division of Experimental Therapeutics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
- Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Toshio Kuronita
- Merck Biopharma Co., Ltd. (an affiliate of Merck KGaA), Tokyo, Japan
| | - Brian Elenbaas
- EMD Serono Research & Development Institute, Inc. (an affiliate of Merck KGaA), Billerica, MA, USA
| | - Pamela Wahra
- EMD Serono Research & Development Institute, Inc. (an affiliate of Merck KGaA), Billerica, MA, USA
| | - Hong Zhang
- EMD Serono Research & Development Institute, Inc. (an affiliate of Merck KGaA), Billerica, MA, USA
| | - Lindsey Crowley
- EMD Serono Research & Development Institute, Inc. (an affiliate of Merck KGaA), Billerica, MA, USA
| | - Molly H Jenkins
- EMD Serono Research & Development Institute, Inc. (an affiliate of Merck KGaA), Billerica, MA, USA
| | - Anderson Clark
- EMD Serono Research & Development Institute, Inc. (an affiliate of Merck KGaA), Billerica, MA, USA
| | - Takashi Kojima
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
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23
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Biagioni A, Peri S, Versienti G, Fiorillo C, Becatti M, Magnelli L, Papucci L. Gastric Cancer Vascularization and the Contribution of Reactive Oxygen Species. Biomolecules 2023; 13:886. [PMID: 37371466 DOI: 10.3390/biom13060886] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 05/19/2023] [Accepted: 05/24/2023] [Indexed: 06/29/2023] Open
Abstract
Blood vessels are the most important way for cancer cells to survive and diffuse in the body, metastasizing distant organs. During the process of tumor expansion, the neoplastic mass progressively induces modifications in the microenvironment due to its uncontrolled growth, generating a hypoxic and low pH milieu with high fluid pressure and low nutrients concentration. In such a particular condition, reactive oxygen species play a fundamental role, enhancing tumor proliferation and migration, inducing a glycolytic phenotype and promoting angiogenesis. Indeed, to reach new sources of oxygen and metabolites, highly aggressive cancer cells might produce a new abnormal network of vessels independently from endothelial cells, a process called vasculogenic mimicry. Even though many molecular markers and mechanisms, especially in gastric cancer, are still unclear, the formation of such intricate, leaky and abnormal vessel networks is closely associated with patients' poor prognosis, and therefore finding new pharmaceutical solutions to be applied along with canonical chemotherapies in order to control and normalize the formation of such networks is urgent.
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Affiliation(s)
- Alessio Biagioni
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50134 Florence, Italy
| | - Sara Peri
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Giampaolo Versienti
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50134 Florence, Italy
| | - Claudia Fiorillo
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50134 Florence, Italy
| | - Matteo Becatti
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50134 Florence, Italy
| | - Lucia Magnelli
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50134 Florence, Italy
| | - Laura Papucci
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50134 Florence, Italy
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24
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Development and Experimental Validation of a Novel Prognostic Signature for Gastric Cancer. Cancers (Basel) 2023; 15:cancers15051610. [PMID: 36900401 PMCID: PMC10000504 DOI: 10.3390/cancers15051610] [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: 11/11/2022] [Revised: 01/18/2023] [Accepted: 02/16/2023] [Indexed: 03/08/2023] Open
Abstract
BACKGROUND Gastric cancer is a malignant tumor with high morbidity and mortality. Therefore, the accurate recognition of prognostic molecular markers is the key to improving treatment efficacy and prognosis. METHODS In this study, we developed a stable and robust signature through a series of processes using machine-learning approaches. This PRGS was further experimentally validated in clinical samples and a gastric cancer cell line. RESULTS The PRGS is an independent risk factor for overall survival that performs reliably and has a robust utility. Notably, PRGS proteins promote cancer cell proliferation by regulating the cell cycle. Besides, the high-risk group displayed a lower tumor purity, higher immune cell infiltration, and lower oncogenic mutation than the low-PRGS group. CONCLUSIONS This PRGS could be a powerful and robust tool to improve clinical outcomes for individual gastric cancer patients.
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25
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Wang Y, Guo H, He F. Circadian disruption: from mouse models to molecular mechanisms and cancer therapeutic targets. Cancer Metastasis Rev 2023; 42:297-322. [PMID: 36513953 DOI: 10.1007/s10555-022-10072-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 11/25/2022] [Indexed: 12/15/2022]
Abstract
The circadian clock is a timekeeping system for numerous biological rhythms that contribute to the regulation of numerous homeostatic processes in humans. Disruption of circadian rhythms influences physiology and behavior and is associated with adverse health outcomes, especially cancer. However, the underlying molecular mechanisms of circadian disruption-associated cancer initiation and development remain unclear. It is essential to construct good circadian disruption models to uncover and validate the detailed molecular clock framework of circadian disruption in cancer development and progression. Mouse models are the most widely used in circadian studies due to their relatively small size, fast reproduction cycle, easy genome manipulation, and economic practicality. Here, we reviewed the current mouse models of circadian disruption, including suprachiasmatic nuclei destruction, genetic engineering, light disruption, sleep deprivation, and other lifestyle factors in our understanding of the crosstalk between circadian rhythms and oncogenic signaling, as well as the molecular mechanisms of circadian disruption that promotes cancer growth. We focused on the discoveries made with the nocturnal mouse, diurnal human being, and cell culture and provided several circadian rhythm-based cancer therapeutic strategies.
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Affiliation(s)
- Yu Wang
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Haidong Guo
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
- Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Feng He
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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26
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Ji D, Feng H, Hou L, Xu Y, Wang X, Zhao W, Pei H, Zhao Q, Chen Q, Tan G. LINC00511, a future star for the diagnosis and therapy of digestive system malignant tumors. Pathol Res Pract 2023; 244:154382. [PMID: 36868095 DOI: 10.1016/j.prp.2023.154382] [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: 09/27/2022] [Revised: 02/17/2023] [Accepted: 02/18/2023] [Indexed: 02/22/2023]
Abstract
The digestive system malignant tumors (DSMTs), mainly consist of digestive tract and digestive gland tumors, become an inescapable culprit to hazard human health worldwide. Due to the huge hysteresis in the cognitive theories of DSMTs occurrence and progression, advances in medical technology have not improved the prognosis. Therefore, more studies on a variety of tumor-associated molecular biomarkers and more detailed disclosure on potential regulatory networks are urgently needed to facilitate the diagnostic and therapeutic strategies of DSMTs. With the development of cancer bioinformatics, a special type of endogenous RNA involved in multi-level cellular function regulation rather than encoding protein, is categorized as non-coding RNAs (ncRNAs) and becomes a hotspot issue in oncology. Among them, long non-coding RNAs (lncRNAs), transcription length > 200 nt, show obvious superiority in both research quantity and dimension compared to microRNAs (miRNAs) and circular RNAs (circRNAs). As a recently discovered lncRNA, LINC00511 has been confirmed to be closely associated with DSMTs and might be exploited as a novel biomarker. In the present review, the comprehensive studies of LINC00511 in DSMTs are summarized, as well as the underlying molecular regulatory networks. In addition, deficiencies in researches are point out and discussed. The Cumulative oncology studies provide a fully credible theoretical basis for identifying the regulatory role of LINC00511 in human DSMTs. LINC00511, proved to be an oncogene in DSMTs, might be defined as a potential biomarker for diagnosis and prognosis evaluation, as well as a rare therapeutic target.
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Affiliation(s)
- Daolin Ji
- Department of Hepatopancreatobiliary Surgery, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, China
| | - Haonan Feng
- Department of Hepatopancreatobiliary Surgery, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Li Hou
- Department of Hepatopancreatobiliary Surgery, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Yi Xu
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital, Harbin Medical University, Harbin, China; Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Xiuhong Wang
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China
| | - Weili Zhao
- Department of Postgraduate Management, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Hongyu Pei
- Department of Hepatopancreatobiliary Surgery, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Qi Zhao
- Department of Hepatopancreatobiliary Surgery, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Qian Chen
- Department of Hepatopancreatobiliary Surgery, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Gang Tan
- Department of Hepatopancreatobiliary Surgery, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, China.
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27
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Ghafari F, Alizadeh AM, Agah S, Irani S, Mokhtare M. Insulin-like growth factor 1 serum levels in different stages of gastric cancer and their association with Helicobacter pylori status. Peptides 2022; 158:170892. [PMID: 36240982 DOI: 10.1016/j.peptides.2022.170892] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Revised: 10/08/2022] [Accepted: 10/08/2022] [Indexed: 11/05/2022]
Abstract
High serum insulin-like growth factor 1 (IGF-1) and positive Helicobacter pylori (H. pylori) may increase the risk of gastric cancer (GC). We aimed to investigate IGF-1 serum levels in different stages of GC patients and their association with H. pylori status. A total of 90 participants, including 60 GC patients and 30 noncancerous (NC) individuals, were included in the present study. IGF-1 serum levels and candidate proteins were assessed using enzyme-linked immunosorbent and immunohistochemistry techniques. Likewise, Giemsa staining was applied to detect H. pylori infection. The candidate genes' expression, including IGF-1R, PI3KCA, AKT1, mTOR1, KRAS, BRAF, and ERK1, was also evaluated by a real-time PCR assay. The results of advanced GC stages indicated a significantly high IHC score for IGF-1R and phosphorylated AKT, mTOR, and ERK proteins compared to the early stages. Moreover, IGF-1 serum levels and the expression of candidate genes were considerably increased in the advanced GC patients compared to the early stages and the positive H. pylori status compared to the negative H. pylori status (P < 0.05). As a result, high IGF-1 serum levels and positive H. pylori status may be correlated with gastric tumor progression, and the inhibition of IGF-1 and the eradication of H. pylori infection might be new therapeutic targets in GC patients.
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Affiliation(s)
- Fatemeh Ghafari
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Ali Mohammad Alizadeh
- Cancer Research Center, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Shahram Agah
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Shiva Irani
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Marjan Mokhtare
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
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28
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Barakeh DH, Alsolme E, Alqubaishi F, Almutairi A, Alhabeeb L, Al Abdulmohsen S, Almohsen SS, Alayed D, AlAnazi SR, AlZahrani M, Binowayn AM, AlOtaibi SS, Alkhureeb FA, Al Shakweer W, Al-Hindi H, Alassiri A, Robinson HA, Abedalthagafi M. Clinicopathologic and genomic characterizations of brain metastases using a comprehensive genomic panel. Front Med (Lausanne) 2022; 9:947456. [PMID: 36507516 PMCID: PMC9729258 DOI: 10.3389/fmed.2022.947456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 11/03/2022] [Indexed: 11/25/2022] Open
Abstract
Central nervous system (CNS) metastasis is the most common brain tumor type in adults. Compared to their primary tumors, these metastases undergo a variety of genetic changes to be able to survive and thrive in the complex tissue microenvironment of the brain. In clinical settings, the majority of traditional chemotherapies have shown limited efficacy against CNS metastases. However, the discovery of potential driver mutations, and the development of drugs specifically targeting affected signaling pathways, could change the treatment landscape of CNS metastasis. Genetic studies of brain tumors have so far focused mainly on common cancers in western populations. In this study, we performed Next Generation Sequencing (NGS) on 50 pairs of primary tumors, including but not limited to colorectal, breast, renal and thyroid tumors, along with their brain metastatic tumor tissue counterparts, from three different local tertiary centers in Saudi Arabia. We identified potentially clinically relevant mutations in brain metastases that were not detected in corresponding primary tumors, including mutations in the PI3K, CDK, and MAPK pathways. These data highlight the differences between primary cancers and brain metastases and the importance of acquiring and analyzing brain metastatic samples for further clinical management.
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Affiliation(s)
- Duna H. Barakeh
- Department of Pathology, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia,Genomics Research Department, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Ebtehal Alsolme
- Genomics Research Department, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Fatimah Alqubaishi
- Genomics Research Department, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Amal Almutairi
- Genomics Research Department, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Lamees Alhabeeb
- Genomics Research Department, King Fahad Medical City, Riyadh, Saudi Arabia,Department of Pathology, King Fahad Medical City, Riyadh, Saudi Arabia
| | | | - Shahd S. Almohsen
- Department of Pathology and Laboratory Medicine, King Abdulaziz Medical City, Riyadh, Saudi Arabia
| | - Doaa Alayed
- Department of Pathology, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia
| | | | - Malak AlZahrani
- Department of Pathology, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia
| | | | - Sarah S. AlOtaibi
- Genomics Research Department, King Fahad Medical City, Riyadh, Saudi Arabia
| | | | - Wafa Al Shakweer
- Department of Pathology, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Hindi Al-Hindi
- Department of Pathology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Ali Alassiri
- Department of Pathology and Laboratory Medicine, King Abdulaziz Medical City, Riyadh, Saudi Arabia
| | | | - Malak Abedalthagafi
- Genomics Research Department, King Fahad Medical City, Riyadh, Saudi Arabia,Department of Pathology and Laboratory Medicine, Emory University Hospital, Atlanta, GA, United States,*Correspondence: Malak Abedalthagafi,
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Investigating the Active Substance and Mechanism of San-Jiu-Wei-Tai Granules via UPLC-QE-Orbitrap-MS and Network Pharmacology. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:1487903. [PMID: 36299773 PMCID: PMC9592199 DOI: 10.1155/2022/1487903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 09/21/2022] [Accepted: 10/07/2022] [Indexed: 11/17/2022]
Abstract
San-Jiu-Wei-Tai granules (SJWTG) are a significant Chinese patent medicine for the treatment of chronic gastritis (CG), having outstanding advantages in long-term treatment; however, the chemical composition and potential mechanism have not been investigated until now. In this study, a rapid separation and identification method based on UPLC-QE-Orbitrap-MS was established, and 95 chemical components from SJWTGs were identified, including 6 chemical components of an unknown source that are not derived from the 8 herbs included in SJWTGs. The identified chemical components were subsequently analysed by network pharmacology, suggesting that the core targets for the treatment of CG with SJWTGs were EGFR, SRC, AKT1, HSP90AA1, MAPK1, and MAPK3 and thus indicating that SJWTGs could reduce the inflammatory response of gastric epithelial cells and prevent persistent chronic inflammation that induces cancerization by regulating the MAPK signalling pathway and the C-type lectin receptor signalling pathway as well as their upstream and downstream pathways in the treatment of CG. The key bioactive components in SJWTGs were identified as 2,6-bis(4-ethylphenyl)perhydro-1,3,5,7-tetraoxanaphth-4-ylethane-1,2-diol, a chemical component of an unknown source, murrangatin, meranzin hydrate, paeoniflorin, and albiflorin. The results of molecular docking showed the strong binding interaction between the key bioactive components and the core targets, demonstrating that the key bioactive components deserve to be further studied and considered as Q-markers. By acting on multiple targets, SJWTG is less susceptible to drug resistance during the long-term treatment of CG, indicating the advantage of Chinese patent medicines. Furthermore, the preventive effect of SJWTGs on gastric cancer also demonstrates the superiority of preventive treatment of disease with traditional Chinese medicine.
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Prognostic Model and Immune Infiltration of Ferroptosis Subcluster-Related Modular Genes in Gastric Cancer. JOURNAL OF ONCOLOGY 2022; 2022:5813522. [PMID: 36276279 PMCID: PMC9584706 DOI: 10.1155/2022/5813522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 08/28/2022] [Accepted: 09/05/2022] [Indexed: 11/18/2022]
Abstract
Background Gastric cancer (GC) is one of the gastrointestinal tumors with the highest mortality rate. The number of GC patients is still high. As a way of iron-dependent programmed cell death, ferroptosis activates lipid peroxidation and accumulates large reactive oxygen species. The role of ferroptosis in GC prognosis was underrepresented. The objective was to investigate the role of ferroptosis-related genes (FRGs) in the prognosis and development of GC. Methods Datasets of GC patients were obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) database that include clinical information and RNA seq data. Through nonnegative matrix factorization (NMF) clustering, we identified and unsupervised cluster analysis of the expression matrix of FRGs. And we constructed the co-expression network between genes and clinical characteristics by consensus weighted gene co-expression network analysis (WGCNA). The prognostic model was constructed by univariate and multivariate regression analysis. The potential mechanisms of development and prognosis in GC were explored by Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, gene ontology (GO), tumor immune microenvironment (TIME), and tumor mutation burden (TMB). Results Two molecular subclusters with different expression patterns of FRGs were identified, which have significantly different survival states. Ferroptosis subcluster-related modular genes were identified by WGCNA. Based on 8 ferroptosis subcluster-related modular genes (collagen triple helix repeat containing 1 (CTHRC1), podoplanin (PDPN), procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2), glutamine-fructose-6-phosphate transaminase 2 (GFPT2), ATP-binding cassette subfamily A member 1 (ABCA1), G protein-coupled receptor 176 (GPR176), serpin family E member 1 (SERPINE1), dual specificity phosphatase 1 (DUSP1)) and clinicopathological features, a nomogram was constructed and validated for their predictive efficiency on GC prognosis. Through receiver operating characteristic (ROC) analysis, the results showed that the area under the curve (AUC) of 1-, 3-, and 5-year survival were 0.721, 0.747, and 0.803, respectively, indicating that the risk-scoring model we constructed had good prognosis efficacy in GC. The degree of immune infiltration in high-risk group was largely higher than low-risk group. It indicated that the immune cells have a good response in high-risk group of GC. The TMB of high-risk group was higher, which could generate more mutations and was more conducive to the body's resistance to the development of cancer. Conclusion The risk-scoring model based on 8 ferroptosis subcluster-related modular genes has shown outstanding advantages in predicting patient prognosis. The interaction of ferroptosis in GC development may provide new insights into exploring molecular mechanisms and targeted therapies for GC patients.
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Ma H, Wu F, Bai Y, Wang T, Ma S, Guo L, Liu G, Leng G, Kong Y, Zhang Y. Licoricidin combats gastric cancer by targeting the ICMT/Ras pathway in vitro and in vivo. Front Pharmacol 2022; 13:972825. [PMID: 36339587 PMCID: PMC9629146 DOI: 10.3389/fphar.2022.972825] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Accepted: 09/15/2022] [Indexed: 12/24/2022] Open
Abstract
Licoricidin, a type of isoflavonoid, is extracted from the root of Glycyrrhiza glabra. It has been widely proven that licoricidin possesses multiple biological activities, including anti-cancer effects and a powerful antimicrobial effect against Helicobacter pylori (H. pylori). However, the exact mechanism of licoricidin against gastric cancer remains unclear. In this study, we comprehensively explored the effects of licoricidin on MGC-803 gastric cancer cells in vitro and in vivo and further elucidated its mechanism of action. Our results revealed that licoricidin exhibited multiple anti-gastric cancer activities, including suppressing proliferation, inducing apoptosis, arresting the cell cycle in G0/G1 phase, and inhibiting the migration and invasion abilities of MGC-803 gastric cancer cells. In addition to this, a total of 5861 proteins were identified by quantitative proteomics research strategy of TMT labeling, of which 19 differential proteins (two upregulated and 17 downregulated) were screened out. Combining bioinformatics analyses and the reported roles in cancer progression of the 19 proteins, we speculated that isoprenyl carboxyl methyltransferase (ICMT) was the most likely target of licoricidin. Western blot assays and IHC assays subsequently proved that licoricidin significantly downregulated the expression of ICMT, both in MGC-803 cells and in xenograft tumors. Moreover, licoricidin effectively reduced the level of active Ras-GTP and blocked the phosphorylation of Raf and Erk, which may be involved in its anti-gastric cancer effects. In summary, we first demonstrated that licoricidin exerted favorable anti-gastric cancer activities via the ICMT/Ras pathway, which suggests that licoricidin, as a natural product, could be a novel candidate for the management of gastric cancer.
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Affiliation(s)
- Hanwei Ma
- Laboratory of Hepatic-Biliary-Pancreatic, Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China
- Department of Pediatric Gastroenterology, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Fahong Wu
- Laboratory of Hepatic-Biliary-Pancreatic, Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Yinliang Bai
- Pharmacy Department, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Tianwei Wang
- Laboratory of Hepatic-Biliary-Pancreatic, Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Shangxian Ma
- Laboratory of Hepatic-Biliary-Pancreatic, Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Liuqing Guo
- Laboratory of Hepatic-Biliary-Pancreatic, Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Guiyuan Liu
- Laboratory of Hepatic-Biliary-Pancreatic, Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Guangxian Leng
- Laboratory of Hepatic-Biliary-Pancreatic, Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Yin Kong
- Laboratory of Hepatic-Biliary-Pancreatic, Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Youcheng Zhang
- Laboratory of Hepatic-Biliary-Pancreatic, Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China
- *Correspondence: Youcheng Zhang,
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Lei ZN, Teng QX, Tian Q, Chen W, Xie Y, Wu K, Zeng Q, Zeng L, Pan Y, Chen ZS, He Y. Signaling pathways and therapeutic interventions in gastric cancer. Signal Transduct Target Ther 2022; 7:358. [PMID: 36209270 PMCID: PMC9547882 DOI: 10.1038/s41392-022-01190-w] [Citation(s) in RCA: 121] [Impact Index Per Article: 40.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 08/14/2022] [Accepted: 09/07/2022] [Indexed: 11/23/2022] Open
Abstract
Gastric cancer (GC) ranks fifth in global cancer diagnosis and fourth in cancer-related death. Despite tremendous progress in diagnosis and therapeutic strategies and significant improvements in patient survival, the low malignancy stage is relatively asymptomatic and many GC cases are diagnosed at advanced stages, which leads to unsatisfactory prognosis and high recurrence rates. With the recent advances in genome analysis, biomarkers have been identified that have clinical importance for GC diagnosis, treatment, and prognosis. Modern molecular classifications have uncovered the vital roles that signaling pathways, including EGFR/HER2, p53, PI3K, immune checkpoint pathways, and cell adhesion signaling molecules, play in GC tumorigenesis, progression, metastasis, and therapeutic responsiveness. These biomarkers and molecular classifications open the way for more precise diagnoses and treatments for GC patients. Nevertheless, the relative significance, temporal activation, interaction with GC risk factors, and crosstalk between these signaling pathways in GC are not well understood. Here, we review the regulatory roles of signaling pathways in GC potential biomarkers, and therapeutic targets with an emphasis on recent discoveries. Current therapies, including signaling-based and immunotherapies exploited in the past decade, and the development of treatment for GC, particularly the challenges in developing precision medications, are discussed. These advances provide a direction for the integration of clinical, molecular, and genomic profiles to improve GC diagnosis and treatments.
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Affiliation(s)
- Zi-Ning Lei
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Qiu-Xu Teng
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Qin Tian
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Wei Chen
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Yuhao Xie
- Institute for Biotechnology, St. John's University, Queens, NY, 11439, USA
| | - Kaiming Wu
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Qianlin Zeng
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Leli Zeng
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China.
| | - Yihang Pan
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China.
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA.
- Institute for Biotechnology, St. John's University, Queens, NY, 11439, USA.
| | - Yulong He
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China.
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Wang X, Zhang L, Chan FKL, Ji J, Yu J, Liang JQ. Gamma-glutamyltransferase 7 suppresses gastric cancer by cooperating with RAB7 to induce mitophagy. Oncogene 2022; 41:3485-3497. [PMID: 35662282 DOI: 10.1038/s41388-022-02339-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 04/25/2022] [Accepted: 04/27/2022] [Indexed: 02/08/2023]
Abstract
We identified gamma-glutamyltransferase 7 (GGT7) to be frequently downregulated in gastric cancer, but its role remains unknown. Here we elucidated the clinical significance, functional roles, and molecular mechanism of GGT7 in gastric cancer. GGT7 was downregulated by promoter methylation and restored by demethylation treatment in gastric cancer cells. GGT7 methylation inversely correlated with mRNA expression in gastric tumors (n = 221; r = -0.686, P < 0.0001). High-expression of GGT7 in adjacent non-tumor tissues was significantly associated with favorable survival in gastric cancer patients (n = 138; P = 0.009), and was an independent prognostic factor by multivariate Cox regression (HR = 0.381, P < 0.05). GGT7 significantly inhibited gastric cancer cell growth, G1-S transition, and migration and invasion abilities. GGT7 also significantly attenuated the growth of subcutaneous xenograft tumors and reduced metastasis to the lung in nude mice. The mitophagy regulator RAB7 was identified as a direct downstream co-player of GGT7 by co-immunoprecipitation followed by mass spectrometry. Growth suppression effect of GGT7 was at least partly dependent on RAB7 by rescue experiments. GGT7 induced autophagy as shown by electron microscopy and confirmed by the increased LC3B and decreased p62. GGT7 recruited RAB7 by direct binding and drove RAB7 to translocate from nucleus to cytoplasm, subsequently mediating mitophagy by increasing mitophagy mediators/inducers. GGT7 inhibited intracellular ROS, which was associated with increased mitophagy, and subsequently suppressed MAPK signaling. Collectively, GGT7 plays a pivotal tumor-suppressing role in gastric cancer by directly binding with RAB7 to induce mitophagy and inhibit ROS and MAPK cascades. GGT7 is an independent prognostic factor for gastric cancer patients.
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Affiliation(s)
- Xiaohong Wang
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
- Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital and Institute, Beijing, China
| | - Lianhai Zhang
- Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital and Institute, Beijing, China
| | - Francis K L Chan
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Jiafu Ji
- Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital and Institute, Beijing, China.
| | - Jun Yu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
| | - Jessie Qiaoyi Liang
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
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Abstract
Mitogen-activated protein kinase (MAPK) pathways are prominently involved in the onset and progression of cancer [...].
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Affiliation(s)
- Elisabetta Rovida
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50134 Florence, Italy;
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Najar MA, Arefian M, Sidransky D, Gowda H, Prasad TSK, Modi PK, Chatterjee A. Tyrosine Phosphorylation Profiling Revealed the Signaling Network Characteristics of CAMKK2 in Gastric Adenocarcinoma. Front Genet 2022; 13:854764. [PMID: 35646067 PMCID: PMC9136244 DOI: 10.3389/fgene.2022.854764] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 03/28/2022] [Indexed: 12/24/2022] Open
Abstract
Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) is a serine/threonine protein kinase which functions via the calcium-triggered signaling cascade with CAMK1, CAMK4, and AMPKα as the immediate downstream substrates. CAMKK2 is reported to be overexpressed in gastric cancer; however, its signaling mechanism is poorly understood. We carried out label-free quantitative tyrosine phosphoproteomics to investigate tyrosine-mediated molecular signaling associated with CAMKK2 in gastric cancer cells. Using a high-resolution Orbitrap Fusion Tribrid Fourier-transform mass spectrometer, we identified 350 phosphotyrosine sites mapping to 157 proteins. We observed significant alterations in 81 phosphopeptides corresponding to 63 proteins upon inhibition of CAMKK2, among which 16 peptides were hyperphosphorylated corresponding to 13 proteins and 65 peptides were hypophosphorylated corresponding to 51 proteins. We report here that the inhibition of CAMKK2 leads to changes in the phosphorylation of several tyrosine kinases such as PKP2, PTK2, EPHA1, EPHA2, PRKCD, MAPK12, among others. Pathway analyses revealed that proteins are differentially phosphorylated in response to CAMKK2 inhibition involved in focal adhesions, actin cytoskeleton, axon guidance, and signaling by VEGF. The western blot analysis upon inhibition and/or silencing of CAMKK2 revealed a decrease in phosphorylation of PTK2 at Y925, c-JUN at S73, and STAT3 at Y705, which was in concordance with the mass spectrometry data. The study indicates that inhibition of CAMKK2 has an anti-oncogenic effect in gastric cells regulating phosphorylation of STAT3 through PTK2/c-JUN in gastric cancer.
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Affiliation(s)
- Mohd. Altaf Najar
- Center for Systems Biology and Molecular Medicine, Yenepoya (Deemed to be University), Mangalore, India
| | - Mohammad Arefian
- Center for Systems Biology and Molecular Medicine, Yenepoya (Deemed to be University), Mangalore, India
| | - David Sidransky
- Department of Oncology and Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Harsha Gowda
- Center for Systems Biology and Molecular Medicine, Yenepoya (Deemed to be University), Mangalore, India
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- Manipal Academy of Higher Education (MAHE), Manipal, India
| | - T. S. Keshava Prasad
- Center for Systems Biology and Molecular Medicine, Yenepoya (Deemed to be University), Mangalore, India
| | - Prashant Kumar Modi
- Center for Systems Biology and Molecular Medicine, Yenepoya (Deemed to be University), Mangalore, India
- *Correspondence: Prashant Kumar Modi, ; Aditi Chatterjee,
| | - Aditi Chatterjee
- Center for Systems Biology and Molecular Medicine, Yenepoya (Deemed to be University), Mangalore, India
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- *Correspondence: Prashant Kumar Modi, ; Aditi Chatterjee,
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Kciuk M, Gielecińska A, Budzinska A, Mojzych M, Kontek R. Metastasis and MAPK Pathways. Int J Mol Sci 2022; 23:ijms23073847. [PMID: 35409206 PMCID: PMC8998814 DOI: 10.3390/ijms23073847] [Citation(s) in RCA: 72] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 03/18/2022] [Accepted: 03/29/2022] [Indexed: 02/07/2023] Open
Abstract
Cancer is a leading cause of death worldwide. In many cases, the treatment of the disease is limited due to the metastasis of cells to distant locations of the body through the blood and lymphatic drainage. Most of the anticancer therapeutic options focus mainly on the inhibition of tumor cell growth or the induction of cell death, and do not consider the molecular basis of metastasis. The aim of this work is to provide a comprehensive review focusing on cancer metastasis and the mitogen-activated protein kinase (MAPK) pathway (ERK/JNK/P38 signaling) as a crucial modulator of this process.
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Affiliation(s)
- Mateusz Kciuk
- Doctoral School of Exact and Natural Sciences, University of Lodz, Banacha Street 12/16, 90-237 Lodz, Poland
- Department of Molecular Biotechnology and Genetics, Faculty of Biology and Environmental Protection, University of Lodz, 12/16 Banacha St., 90-237 Lodz, Poland; (A.G.); (R.K.)
- Correspondence:
| | - Adrianna Gielecińska
- Department of Molecular Biotechnology and Genetics, Faculty of Biology and Environmental Protection, University of Lodz, 12/16 Banacha St., 90-237 Lodz, Poland; (A.G.); (R.K.)
| | - Adrianna Budzinska
- Laboratory of Mitochondrial Biochemistry, Department of Bioenergetics, Faculty of Biology, Adam Mickiewicz University, 61-614 Poznan, Poland;
| | - Mariusz Mojzych
- Department of Chemistry, Siedlce University of Natural Sciences and Humanities, 3 Maja 54, 08-110 Siedlce, Poland;
| | - Renata Kontek
- Department of Molecular Biotechnology and Genetics, Faculty of Biology and Environmental Protection, University of Lodz, 12/16 Banacha St., 90-237 Lodz, Poland; (A.G.); (R.K.)
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Hsieh HL, Yu MC, Cheng LC, Chu MY, Huang TH, Yeh TS, Tsai MM. Quercetin exerts anti-inflammatory effects via inhibiting tumor necrosis factor-α-induced matrix metalloproteinase-9 expression in normal human gastric epithelial cells. World J Gastroenterol 2022; 28:1139-1158. [PMID: 35431500 PMCID: PMC8985486 DOI: 10.3748/wjg.v28.i11.1139] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 12/23/2021] [Accepted: 02/12/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Gastric injury is the most common digestive system disease worldwide and involves inflammation, which can lead to gastric ulcer or gastric cancer (GC). Matrix metallopeptidase-9 [MMP-9 (gelatinase-B)] plays an important role in inflammation and GC progression. Quercetin and quercetin-rich diets represent potential food supplements and a source of medications for treating gastric injury given their anti-inflammatory activities. However, the effects and mechanisms of action of quercetin on human chronic gastritis and whether quercetin can relieve symptoms remain unclear. AIM To assess whether tumor necrosis factor-α (TNF-α)-induced MMP-9 expression mediates the anti-inflammatory effects of quercetin in normal human gastric mucosal epithelial cells. METHODS The normal human gastric mucosa epithelial cell line GES-1 was used to establish a normal human gastric epithelial cell model of TNF-α-induced MMP-9 protein overexpression to evaluate the anti-inflammatory effects of quercetin. The cell counting Kit-8 assay was used to evaluate the effects of varying quercetin doses on cell viability in the normal GES-1 cell line. Cell migration was measured using Transwell assay. The expression of proto-oncogene tyrosine-protein kinase Src (c-Src), phospho (p)-c-Src, extracellular-signal-regulated kinase 2 (ERK2), p-ERK1/2, c-Fos, p-c-Fos, nuclear factor kappa B (NF-κB/p65), and p-p65 and the effects of their inhibitors were examined using Western blot analysis and measurement of luciferase activity. p65 expression was detected by immunofluorescence. MMP-9 mRNA and protein levels were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and gelatin zymography, respectively. RESULTS qRT-PCR and gelatin zymography showed that TNF-α induced MMP-9 mRNA and protein expression in a dose- and time-dependent manner. These effects were reduced by the pretreatment of GES-1 cells with quercetin or a TNF-α antagonist (TNFR inhibitor) in a dose- and time-dependent manner. Quercetin and TNF-α antagonists decreased the TNF-α-induced phosphorylation of c-Src, ERK1/2, c-Fos, and p65 in a dose- and time-dependent manner. Quercetin, TNF-α antagonist, PP1, U0126, and tanshinone IIA (TSIIA) reduced TNF-α-induced c-Fos phosphorylation and AP-1-Luciferase (Luc) activity in a dose- and time-dependent manner. Pretreatment with quercetin, TNF-α antagonist, PP1, U0126, or Bay 11-7082 reduced TNF-α-induced p65 phosphorylation and translocation and p65-Luc activity in a dose- and time-dependent manner. TNF-α significantly increased GES-1 cell migration, and these results were reduced by pretreatment with quercetin or a TNF-α antagonist. CONCLUSION Quercetin significantly downregulates TNF-α-induced MMP-9 expression in GES-1 cells via the TNFR-c-Src-ERK1/2 and c-Fos or NF-κB pathways.
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Affiliation(s)
- Hsi-Lung Hsieh
- Department of Nursing, Division of Basic Medical Sciences, Chang-Gung University of Science and Technology, Taoyuan 333, Taiwan
- Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan
- Department of Neurology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Ming-Chin Yu
- Department of General Surgery, New Taipei Municipal TuCheng Hospital, New Taipei 236, Taiwan
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
- Department of General Surgery, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Li-Ching Cheng
- Department of Nursing, Division of Basic Medical Sciences, Chang-Gung University of Science and Technology, Taoyuan 333, Taiwan
- Department of General Surgery, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Mei-Yi Chu
- Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan
| | - Tzu-Hao Huang
- Department of Nursing, Division of Basic Medical Sciences, Chang-Gung University of Science and Technology, Taoyuan 333, Taiwan
| | - Ta-Sen Yeh
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
- Department of General Surgery, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Ming-Ming Tsai
- Department of Nursing, Division of Basic Medical Sciences, Chang-Gung University of Science and Technology, Taoyuan 333, Taiwan
- Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan
- Department of General Surgery, New Taipei Municipal TuCheng Hospital, New Taipei 236, Taiwan
- Department of General Surgery, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
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Liu Y, Ao X, Wang Y, Li X, Wang J. Long Non-Coding RNA in Gastric Cancer: Mechanisms and Clinical Implications for Drug Resistance. Front Oncol 2022; 12:841411. [PMID: 35155266 PMCID: PMC8831387 DOI: 10.3389/fonc.2022.841411] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 01/10/2022] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide, with high recurrence and mortality rate. Chemotherapy, including 5-fluorouracil (5-FU), adriamycin (ADR), vincristine (VCR), paclitaxel (PTX), and platinum drugs, remains one of the fundamental methods of GC treatment and has efficiently improved patients’ prognosis. However, most patients eventually develop resistance to chemotherapeutic agents, leading to the failure of clinical treatment and patients’ death. Recent studies suggest that long non-coding RNAs (lncRNAs) are involved in the drug resistance of GC by modulating the expression of drug resistance-related genes via sponging microRNAs (miRNAs). Moreover, lncRNAs also play crucial roles in GC drug resistance via a variety of mechanisms, such as the regulation of the oncogenic signaling pathways, inhibition of apoptosis, induction of autophagy, modulation of cancer stem cells (CSCs), and promotion of the epithelial-to-mesenchymal transition (EMT) process. Some of lncRNAs exhibit great potential as diagnostic and prognostic biomarkers, as well as therapeutic targets for GC patients. Therefore, understanding the role of lncRNAs and their mechanisms in GC drug resistance may provide us with novel insights for developing strategies for individual diagnosis and therapy. In this review, we summarize the recent findings on the mechanisms underlying GC drug resistance regulated by lncRNAs. We also discuss the potential clinical applications of lncRNAs as biomarkers and therapeutic targets in GC.
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Affiliation(s)
- Ying Liu
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
- *Correspondence: Ying Liu,
| | - Xiang Ao
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Yu Wang
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Xiaoge Li
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Jianxun Wang
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
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39
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Kinases and therapeutics in pathogen mediated gastric cancer. Mol Biol Rep 2022; 49:2519-2530. [PMID: 35031925 DOI: 10.1007/s11033-021-07063-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 12/08/2021] [Indexed: 10/19/2022]
Abstract
INTRODUCTION Many pathogens have coexisted with humans for millennia and can cause chronic inflammation which is the cause of gastritis. Gastric cancer (GC) is associated with 8.8% of cancer related deaths, making it one of the leading causes of cancer related deaths worldwide. This review is intended to give brief information about Helicobacter pylori (H. pylori), Epstein-Barr virus (EBV), human cytomegalovirus (HCMV) role in GC and associated kinases. These organisms can trigger multiple cellular pathways aiming for unnatural cellular proliferation, apoptosis, migration and inflammatory response. Kinases also can activate and deactivate the signalling leading to aforementioned pathways. Therefore, studying kinases is inevitable. MATERIAL AND METHODS This review is the comprehensive collection of information from different data sources such as journals, book, book chapters and verified online information. CONCLUSION Kinase amplifications could be used as diagnostic, prognostic, and predictive biomarkers in various cancer types. Hence targeting kinase and related signalling molecules could be considered as a potential approach to prevent cancer through these organisms. Here we summarize the brief information about the role of kinases, signalling and their therapeutics in GC concerning H. pylori, EBV and HCMV.
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40
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Liu Y, Ao X, Ji G, Zhang Y, Yu W, Wang J. Mechanisms of Action And Clinical Implications of MicroRNAs in the Drug Resistance of Gastric Cancer. Front Oncol 2021; 11:768918. [PMID: 34912714 PMCID: PMC8667691 DOI: 10.3389/fonc.2021.768918] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 11/15/2021] [Indexed: 12/13/2022] Open
Abstract
Gastric cancer (GC) is one of the most common malignant tumors of digestive systems worldwide, with high recurrence and mortality. Chemotherapy is still the standard treatment option for GC and can effectively improve the survival and life quality of GC patients. However, with the emergence of drug resistance, the clinical application of chemotherapeutic agents has been seriously restricted in GC patients. Although the mechanisms of drug resistance have been broadly investigated, they are still largely unknown. MicroRNAs (miRNAs) are a large group of small non-coding RNAs (ncRNAs) widely involved in the occurrence and progression of many cancer types, including GC. An increasing amount of evidence suggests that miRNAs may play crucial roles in the development of drug resistance by regulating some drug resistance-related proteins as well as gene expression. Some also exhibit great potential as novel biomarkers for predicting drug response to chemotherapy and therapeutic targets for GC patients. In this review, we systematically summarize recent advances in miRNAs and focus on their molecular mechanisms in the development of drug resistance in GC progression. We also highlight the potential of drug resistance-related miRNAs as biomarkers and therapeutic targets for GC patients.
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Affiliation(s)
- Ying Liu
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China.,School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Xiang Ao
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Guoqiang Ji
- Clinical Laboratory, Linqu People's Hospital, Linqu, China
| | - Yuan Zhang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Wanpeng Yu
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Jianxun Wang
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
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41
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Zhang S, Xiang X, Liu L, Yang H, Cen D, Tang G. Bioinformatics Analysis of Hub Genes and Potential Therapeutic Agents Associated with Gastric Cancer. Cancer Manag Res 2021; 13:8929-8951. [PMID: 34876855 PMCID: PMC8643151 DOI: 10.2147/cmar.s341485] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 11/16/2021] [Indexed: 12/31/2022] Open
Abstract
Purpose The current treatment methods available for advanced gastric cancer are not very promising. Hence, it is important to explore novel biomarkers and potential therapeutic agents to treat gastric cancer (GC). This study aimed to identify hub genes associated with GC prognosis and explore potential drugs for its treatment. Materials and Methods Three gene expression data of GC and normal tissues were downloaded from the Gene Expression Omnibus (GEO) and processed to identify the differentially expressed genes (DEGs). We conducted a comprehensive analysis of DEGs, including functional enrichment analysis, construction of protein-protein interaction (PPI) network, identification of hub genes, survival analysis and expression verification of hub genes. Finally, we constructed the network of miRNA-mRNA, and predicted the drugs that might be effective for GC treatment. Results A total of 340 DEGs, including 94 up-regulated and 246 down-regulated genes, were identified. Among the up-regulated DEGs, the enrichment terms were primarily related to tumorigenesis and tumor progression, extracellular matrix organization, and collagen catabolic process. Additionally, 10 hub genes (FN1, COL3A1, COL1A2, BGN, THBS2, COL5A2, THBS1, COL5A1, SPARC, and COL4A1) were identified, out of which 7 genes were significantly associated with poor overall survival (OS) in GC. The expression levels of these 7 hub genes were verified using real-time PCR, immunohistochemistry, and the GEPIA2 (Gene Expression Profiling Interactive Analysis) server. A regulatory network of miRNA-mRNA was also constructed, and the top 4 interactive miRNAs (hsa-miR-29b-3p, hsa-miR-140-3p, hsa-miR-29a-3p, and hsa-miR-29c-3p) that targeted the most hub genes were identified. Finally, fourteen small molecules were predicted to be effective in treating GC. Conclusion The identification of the hub genes, miRNA-mRNA network, and potential candidate drugs associated with GC provides new insights into the molecular mechanisms and treatment of GC.
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Affiliation(s)
- Shiyu Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning City, Guangxi Province, People's Republic of China
| | - Xuelian Xiang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning City, Guangxi Province, People's Republic of China
| | - Li Liu
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning City, Guangxi Province, People's Republic of China
| | - Huiying Yang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning City, Guangxi Province, People's Republic of China
| | - Dongliang Cen
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning City, Guangxi Province, People's Republic of China
| | - Guodu Tang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning City, Guangxi Province, People's Republic of China
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Liu X, Wang S, Li J, Zhang J, Liu D. Regulatory effect of traditional Chinese medicines on signaling pathways of process from chronic atrophic gastritis to gastric cancer. CHINESE HERBAL MEDICINES 2021; 14:5-19. [PMID: 36120132 PMCID: PMC9476726 DOI: 10.1016/j.chmed.2021.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 04/23/2021] [Accepted: 10/12/2021] [Indexed: 01/30/2023] Open
Affiliation(s)
- Xinnan Liu
- Tianjin Modern Innovation Chinese Medicine Technology Co., Ltd., Tianjin 300380, China
- Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Shuping Wang
- Department of Pharmacy, Tianjin Provincial Corps Hospital, Chinese People’s Armed Police Forces, Tianjin 300162, China
| | - Jingyang Li
- Logistics College of Chinese People’s Armed Police Forces, Tianjin 300309, China
| | - Jingze Zhang
- Tianjin Modern Innovation Chinese Medicine Technology Co., Ltd., Tianjin 300380, China
- Corresponding authors.
| | - Dailin Liu
- Tianjin Modern Innovation Chinese Medicine Technology Co., Ltd., Tianjin 300380, China
- Corresponding authors.
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Carnosic Acid Induces Antiproliferation and Anti-Metastatic Property of Esophageal Cancer Cells via MAPK Signaling Pathways. JOURNAL OF ONCOLOGY 2021; 2021:4451533. [PMID: 34824582 PMCID: PMC8610725 DOI: 10.1155/2021/4451533] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 11/02/2021] [Indexed: 01/01/2023]
Abstract
Background Carnosic acid (CA) is a polyphenolic diterpene extracted from rosemary. Reports have shown that CA possesses anticancer activity. However, whether CA inhibits esophageal squamous cell carcinoma, an aggressive type of esophageal cancer, remains untested. Methods The effects of CA on cell survival, migration, and apoptosis were evaluated by a combination of MTT, colony formation assay, flow cytometry, and Transwell assay. The potential signaling pathways involved were investigated via Western blot assay. Results CA dose-dependently inhibited cell proliferation, apoptosis, migration, and colony formation. Mechanistically, CA arrested the cell cycle at G2/M phase, promoted cell apoptosis, induced DNA damage, and inhibited the MAPK signaling pathways. Conclusion Our results suggest that CA is a potential anticancer drug for esophageal squamous cell carcinoma.
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Methylation patterns of Tf2 retrotransposons linked to rapid adaptive stress response in the brown planthopper (Nilaparvata lugens). Genomics 2021; 113:4214-4226. [PMID: 34774681 DOI: 10.1016/j.ygeno.2021.11.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 10/12/2021] [Accepted: 11/07/2021] [Indexed: 11/23/2022]
Abstract
Transposable elements (TEs) exhibit vast diversity across insect orders and are one of the major factors driving insect evolution and speciation. Presence of TEs can be both beneficial and deleterious to their host. While it is well-established that TEs impact life-history traits, adaptations and survivability of insects under hostile environments, the influence of the ecological niche on TE-landscape remains unclear. Here, we analysed the dynamics of Tf2 retrotransposons in the brown planthopper (BPH), under environmental fluctuations. BPH, a major pest of rice, is found in almost all rice-growing ecosystems. We believe genome plasticity, attributed to TEs, has allowed BPH to adapt and colonise novel ecological niches. Our study revealed bimodal age-distribution for Tf2 elements in BPH, indicating the occurrence of two major transpositional events in its evolutionary history and their contribution in shaping BPH genome. While TEs can provide genome flexibility and facilitate adaptations, they impose massive load on the genome. Hence, we investigated the involvement of methylation in modulating transposition in BPH. We performed comparative analyses of the methylation patterns of Tf2 elements in BPH feeding on resistant- and susceptible-rice varieties, and also under pesticide stress, across different life-stages. Results confirmed that methylation, particularly in non-CG context, is involved in TE regulation and dynamics under stress. Furthermore, we observed differential methylation for BPH adults and nymphs, emphasising the importance of screening juvenile life-stages in understanding adaptive-stress-responses in insects. Collectively, this study enhances our understanding of the role of transposons in influencing the evolutionary trajectory and survival strategies of BPH across generations.
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45
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Scavo MP, Rizzi F, Depalo N, Armentano R, Coletta S, Serino G, Fanizza E, Pesole PL, Cervellera A, Carella N, Curri ML, Giannelli G. Exosome Released FZD10 Increases Ki-67 Expression via Phospho-ERK1/2 in Colorectal and Gastric Cancer. Front Oncol 2021; 11:730093. [PMID: 34671555 PMCID: PMC8522497 DOI: 10.3389/fonc.2021.730093] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 09/03/2021] [Indexed: 12/18/2022] Open
Abstract
Frizzled (FZD) proteins are primary receptors for Wnt signaling that activates the mitogen-activated protein kinase (MAPK) pathways. Dysfunction of Wnt signals with consequently abnormal activation of MAPK3 pathways was found in colorectal cancer (CRC) and gastric cancer (GC). Upregulation of FZD10 protein, localized in the exosomes isolated from plasma of CRC and GC patients, was associated with a poor prognosis. Herein, the expression levels of circulating FZD10 were found to be strongly correlated to their expression levels in the corresponding tissues in CRC and GC patients. Bioinformatic prediction revealed a link between FZD10 and Ki-67 through MAPK3. In both CRC and GC tissues, pERK1/2 levels were significantly increased at more advanced disease stages, and pERK1/2 and Ki-67 were correlated. Silencing of FZD10 in CRC and GC cells resulted in a significant reduction of pERK1/2 and Ki-67 expression, while subsequent treatment with exogenous exosomes partially restored their expression levels. The strong correlation between the expression of Ki-67 in tissues and of FZD10 in exosomes suggests that the exosome-delivered FZD10 may be a promising novel prognostic and diagnostic biomarker for CRC and GC.
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Affiliation(s)
- Maria Principia Scavo
- Personalized Medicine Laboratory, National Institute of Gastroenterology “S. De Bellis” Research Hospital, Bari, Italy
| | - Federica Rizzi
- University of Bari “A. Moro,” Chemistry Department, Bari, Italy
- Institute for Chemical–Physical Processes (IPCF)–National Research Council Secondary Site (CNR SS) Bari, Bari, Italy
| | - Nicoletta Depalo
- Institute for Chemical–Physical Processes (IPCF)–National Research Council Secondary Site (CNR SS) Bari, Bari, Italy
| | - Raffaele Armentano
- Department of Pathology, National Institute of Gastroenterology “S. de Bellis,” Research Hospital, Bari, Italy
| | - Sergio Coletta
- Department of Pathology, National Institute of Gastroenterology “S. de Bellis,” Research Hospital, Bari, Italy
| | - Grazia Serino
- Experimental Immunopathology Laboratory, National Institute of Gastroenterology “S. de Bellis,” Research Hospital, Bari, Italy
| | - Elisabetta Fanizza
- University of Bari “A. Moro,” Chemistry Department, Bari, Italy
- Institute for Chemical–Physical Processes (IPCF)–National Research Council Secondary Site (CNR SS) Bari, Bari, Italy
| | - Pasqua Letizia Pesole
- Laboratory of Clinical Pathology, National Institute of Gastroenterology, “S de Bellis” Research Hospital, Bari, Italy
| | - Alessandra Cervellera
- Laboratory of Clinical Pathology, National Institute of Gastroenterology, “S de Bellis” Research Hospital, Bari, Italy
| | - Nicola Carella
- Laboratory of Clinical Pathology, National Institute of Gastroenterology, “S de Bellis” Research Hospital, Bari, Italy
| | - Maria Lucia Curri
- University of Bari “A. Moro,” Chemistry Department, Bari, Italy
- Institute for Chemical–Physical Processes (IPCF)–National Research Council Secondary Site (CNR SS) Bari, Bari, Italy
| | - Gianluigi Giannelli
- Scientific Direction, National Institute of Gastroenterology “S. De Bellis” Research Hospital, Bari, Italy
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Li C, Wang N, Rao P, Wang L, Lu D, Sun L. Role of the microRNA-29 family in myocardial fibrosis. J Physiol Biochem 2021; 77:365-376. [PMID: 34047925 DOI: 10.1007/s13105-021-00814-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Accepted: 04/01/2021] [Indexed: 12/11/2022]
Abstract
Myocardial fibrosis (MF) is an inevitable pathological process in the terminal stage of many cardiovascular diseases, often leading to serious cardiac dysfunction and even death. Currently, microRNA-29 (miR-29) is thought to be a novel diagnostic and therapeutic target of MF. Understanding the underlying mechanisms of miR-29 that regulate MF will provide a new direction for MF therapy. In the present review, we concentrate on the underlying signaling pathway of miR-29 affecting MF and the crosstalk regulatory relationship among these pathways to illustrate the complex regulatory network of miR-29 in MF. Additionally, based on our mechanistic understanding, we summarize opportunities and challenges of miR-29-based MF diagnosis and therapy.
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Affiliation(s)
- Changyan Li
- Science and Technology Achievement Incubation Center, Kunming Medical University, 1168 West Chunrong Road, Yuhua Avenue, Chenggong District, Kunming, 650500, Yunnan, China
| | - Nan Wang
- Science and Technology Achievement Incubation Center, Kunming Medical University, 1168 West Chunrong Road, Yuhua Avenue, Chenggong District, Kunming, 650500, Yunnan, China
| | - Peng Rao
- Department of Cardiology, The Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, Yunnan, China
| | - Limeiting Wang
- Science and Technology Achievement Incubation Center, Kunming Medical University, 1168 West Chunrong Road, Yuhua Avenue, Chenggong District, Kunming, 650500, Yunnan, China
| | - Di Lu
- Science and Technology Achievement Incubation Center, Kunming Medical University, 1168 West Chunrong Road, Yuhua Avenue, Chenggong District, Kunming, 650500, Yunnan, China.
| | - Lin Sun
- Department of Cardiology, The Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, Yunnan, China.
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Ye Z, Hu Y. TGF‑β1: Gentlemanly orchestrator in idiopathic pulmonary fibrosis (Review). Int J Mol Med 2021; 48:132. [PMID: 34013369 PMCID: PMC8136122 DOI: 10.3892/ijmm.2021.4965] [Citation(s) in RCA: 107] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Accepted: 04/29/2021] [Indexed: 01/09/2023] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a worldwide disease characterized by the chronic and irreversible decline of lung function. Currently, there is no drug to successfully treat the disease except for lung transplantation. Numerous studies have been devoted to the study of the fibrotic process of IPF and findings showed that transforming growth factor‑β1 (TGF‑β1) plays a central role in the development of IPF. TGF‑β1 promotes the fibrotic process of IPF through various signaling pathways, including the Smad, MAPK, and ERK signaling pathways. There are intersections between these signaling pathways, which provide new targets for researchers to study new drugs. In addition, TGF‑β1 can affect the fibrosis process of IPF by affecting oxidative stress, epigenetics and other aspects. Most of the processes involved in TGF‑β1 promote IPF, but TGF‑β1 can also inhibit it. This review discusses the role of TGF‑β1 in IPF.
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Affiliation(s)
- Zhimin Ye
- Department of Pathology, Basic Medical School, Central South University, Changsha, Hunan 410006, P.R. China
| | - Yongbin Hu
- Department of Pathology, Basic Medical School, Central South University, Changsha, Hunan 410006, P.R. China
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Najar MA, Modi PK, Ramesh P, Sidransky D, Gowda H, Prasad TSK, Chatterjee A. Molecular Profiling Associated with Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CAMKK2)-Mediated Carcinogenesis in Gastric Cancer. J Proteome Res 2021; 20:2687-2703. [PMID: 33844560 DOI: 10.1021/acs.jproteome.1c00008] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Gastric cancer is the fifth most common cancer and the third leading cause of cancer-related death worldwide. We showed previously that calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2), a serine-threonine kinase, is highly expressed in gastric cancer and leads to progression. In the present study, we identified the molecular networks involved in CAMKK2-mediated progression of gastric adenocarcinoma. Treatment of gastric cancer cell lines with a CAMKK2 inhibitor, STO-609, resulted in decreased cell migration, invasion, and colony-forming ability and a G1/S-phase arrest. In addition, tandem mass tag (TMT)-based quantitative proteomic analysis resulted in the identification of 7609 proteins, of which 219 proteins were found to be overexpressed and 718 downregulated (1.5-fold). Our data identified several key downregulated proteins involved in cell division and cell proliferation, which included DNA replication licensing factors, replication factor C, origin recognition complex, replication protein A and GINS, and mesenchymal markers, upon CAMKK2 inhibition. Immunoblotting and immunofluorescence results showed concordance with our mass spectroscopy data. Taken together, our study supports CAMKK2 as a novel therapeutic target in gastric cancer.
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Affiliation(s)
- Mohd Altaf Najar
- Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore 575018, India
| | - Prashant Kumar Modi
- Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore 575018, India
| | - Poornima Ramesh
- Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore 575018, India
| | - David Sidransky
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, United States
| | - Harsha Gowda
- Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore 575018, India.,Institute of Bioinformatics, International Technology Park, Bangalore, Karnataka 560066, India.,Manipal Academy of Higher Education (MAHE), Manipal 576104, Karnataka, India
| | - T S Keshava Prasad
- Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore 575018, India
| | - Aditi Chatterjee
- Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore 575018, India.,Institute of Bioinformatics, International Technology Park, Bangalore, Karnataka 560066, India.,Manipal Academy of Higher Education (MAHE), Manipal 576104, Karnataka, India
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49
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Ma RR, Zhang H, Chen HF, Zhang GH, Tian YR, Gao P. MiR-19a/miR-96-mediated low expression of KIF26A suppresses metastasis by regulating FAK pathway in gastric cancer. Oncogene 2021; 40:2524-2538. [PMID: 33674746 DOI: 10.1038/s41388-020-01610-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 11/27/2020] [Accepted: 12/09/2020] [Indexed: 01/31/2023]
Abstract
Gastric cancer (GC) is one of the most common malignant neoplasms. Invasion and metastasis are the main causes of GC-related deaths. Recently, kinesins were discovered to be involved in tumor development. The aim of this study was to elucidate the roles of kinesin superfamily protein 26A (KIF26A) in GC and its underlying molecular mechanism in regulating tumor invasion and metastasis. Using real-time quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC), we showed that KIF26A expression was lower in GC tissues without lymph node metastasis (LNM) than in nontumorous gastric mucosa, and even lower in GC tissues with LNM than in GC tissues without LNM. Functional experiments showed that KIF26A inhibited migration and invasion of GC cells. We further identified focal-adhesion kinase (FAK), phosphatidylinositol 3-kinase regulatory subunit alpha (PI3KR1), VAV3, Rac1 and p21-activated kinase 2, and β-PAK (PAK3) as downstream effectors of KIF26A in the focal-adhesion pathway, and we found that KIF26A could regulate FAK mRNA expression through inhibiting c-MYC by MAPK pathway. c-MYC could bind to the promoter of FAK and activate FAK transcription. Moreover, we found that KIF26A-mediated inactivation of the focal-adhesion pathway could reduce the occurrence of the epithelial-to-mesenchymal transition (EMT) by increasing expression of E-cadherin and reducing that of Snail. Luciferase assays and Western blotting revealed that miR-19a and miR-96 negatively regulate KIF26A. Finally, we found that decreased expression of KIF26A has been positively correlated with histological differentiation, Lauren classification, LNM, distal metastasis, and clinical stage, as well as poor survival in patients with GC. These data indicate that KIF26A could inhibit GC migration and invasion by regulating the focal-adhesion pathway and repressing the occurrence of EMT.
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Affiliation(s)
- Ran-Ran Ma
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, PR China.,Department of Pathology, Qilu Hospital, Shandong University, Jinan, PR China
| | - Hui Zhang
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, PR China.,Department of Pathology, Qilu Hospital, Shandong University, Jinan, PR China
| | - Hong-Fang Chen
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, PR China.,Department of Pathology, Yidu Central Hospital of Weifang, Weifang, PR China
| | - Guo-Hao Zhang
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, PR China
| | - Ya-Ru Tian
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, PR China
| | - Peng Gao
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, PR China. .,Department of Pathology, Qilu Hospital, Shandong University, Jinan, PR China.
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50
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Wu X, Liu J, Zhu C, Ma M, Chen X, Liu Y, Xia N, Dong Q. Identification of Potential Biomarkers of Prognosis-Related Long Non-Coding RNA (lncRNA) in Pediatric Rhabdoid Tumor of the Kidney Based on ceRNA Networks. Med Sci Monit 2020; 26:e927725. [PMID: 33328429 PMCID: PMC7754694 DOI: 10.12659/msm.927725] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Long non-coding RNA (lncRNA) can act as competing endogenous RNA (ceRNA) during tumor development. However, no study has elucidated the ceRNA network in pediatric rhabdoid tumor of the kidney (RTK) and its prognostic-related lncRNAs. The goal of the present study was to identify potential biomarkers of prognostic-related lncRNAs. MATERIAL AND METHODS RNA sequencing and clinical data were procured from the TARGET database. The "EdgeR" package was used to obtain differentially expressed lncRNA (DElncRNA), differentially expressed messenger RNAs (DEmRNA), and differentially expressed microRNAs (DEmiRNA). Cytoscape software was used to construct a ceRNA network. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were conducted on the ceRNA network-related DEmRNA. The Kaplan-Meier method was used for predicting survival with ceRNA network-related DElncRNA. Univariate and multivariate Cox analyses were used to identify prognosis-related lncRNAs in the ceRNA network, and an RTK prognostic signature was constructed. RESULTS We identified 1109 DElncRNAs, 215 DEmiRNAs, and 3436 DEmRNAs; and 107 DElncRNAs, 21 DEmiRNAs, and 74 DEmRNAs were included in the ceRNA regulatory network. GO enrichment analysis and KEGG pathway enrichment indicated that the DEmRNAs were mainly related to the regulation of phospholipase C activity and the MAPK signaling pathway. Survival analysis showed that 9 of 107 DElncRNAs were correlated with prognosis (P<0.05). Univariate and multivariate Cox analysis identified 4 DElncRNAs (HNF1A-AS1, TPTEP1, SNHG6, and ZNF503-AS2) to establish a predictive model and can be used as independent prognostic biomarkers. CONCLUSIONS We constructed a ceRNA network that reveals potential lncRNA biomarkers for pediatric RTK.
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Affiliation(s)
- Xiongwei Wu
- Department of Pediatric Surgery, Affiliated Hospital of Qingdao University, Qingdao, Shandong, China (mainland)
| | - Jie Liu
- Department of Pediatric Surgery, Affiliated Hospital of Qingdao University, Qingdao, Shandong, China (mainland)
| | - Chengzhan Zhu
- Shandong Key Laboratory of Digital Medicine and Computer Assisted Surgery, Qingdao, Shandong, China (mainland)
| | - Mingdi Ma
- Department of Pediatric Surgery, Affiliated Hospital of Qingdao University, Qingdao, Shandong, China (mainland)
| | - Xin Chen
- Department of Pediatric Surgery, Affiliated Hospital of Qingdao University, Qingdao, Shandong, China (mainland)
| | - Yusheng Liu
- Department of Pediatric Surgery, Affiliated Hospital of Qingdao University, Qingdao, Shandong, China (mainland)
| | - Nan Xia
- Shandong Key Laboratory of Digital Medicine and Computer Assisted Surgery, Qingdao, Shandong, China (mainland)
| | - Qian Dong
- Department of Pediatric Surgery, Affiliated Hospital of Qingdao University, Qingdao, Shandong, China (mainland).,Shandong Key Laboratory of Digital Medicine and Computer Assisted Surgery, Qingdao, Shandong, China (mainland)
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