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Yuan S, Bi X, Shayiti F, Niu Y, Chen P. Relationship between circulating miRNA-222-3p and miRNA-136-5p and the efficacy of docetaxel chemotherapy in metastatic castration-resistant prostate cancer patients. BMC Urol 2024; 24:275. [PMID: 39709424 DOI: 10.1186/s12894-024-01666-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 12/02/2024] [Indexed: 12/23/2024] Open
Abstract
BACKGROUND Metastatic castration-resistant prostate cancer is the most dangerous stage of prostate cancer, with a high mortality rate. Docetaxel chemotherapy is one of the most effective treatment methods currently, but some patients do not respond to chemotherapy. To avoid unnecessary toxicity in non-responders, this study explores the potential of circulating microRNAs as early biomarkers of docetaxel response in patients with metastatic castration-resistant prostate cancer. METHODS PC3 cells and DU145 cells were divided into the control, NC mimics, and miRNA-136-5p-mimics groups. Cell viability was measured using the CCK-8 assay. Cell apoptosis was determined by flow cytometry. Cell migration and invasion abilities were evaluated using the Transwell assay. Real-time quantitative PCR was used to measure the miRNA levels in cells and peripheral blood of patients. The miRNA-136-5p target genes were predicted by using the PITA, TargetScan, and miRanda databases. The target genes were analyzed with KEGG pathway analysis. RESULTS In both PC3 and DU145 cells, the miRNA-136-5p-mimics group exhibited significantly increased cell survival rates, migration and invasion numbers, and significantly decreased apoptosis rates than the control group (p < 0.05). The miRNA-222-3p and miRNA-136-5p levels were significantly increased in docetaxel-resistant PC3 and DU145 cells (p < 0.05). The levels of circulating miRNA-222-3p and miRNA-136-5p were significantly associated with docetaxel treatment (p < 0.05). Higher levels of miRNA-222-3p were observed in non-responsive patients (p < 0.05). The area under the curve for miRNA-222-3p was 0.76 (95%CI: 0.55-0.97), indicating its effectiveness as a predictive factor for non-responsive patients to docetaxel. Patients with high expression of miRNA-34c-5p after docetaxel chemotherapy had shorter overall survival times (P < 0.05). Bioinformatics analysis identified 110 potential target genes of miRNA-136-5p. KEGG revealed that these genes were mainly distributed in three pathways. Among them, the PI3K-AKT pathway was closely related to the metastasis of prostate cancer cells. CONCLUSION Our study demonstrates that miRNA-136-5p promotes the proliferation and invasion of PC3 and DU145 cells while inhibiting apoptosis. Circulating miRNA-222-3p may serve as a biomarker for early therapeutic response to docetaxel, and further clinical investigation is warranted. Additionally, miRNA-136-5p may have anti-cancer effects during docetaxel chemotherapy in metastatic castration-resistant prostate cancer.
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Affiliation(s)
- Shuai Yuan
- Department of Urology, Affiliated Cancer Hospital of Xinjiang Medical University, No. 789 Suzhou East Street, Urumqi，Xinjiang, 830011, P.R. China
| | - Xing Bi
- Department of Urology, Affiliated Cancer Hospital of Xinjiang Medical University, No. 789 Suzhou East Street, Urumqi，Xinjiang, 830011, P.R. China
| | - Furhati Shayiti
- Department of Urology, Affiliated Cancer Hospital of Xinjiang Medical University, No. 789 Suzhou East Street, Urumqi，Xinjiang, 830011, P.R. China
| | - Yue Niu
- Department of Urology, Affiliated Cancer Hospital of Xinjiang Medical University, No. 789 Suzhou East Street, Urumqi，Xinjiang, 830011, P.R. China
| | - Peng Chen
- Department of Urology, Affiliated Cancer Hospital of Xinjiang Medical University, No. 789 Suzhou East Street, Urumqi，Xinjiang, 830011, P.R. China.
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Zhang D, Yin L, Lin Z, Yu C, Li J, Ren P, Yang C, Qiu M, Liu Y. miR-136-5p/FZD4 axis is critical for Wnt signaling-mediated myogenesis and skeletal muscle regeneration. J Cell Physiol 2024; 239:e31046. [PMID: 37218742 DOI: 10.1002/jcp.31046] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 05/04/2023] [Accepted: 05/10/2023] [Indexed: 05/24/2023]
Abstract
Skeletal muscle can undergo a regenerative process in response to injury or disease to maintain muscle quality and function. Myogenesis depends on the proliferation and differentiation of myoblasts, and miRNAs can maintain the balance between them by precisely regulating many key factors in the myogenic network. Here, we found that miR-136-5p was significantly upregulated during the proliferation and differentiation of C2C12 cells. We demonstrate that miR-136-5p acts as a myogenic negative regulator during the development of mouse C2C12 myoblasts. In terms of mechanism, miR-136-5p inhibits the formation of β-catenin/LEF/TCF DNA-binding factor transcriptional regulatory complex by targeting FZD4, a gating protein in the Wnt signaling pathway, thereby enhancing downstream myogenic factors and finally promoting myoblast proliferation and differentiation. In addition, in BaCl2-induced muscle injury mouse model, miR-136-5p knockdown accelerated the regeneration of skeletal muscle after injury, and further led to the improvement of gastrocnemius muscle mass and muscle fiber diameter, while being suppressed by shFZD4 lentivirus infection. In summary, these results demonstrate the essential role of miR-136-5p/FZD4 axis in skeletal muscle regeneration. Given the conservation of miR-136-5p among species, miR-136-5p may be a new target for treating human skeletal muscle injury and improving the production of animal meat products.
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Affiliation(s)
- Donghao Zhang
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Lingqian Yin
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Zhongzhen Lin
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Chunlin Yu
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, China
- Animal Breeding and Genetics Key Laboratory of Sichuan Province, Sichuan Animal Science Academy, Chengdu, Sichuan, China
| | - Jingjing Li
- School of Life Science and Engineering, Southwest University of Science and Technology, Mianyang, Sichuan, China
| | - Peng Ren
- School of Life Science and Engineering, Southwest University of Science and Technology, Mianyang, Sichuan, China
| | - Chaowu Yang
- Animal Breeding and Genetics Key Laboratory of Sichuan Province, Sichuan Animal Science Academy, Chengdu, Sichuan, China
| | - Mohan Qiu
- Animal Breeding and Genetics Key Laboratory of Sichuan Province, Sichuan Animal Science Academy, Chengdu, Sichuan, China
| | - Yiping Liu
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, China
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Pu J, Yan X, Zhang H. The potential of circular RNAs as biomarkers and therapeutic targets for gastric cancer: A comprehensive review. J Adv Res 2024:S2090-1232(24)00551-4. [PMID: 39617262 DOI: 10.1016/j.jare.2024.11.032] [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: 07/11/2024] [Revised: 11/22/2024] [Accepted: 11/26/2024] [Indexed: 12/08/2024] Open
Abstract
BACKGROUND Gastric cancer (GC) is a global health concern, contributing significantly to cancer-related mortality rates. Early detection is vital for improving patient outcomes. Recently, circular RNAs (circRNAs) have emerged as crucial players in the development and progression of various cancers, including GC. AIM This comprehensive review underscores the promising potential of circRNAs as innovative biomarkers for the early diagnosis of GC, as well as their possible utility as therapeutic targets for this life-threatening disease. Specifically, the review focuses on recent findings, mechanistic insights, and clinical applications of circRNAs in GC. KEY SCIENTIFIC CONCEPTS OF REVIEW Dysregulation of circRNAs has been consistently observed in GC tissues, offering potential diagnostic value due to their stability in bodily fluids such as blood and urine. For instance, circPTPN22 and hsa_circ_000200. Furthermore, the expression levels of circRNAs such as circCUL2, hsa_circ_0000705 and circSHKBP1 have shown strong associations with critical clinical features of GC, including diagnosis, prognosis, tumor size, lymph node metastasis, tumor-node-metastasis (TNM) stage, and treatment response. Additionally, circRNAs such as circBGN, circLMO7, and circMAP7D1 have shown interactions with specific microRNAs (miRNAs), proteins, and other molecules that play key roles in development and progression of GC. This further highlighting their potential as therapeutic targets. Despite their potential, several challenges need to be addressed to effectively apply circRNAs as GC biomarkers. These include standardizing detection methods, establishing cutoff values for diagnostic accuracy, and validating findings in larger patient cohorts. Moreover, the functional mechanisms by which circRNAs contribute to GC pathogenesis and therapeutic resistance warrant further investigation. Advances in circRNAs research could provide valuable insights into the early detection and targeted treatment of GC, ultimately improving patient outcomes.
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Affiliation(s)
- Junlin Pu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xiuli Yan
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China.
| | - Hui Zhang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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Liu W, Li Y, Fan L, Zhang M, Zhao X, Song Y, Huo B, Wang B, Wang Y, Song C, Song B, Tan B. Bioinformatics- and quantitative proteomics-based identification of gastric adenocarcinoma-related proteins and analysis. Am J Cancer Res 2024; 14:5286-5303. [PMID: 39659938 PMCID: PMC11626274 DOI: 10.62347/bvfo4627] [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: 09/14/2024] [Accepted: 10/30/2024] [Indexed: 12/12/2024] Open
Abstract
BACKGROUND The emergence of immune resistance and a lack of effective therapeutic targets have become significant challenges in immunotherapy, highlighting the urgent need for new molecular markers and treatment targets. Moreover, the significance and mechanisms of PGRN (Progranulin) in gastric cancer remain ambiguous. OBJECTIVE To identify differentially expressed proteins in gastric cancer and elucidate the function and mechanism of PGRN. METHODS The data-independent acquisition proteomics was used to identify the differentially expressed proteins in gastric adenocarcinoma and the corresponding paraneoplastic tissues, providing a comprehensive dataset of gastric cancer-related proteins. The function and mechanism of PGRN in gastric cancer were further explored using a series of experiments, including RT-qPCR (Real Time-Quantitative Polymerase Chain Reaction), cell transfection, cell viability assays, cell scratch, immunohistochemistry and Transwell assays, Western blot, and a mouse tumor-bearing model. These investigations were combined with bioinformatics analyses to examine the relationship between PGRN expression and clinical-pathological characteristics, confirming its high expression of PGRN in gastric cancer tissues. RESULTS We identified a large number of differentially expressed proteins between gastric cancer and adjacent tissues and conducted an initial functional analysis. Further studies on PGRN showed that it was associated with gastric cancer prognosis and lymph node metastasis. The inhibition of PGRN expression led to reduced cell viability, migration, and invasion, with corresponding changes in related genes and proteins. In a mouse tumor-bearing model, the tumor growth of the subcutaneously transplanted tumors in nude mice was reduced after the inhibition of PGRN expression. An in-depth functional analysis of PGRN was performed using bioinformatics to predict protein interactions, miRNA regulation, and relationships with multiple immune cell types. Enrichment analysis indicated that PGRN is involved in multiple signaling pathways, with the MAPK (Mitogen-Activated Protein Kinase) pathway selected for validation. In AGS and HGC27 cells, PGRN inhibition led to increased expression of phosphorylated p38 (p-p38) in the MAPK pathway, suggesting that PGRN may promote gastric cancer development by regulating p-p38. CONCLUSIONS This study identified significant differences in protein expression between gastric adenocarcinoma and adjacent tissues, with PGRN emerging as a key protein influencing gastric cancer proliferation, migration, and invasion. These findings suggest that PGRN could serve as a potential therapeutic target for gastric cancer.
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Affiliation(s)
- Wenbo Liu
- Third Department of Surgery, The Fourth Hospital of Hebei Medical UniversityShijiazhuang 050011, Hebei, China
| | - Yong Li
- Third Department of Surgery, The Fourth Hospital of Hebei Medical UniversityShijiazhuang 050011, Hebei, China
| | - Liqiao Fan
- Third Department of Surgery, The Fourth Hospital of Hebei Medical UniversityShijiazhuang 050011, Hebei, China
| | - Mingming Zhang
- Clinical Medicine Research Center, Hebei General HospitalShijiazhuang 050051, Hebei, China
| | - Xiaohan Zhao
- Department of Radiotherapy, The Fourth Hospital of Hebei Medical UniversityShijiazhuang 050011, Hebei, China
| | - Yanru Song
- Research Center, The Fourth Hospital of Hebei Medical UniversityShijiazhuang 050011, Hebei, China
| | - Bingjie Huo
- Department of Traditional Chinese Medicine, The Fourth Hospital of Hebei Medical UniversityShijiazhuang 050011, Hebei, China
| | - Bingyu Wang
- Third Department of Surgery, The Fourth Hospital of Hebei Medical UniversityShijiazhuang 050011, Hebei, China
| | - Yingying Wang
- Third Department of Surgery, The Fourth Hospital of Hebei Medical UniversityShijiazhuang 050011, Hebei, China
| | - Chao Song
- Third Department of Surgery, The Fourth Hospital of Hebei Medical UniversityShijiazhuang 050011, Hebei, China
| | - Buyun Song
- Third Department of Surgery, The Fourth Hospital of Hebei Medical UniversityShijiazhuang 050011, Hebei, China
| | - Bibo Tan
- Third Department of Surgery, The Fourth Hospital of Hebei Medical UniversityShijiazhuang 050011, Hebei, China
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Liao X, Li T, Yang L, Li H, Li W, Liu Y, Xie Z. Tumor-Derived Exosomal Circular RNA Pinin Induces FGF13 Expression to Promote Colorectal Cancer Progression through miR-1225-5p. Gut Liver 2024; 18:1014-1025. [PMID: 38384181 PMCID: PMC11565002 DOI: 10.5009/gnl230304] [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: 08/03/2023] [Revised: 10/09/2023] [Accepted: 10/24/2023] [Indexed: 02/23/2024] Open
Abstract
Background/Aims : Colorectal cancer (CRC) is a common malignant tumor, and circular RNAs (circRNAs) are abnormally expressed in CRC. However, the function and underlying mechanism of circRNA pinin (circ-PNN; hsa_circ_0101802) in CRC remain unclear. Methods : Exosomes were isolated from the plasma of CRC patients and identified by transmission electron microscopy and Western blotting. The RNA expression levels of circ-PNN, miR-1225-5p, and fibroblast growth factor 13 (FGF13) were measured by quantitative real-time polymerase chain reaction. Cell proliferation was detected by Cell Counting K-8, colony formation, and 5-ethynyl-2'-deoxyuridine assays. Cell apoptosis was assessed by flow cytometry. The expression of apoptosis and metastasis-related proteins was evaluated by Western blotting. The associations among circ-PNN, miR-1225-5p, and FGF13 were confirmed by dual-luciferase report assay and RNA immunoprecipitation assay. A xenograft model was used to verify the function of circ-PNN in tumor formation in vivo. Results : circ-PNN expression was upregulated in plasmic exosomes derived from CRC patients. The expression of circ-PNN and FGF13 was upregulated, while miR-1225-5p expression was downregulated in CRC cells incubated with plasmic exosomes derived from CRC patients. Tumor-derived exosomes promoted the proliferation, migration, and invasion but inhibited apoptosis of CRC cells. Moreover, the addition of tumor-derived exosomes partly reversed the inhibitory effect of circ-PNN knockdown on CRC tumor progression in vitro and in vivo. Thus, circ-PNN acts as a sponge for miR-1225-5p to regulate FGF13 expression. Conclusions : Tumor-derived exosomal circ-PNN promoted CRC progression through the regulation of the miR-1225-5p/FGF13 pathway, providing a potential therapeutic target for CRC.
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Affiliation(s)
- Xianghui Liao
- Departments of Digestive Oncology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Tuhua Li
- Departments of Digestive Oncology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Li Yang
- Departments of Digestive Oncology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Haiwen Li
- Departments of Head and Neck Oncology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Weiru Li
- Departments of Digestive Oncology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Yuting Liu
- Departments of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Zhong Xie
- Departments of Digestive Oncology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
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Gao Q, Cheng X, Gao X. Circ_0089761 accelerates colorectal cancer metastasis and immune escape via miR-27b-3p/PD-L1 axis. Physiol Rep 2024; 12:e70137. [PMID: 39632246 PMCID: PMC11617067 DOI: 10.14814/phy2.70137] [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: 08/06/2024] [Revised: 11/15/2024] [Accepted: 11/15/2024] [Indexed: 12/07/2024] Open
Abstract
Circular RNAs have been implicated as critical regulators in the initiation and progression of colorectal cancer (CRC). This study was intended to elucidate the functional significance of the circ_0089761/miR-27b-3p/programmed cell death ligand 1 (PD-L1) axis in CRC. Our findings indicated that circ_0089761 expression was significantly elevated in CRC tissues and cell lines. Furthermore, the high expression of circ_0089761 was correlated with TNM stage and tumor size. Silencing circ_0089761 inhibited CRC cell proliferation, migration, and invasion, and increased apoptosis. Mechanistically, circ_0089761 facilitated its biological function by binding to miR-27b-3p to upregulate PD-L1 expression in CRC. Coculture experiments confirmed that low expression of circ_0089761 impeded CD8 + T cell apoptosis and depletion, activated CD8 + T cell function, and increased secretion of the immune effector cytokines IFN-γ, TNF-α, perforin, and granzyme-B. MiR-27b-3p inhibition or PD-L1 overexpression partially impeded CD8 + T cell function. The circ_0089761/miR-27b-3p/PD-L1 axis is postulated to exert pivotal functions in the mechanistic progression of CRC. Furthermore, it holds promising prospects as a feasible biomarker and therapeutic target for CRC.
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Affiliation(s)
- Qizhong Gao
- Department of Gastrointestinal SurgeryAffiliated Hospital of Jiangnan UniversityWuxiJiangsuChina
| | - Xiaowei Cheng
- Internal Medicine OncologyAffiliated Hospital of Jiangnan UniversityWuxiJiangsuChina
| | - Xiang Gao
- Internal Medicine OncologyAffiliated Hospital of Jiangnan UniversityWuxiJiangsuChina
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Ahn HR, Kim S, Baek GO, Yoon MG, Kang M, Ng JT, Go Y, Lim SB, Yoon JH, Jeong JY, Han JE, Kim SS, Cheong JY, Eun JW, Cho HJ. Effect of Sortilin1 on promoting angiogenesis and systemic metastasis in hepatocellular carcinoma via the Notch signaling pathway and CD133. Cell Death Dis 2024; 15:634. [PMID: 39209807 PMCID: PMC11362463 DOI: 10.1038/s41419-024-07016-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 08/16/2024] [Accepted: 08/19/2024] [Indexed: 09/04/2024]
Abstract
Hepatocellular carcinoma (HCC) is known to be lethal disease. However, its prognosis remains poor, primarily because the precise oncogenic mechanisms underlying HCC progression remain elusive, thus hampering effective treatment. Here, we aimed to identify the potential oncogenes in HCC and elucidate the underlying mechanisms of their action. To identify potential candidate genes, an integrative analysis of eight publicly available genomic datasets was performed, and the functional implications of the identified genes were assessed in vitro and in vivo. Sortilin 1 (SORT1) was identified as a potential candidate oncogene in HCC, and its overexpression in HCC cells was confirmed by analyzing spatial transcriptomic and single-cell data. Silencing SORT1 in Huh-7 and Hep3B cells significantly reduced HCC progression in vitro and in vivo. Functional analyses of oncogenic pathways revealed that SORT1 expression regulated the Notch signaling pathway activation and CD133 expression. Furthermore, analysis of epigenetic regulation of the candidate gene and its clinical implications using The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA LIHC) and our HCC cohort (AJOU_HCC cohort) data demonstrated an inverse correlation between the methylation status of the SORT1 promoter region, specifically at the cg16988986 site, and SORT1 mRNA expression, indicating the epigenetic regulation of SORT1 in HCC. In addition, the distinct methylation status of cg16988986 was significantly associated with patient survival. In conclusion, SORT1 plays a pivotal role in HCC by activating the Notch signaling pathway and increasing CD133 expression. These findings suggest SORT1 as a promising therapeutic target for HCC.
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MESH Headings
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/metabolism
- Humans
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Liver Neoplasms/metabolism
- Adaptor Proteins, Vesicular Transport/metabolism
- Adaptor Proteins, Vesicular Transport/genetics
- Signal Transduction
- Animals
- Cell Line, Tumor
- Receptors, Notch/metabolism
- Receptors, Notch/genetics
- AC133 Antigen/metabolism
- AC133 Antigen/genetics
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/metabolism
- Gene Expression Regulation, Neoplastic
- Mice
- Male
- Mice, Nude
- Neoplasm Metastasis
- Female
- Mice, Inbred BALB C
- Epigenesis, Genetic
- Angiogenesis
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Affiliation(s)
- Hye Ri Ahn
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, South Korea
- Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, South Korea
| | - Sujin Kim
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, South Korea
- Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, South Korea
| | - Geum Ok Baek
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, South Korea
| | - Moon Gyeong Yoon
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, South Korea
| | - Minji Kang
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, South Korea
- Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, South Korea
| | - Jestlin Tianthing Ng
- Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, South Korea
- Department of Biochemistry & Molecular Biology, Ajou University School of Medicine, Suwon, South Korea
| | - Yunjin Go
- Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, South Korea
- Department of Biochemistry & Molecular Biology, Ajou University School of Medicine, Suwon, South Korea
| | - Su Bin Lim
- Department of Biochemistry & Molecular Biology, Ajou University School of Medicine, Suwon, South Korea
| | - Jung Hwan Yoon
- Department of Pathology College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Jee-Yeong Jeong
- Department of Biochemistry College of Medicine, Kosin University Gamchen-ro, Busan, South Korea
| | - Ji Eun Han
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, South Korea
| | - Soon Sun Kim
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, South Korea
| | - Jae Youn Cheong
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, South Korea
| | - Jung Woo Eun
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, South Korea.
| | - Hyo Jung Cho
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, South Korea.
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Li Y, Wang Z, Gao P, Cao D, Dong R, Zhu M, Fei Y, Zuo X, Cai J. CircRHBDD1 promotes immune escape via IGF2BP2/PD-L1 signaling and acts as a nanotherapeutic target in gastric cancer. J Transl Med 2024; 22:704. [PMID: 39080693 PMCID: PMC11289934 DOI: 10.1186/s12967-024-05498-9] [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: 04/10/2024] [Accepted: 07/09/2024] [Indexed: 08/02/2024] Open
Abstract
BACKGROUND Circular RNAs (circRNAs) have been implicated in the development and progression of gastric cancer (GC). However, it remains unclear whether dysregulated circRNA affects immune escape and the efficacy of immunotherapy in GC. Our aim is to investigate the molecular mechanism of circRNA affecting GC immunotherapy and identify effective molecular therapeutic targets. METHODS The differential expression profile of circRNAs was established through circRNA sequencing, comparing three paired GC tissues with their adjacent non-cancerous gastric tissues. The expression level of circRHBDD1 in GC tissues was then assessed using quantitative reverse transcription polymerase chain reaction (qRT-PCR). The biological characteristics of circRHBDD1 were verified through a series of experiments, including agarose gel electrophoresis assays, RNase R treatment, and actinomycin D experiments. The prognostic value of circRHBDD1 in GC was evaluated by conducting both univariate and multivariate survival analyses. Furthermore, loss- and gain-of-function approaches were utilized to investigate the impact of circRHBDD1 on GC immune escape. RNA-sequencing, immunoprecipitation, flow cytometry, and methylated RNA immunoprecipitation (meRIP) analysis were performed to elucidate the underlying molecular mechanisms. RESULTS We discovered that circRHBDD1 exhibited remarkably high expression levels in GC tissues and cell lines. Notably, the high expression of circRHBDD1 was significantly correlated with poor overall survival and disease-free survival among GC patients. Both in vitro and in vivo experiments revealed that circRHBDD1 upregulated the expression of PD-L1 and impeded the infiltration of CD8+ T cells. Further, we found that circRHBDD1 binds to IGF2BP2, disrupting the interaction between E3 ligase TRIM25 and IGF2BP2, and ultimately inhibiting IGF2BP2 ubiquitination and degradation. Intriguingly, IGF2BP2 enhances PD-L1 mRNA stability through m6A modification. Additionally, we developed Poly (lactide-co-glycolic acid) (PLGA)-Polyethylene glycol (PEG)-based nanoparticles loaded with circRHBDD1 siRNA. In vivo experiments validated that the combination of PLGA-PEG(si-circRHBDD1) and anti-PD-1 offers a safe and efficacious nano-drug regimen for cancer immunotherapy. CONCLUSION Our results demonstrated that circRHBDD1 promoted GC immune escape by upregulating the expression of PD-L1 and reprogramming T cell-mediated immune response. Inhibition of circRHBDD1 expression could potentially enhance the response of GC patients to immunotherapy, thus improving treatment outcomes. Additionally, the development of a nanodrug delivery system provides a feasible approach for future clinical applications.
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Affiliation(s)
- Yanna Li
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, 241001, China
| | - Zhixiong Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, 241001, China
| | - Peng Gao
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, 241001, China
| | - Danping Cao
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, 241001, China
| | - Runyu Dong
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, 241001, China
| | - Menglin Zhu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, 241001, China
| | - Yao Fei
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, 241001, China
| | - Xueliang Zuo
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, 241001, China.
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wannan Medical College, Wuhu, 241001, China.
| | - Juan Cai
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wannan Medical College, Wuhu, 241001, China.
- Department of Oncology, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, 241001, China.
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9
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Chen X, Wei H, Yue A, Zhang H, Zheng Y, Sun W, Zhou Y, Wang Y. KPNA2 promotes the progression of gastric cancer by regulating the alternative splicing of related genes. Sci Rep 2024; 14:17140. [PMID: 39060340 PMCID: PMC11282077 DOI: 10.1038/s41598-024-66678-7] [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: 01/09/2024] [Accepted: 07/03/2024] [Indexed: 07/28/2024] Open
Abstract
RNA-binding proteins (RBPs) play critical roles in genome regulation. In this study, we explored the latent function of KPNA2, which is an essential member of the RBP family, in the regulation of alternative splicing (AS) in gastric cancer (GC). We analyzed the role of KPNA2 in regulating differential expression and AS via RNA sequencing (RNA-seq) and improved RNA immunoprecipitation sequencing (iRIP-seq). Clinical specimens were used to analyze the associations between KPNA2 expression and clinicopathological characteristics. CCK8 assays, transwell assays and wound healing assays were performed to explore the effect of KPNA2/WDR62 on GC cell progression. KPNA2 was shown to be highly expressed in GC cells and tissues and associated with lymph node metastases. KPNA2 promoted the proliferation, migration and invasion of GC cells and primarily regulated exon skipping, alternative 3's splice sites (A3SSs), alternative 5' splice sites (A5SSs), and cassette exons. We further revealed that KPNA2 participated in biological processes related to cell proliferation, and the immune response in GC via the regulation of transcription. In addition, KPNA2 preferentially bound to intron regions. Notably, KPNA2 regulated the A3SS AS mode of WDR62, and upregulation of WDR62 reversed the KPNA2 downregulation-induced inhibition of GC cell proliferation, migration and invasion. Finally, we discovered that the AS of immune-related molecules could be regulated by KPNA2. Overall, our results demonstrated for the first time that KPNA2 functions as an oncogenic splicing factor in GC that regulated the AS and differential expression of GC-related genes, and KPNA2 may be a potential target for GC treatment.
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Affiliation(s)
- Xia Chen
- The First Clinical Medical College, Lanzhou University, Lanzhou, 730000, China
- Department of Gastroenterology, Key Laboratory for Gastrointestinal Diseases of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, 730000, Gansu Province, China
- Gansu Province Clinical Research Center for Digestive Diseases, The First Hospital of Lanzhou University, Lanzhou, 730000, China
| | - Hui Wei
- The First Clinical Medical College, Lanzhou University, Lanzhou, 730000, China
- Department of Gastroenterology, Key Laboratory for Gastrointestinal Diseases of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, 730000, Gansu Province, China
- Gansu Province Clinical Research Center for Digestive Diseases, The First Hospital of Lanzhou University, Lanzhou, 730000, China
| | - Ailin Yue
- The First Clinical Medical College, Lanzhou University, Lanzhou, 730000, China
- Department of Gastroenterology, Key Laboratory for Gastrointestinal Diseases of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, 730000, Gansu Province, China
- Gansu Province Clinical Research Center for Digestive Diseases, The First Hospital of Lanzhou University, Lanzhou, 730000, China
| | - Huiyun Zhang
- The First Clinical Medical College, Lanzhou University, Lanzhou, 730000, China
- Department of Gastroenterology, Key Laboratory for Gastrointestinal Diseases of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, 730000, Gansu Province, China
- Gansu Province Clinical Research Center for Digestive Diseases, The First Hospital of Lanzhou University, Lanzhou, 730000, China
| | - Ya Zheng
- Department of Gastroenterology, Key Laboratory for Gastrointestinal Diseases of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, 730000, Gansu Province, China
- Gansu Province Clinical Research Center for Digestive Diseases, The First Hospital of Lanzhou University, Lanzhou, 730000, China
| | - Weiming Sun
- Department of Endocrinology, The First Hospital of Lanzhou University, Lanzhou, 730000, China
| | - Yongning Zhou
- Department of Gastroenterology, Key Laboratory for Gastrointestinal Diseases of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, 730000, Gansu Province, China.
- Gansu Province Clinical Research Center for Digestive Diseases, The First Hospital of Lanzhou University, Lanzhou, 730000, China.
| | - Yuping Wang
- Department of Gastroenterology, Key Laboratory for Gastrointestinal Diseases of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, 730000, Gansu Province, China.
- Gansu Province Clinical Research Center for Digestive Diseases, The First Hospital of Lanzhou University, Lanzhou, 730000, China.
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Wei G, Chen X, Ruan T, Ma X, Zhu X, Wen W, He D, Tao K, Wu C. Human gastric cancer progression and stabilization of ATG2B through RNF5 binding facilitated by autophagy-associated CircDHX8. Cell Death Dis 2024; 15:410. [PMID: 38866787 PMCID: PMC11169566 DOI: 10.1038/s41419-024-06782-8] [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: 01/11/2024] [Revised: 05/23/2024] [Accepted: 05/28/2024] [Indexed: 06/14/2024]
Abstract
The role of circDHX8 in the interplay between autophagy and gastric cancer (GC) progression remains unclear. In this study, we investigated the mechanism underlying the role of hsa_circ_003899 (circDHX8) in the malignancy of GC. Differential expression of circRNAs between GC and normal tissues was determined using circle-seq and microarray datasets (GSE83521). These circRNAs were validated using qPCR and Sanger sequencing. The function of circDHX8 was investigated through interference with circDHX8 expression experiments using in vitro and in vivo functional assays. Western blotting, immunofluorescence, and transmission electron microscopy were used to establish whether circDHX8 promoted autophagy in GC cells. To elucidate the mechanism underlying the circDHX8-mediated regulation of autophagy, we performed bioinformatics analysis, RNA pull-down, mass spectrometry (MS), RNA immunoprecipitation (RIP), and other western Blot related experiments. Hsa_circ_0003899 (circDHX8) was identified as upregulated and shown to enhance the malignant progression in GC cells by promoting cellular autophagy. Mechanistically, circDHX8 increased ATG2B protein levels by preventing ubiquitin-mediated degradation, thereby facilitating cell proliferation and invasion in GC. Additionally, circDHX8 directly interacts with the E3 ubiquitin-protein ligase RNF5, inhibiting the RNF5-mediated degradation of ATG2B. Concurrently, ATG2B, an acetylated protein, is subjected to SIRT1-mediated deacetylation, enhancing its binding to RNF5. Consequently, we established a novel mechanism for the role of circDHX8 in the malignant progression of GC.
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Affiliation(s)
- Guanxin Wei
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xiang Chen
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Tuo Ruan
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xianxiong Ma
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xiuxian Zhu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Wenhao Wen
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Danzeng He
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Kaixiong Tao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Chuanqing Wu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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11
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Zhang M, Xu T, Tong D, Yu X, Liu B, Jiang L, Liu K. MiR-136-5p in cancer: Roles, mechanisms, and chemotherapy resistance. Gene 2024; 909:148265. [PMID: 38346459 DOI: 10.1016/j.gene.2024.148265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 01/25/2024] [Accepted: 02/06/2024] [Indexed: 02/29/2024]
Abstract
MicroRNAs (miRNAs) have emerged as important regulators of gene expression, and the deregulation of their activity has been linked to the onset and progression of a variety of human malignancies. Among these miRNAs, miR-136-5p has attracted significant attention due to its diverse roles in cancer biology. Mostly, miR-136-5p is downregulated in malignancies. It could inhibit viability, proliferation, migration, invasion and promote apoptosis of tumor cells. This review article provides a comprehensive overview of the current understanding of miR-136-5p in different sorts of human cancers: genital tumors, head and neck tumors, tumors from the digestive and urinary systems, skin cancers, neurologic tumors, pulmonary neoplasms and other cancers by discussing its molecular mechanisms, functional roles, and impact in chemotherapies. In conclusion, miR-136-5p could be a promising new biomarker and potential clinical therapeutic target.
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Affiliation(s)
- Manlin Zhang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Tongtong Xu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Deming Tong
- Department of General Surgery, General Hospital of Northern Theater Command, Shenyang, China
| | - Xiaodan Yu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Boya Liu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Lili Jiang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.
| | - Kuiran Liu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.
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12
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Yang YP, Bai M, Cheng YX, Feng X, Zhang YY, Zhang YY, Liu MY, Duan YQ. Based on the prognosis model of immunogenes, the prognosis model was constructed to predict the invasion of immune genes and immune cells related to primary liver cancer and its experimental validation. Heliyon 2024; 10:e27362. [PMID: 38560168 PMCID: PMC10980948 DOI: 10.1016/j.heliyon.2024.e27362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 02/28/2024] [Accepted: 02/28/2024] [Indexed: 04/04/2024] Open
Abstract
Background Primary liver cancer (PLC) is a prevalent malignancy of the digestive system characterized by insidious symptom onset and a generally poor prognosis. Recent studies have highlighted a significant correlation between the initiation and prognosis of liver cancer and the immune function of PLC patients. Purpose Revealing the expression of PLC-related immune genes and the characteristics of immune cell infiltration provides assistance for the analysis of clinical pathological parameters and prognosis of PLC patients. Methods PLC-related differentially expressed genes (DEGs) with a median absolute deviation (MAD > 0.5) were identified from TCGA and GEO databases. These DEGs were intersected with immune-related genes (IRGs) from the ImmPort database to obtain PLC-related IRGs. The method of constructing a prognostic model through immune-related gene pairs (IRGPs) is used to obtain IRGPs and conduct the selection of central immune genes. The central immune genes obtained from the selection of IRGPs are validated in PLC. Subsequently, the relative proportions of 22 types of immune cells in different immune risk groups are evaluated, and the differential characteristics of PLC-related immune cells are verified through animal experiments. Results Through database screening and the construction of an IRGP prognosis model, 84 pairs of IRGPs (P < 0.001) were ultimately obtained. Analysis of these 84 IRGPs revealed 11 central immune genes related to PLC, showing differential expression in liver cancer tissues compared to normal liver tissues. Results from the CiberSort platform indicate differential expression of immune cells such as naive B cells, macrophages, and neutrophils in different immune risk groups. Animal experiments demonstrated altered immune cell proportions in H22 tumor-bearing mice, validating findings from peripheral blood and spleen homogenate analyses. Conclusion Our study successfully predicted and validated PLC-related IRGs and immune cells, suggesting their potential as prognostic indicators and therapeutic targets for PLC.
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Affiliation(s)
- Yu-Ping Yang
- Gansu University of Traditional Chinese Medicine, College of Basic Medical Sciences, Lanzhou, 730000, PR China
| | - Min Bai
- Gansu University of Traditional Chinese Medicine, College of Basic Medical Sciences, Lanzhou, 730000, PR China
| | - Yin-Xia Cheng
- Ningxia Medical University, College of Traditional Chinese Medicine, Yinchuan, 750000, PR China
| | - Xin Feng
- Gansu University of Traditional Chinese Medicine, College of Basic Medical Sciences, Lanzhou, 730000, PR China
| | - Yan-Ying Zhang
- Gansu University of Traditional Chinese Medicine, College of Basic Medical Sciences, Lanzhou, 730000, PR China
| | - Yuan-Yuan Zhang
- Gansu University of Traditional Chinese Medicine, College of Basic Medical Sciences, Lanzhou, 730000, PR China
| | - Meng-Ya Liu
- Gansu University of Traditional Chinese Medicine, College of Basic Medical Sciences, Lanzhou, 730000, PR China
| | - Yong-Qiang Duan
- Ningxia Medical University, College of Traditional Chinese Medicine, Yinchuan, 750000, PR China
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13
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Tan G, Zheng S, Zhou B, Mo Z, Zhang Q, Zhang D, Li A, Liu X. Spleen tyrosine kinase facilitates the progression of papillary thyroid cancer regulated by the hsa_circ_0006417/miR-377-3p axis. ENVIRONMENTAL TOXICOLOGY 2024; 39:421-434. [PMID: 37792549 DOI: 10.1002/tox.23982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 08/20/2023] [Accepted: 09/18/2023] [Indexed: 10/06/2023]
Abstract
Papillary thyroid cancer (PTC) is a prevalent malignancy worldwide. Spleen tyrosine kinase (SYK) is a crucial enzyme that participates in various biological processes, including cancer progression. This study aims to uncover the biological function of SYK in PTC. SYK expression patterns in PTC were evaluated using quantitative real time polymerase chain reaction (qRT-PCR), immunohistochemistry (IHC), and western blot. Cell function assays were performed to assess the effects of SYK on PTC. Bioinformatics analysis was conducted to identify intriguing microRNA (miRNA) and circular RNA (circRNA). Dual-Luciferase Reporter or RNA immunoprecipitation assays were used to investigate the correlation among SYK, miR-377-3p, and hsa_circ_0006417. SYK was upregulated in PTC. Overexpression of SYK exhibited a positive correlation with tumor size, lymph node metastasis, and unfavorable disease-free survival. Functional assays revealed that SYK exerted tumorigenic effect on PTC cells through mTOR/4E-BP1 pathway. Mechanistically, hsa_circ_0006417 and miR-377-3p regulated SYK expression, offering modulating its tumor-promoting effects. Collectively, SYK acts as an oncogene in PTC through mTOR/4E-BP1 pathway, which is regulated by the hsa_circ_0006417/miR-377-3p axis, thereby providing a potential alternative for PTC treatment.
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Affiliation(s)
- Guangmou Tan
- Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
- Cancer Center, Southern Medical University, Guangzhou, China
- Department of Head and Neck Surgery, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Shiyang Zheng
- Department of Head and Neck Surgery, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Boxuan Zhou
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhaohong Mo
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qiong Zhang
- Department of Pathology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Donghui Zhang
- Department of Pathology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Aimin Li
- Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
- Cancer Center, Southern Medical University, Guangzhou, China
| | - Xinhui Liu
- Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
- Cancer Center, Southern Medical University, Guangzhou, China
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14
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Bao H, Li J, Dong Q, Liang Z, Yang C, Xu Y. Circular RNAs in pancreatic cancer progression. Clin Chim Acta 2024; 552:117633. [PMID: 37949391 DOI: 10.1016/j.cca.2023.117633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Revised: 11/03/2023] [Accepted: 11/05/2023] [Indexed: 11/12/2023]
Abstract
Pancreatic cancer (PC), typically diagnosed at relatively advanced stages with poor prognosis, is a dominant cause of cancer-related deaths worldwide. Accumulating evidence demonstrates that circular RNAs (circRNAs) are abnormally expressed in diverse tumors and affect tumorigenesis and progression. In this article, we examine the roles of circRNAs in regulation of PC progression. Additionally, circRNAs enriched in exosomes could be transferred among PC cells to modulate malignancy. Characterization of regulatory mechanisms involving circRNAs in general and PC specifically will enable earlier detection and potential development of therapeutic strategies.
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Affiliation(s)
- Haolin Bao
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Jiehan Li
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Qingfu Dong
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Zixin Liang
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Chengru Yang
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Yi Xu
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China; Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China; Key Laboratory of Basic Pharmacology of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563006, China; Key Laboratory of Functional and Clinical Translational Medicine, Fujian Province University, Xiamen Medical College, Xiamen, Fujian 361000, China; Anhui Province Key Laboratory of Translational Cancer Research, Bengbu Medical College, Bengbu, Anhui 233030, China; Jiangsu Province Engineering Research Center of Tumor Targeted Nano Diagnostic and Therapeutic Materials, Yancheng Teachers University, Yancheng, Jiangsu 224007, China; Key Laboratory of Biomarkers and In Vitro Diagnosis Translation of Zhejiang Province, Hangzhou, Zhejiang 310000, China; Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian 350122, China; State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China; Key Laboratory of Intelligent Pharmacy and Individualized Therapy of Huzhou and Department of Pharmacy, Changxing People's Hospital, Changxing, Zhejiang 313000, China.
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15
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Yan J, Yang J, Shen H, Gao R, Lv S. Sinomenine regulates circTRPM7-related pathway to inhibit gastric cancer cell growth and metastasis. Chem Biol Drug Des 2023; 102:870-881. [PMID: 37495546 DOI: 10.1111/cbdd.14297] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 05/24/2023] [Accepted: 07/12/2023] [Indexed: 07/28/2023]
Abstract
Sinomenine has been found to have antitumor effects in a variety of cancers, including gastric cancer. Circular RNA (circRNA) is an important regulator of gastric cancer progression. However, it is not known whether Sinomenine mediates gastric cancer processes by regulating circRNA-related pathways. Quantitative real-time PCR was used to measure the expression of circTRPM7, microRNA-145-5p (miR-145-5p), and pre-B-cell leukemia homeobox 3 (PBX3). MTT assay, colony formation assay, EdU assay, transwell assay, wound-healing assay, and flow cytometry were used to detect cell proliferation, migration, invasion, and apoptosis. The expression of related proteins was detected by Western blot. Mechanically, the interaction of miR-145-5p with circTRPM7/PBX3 was validated by dual-luciferase reporter assay and RIP assay. Our study showed that circTRPM7 expression was reduced in Sinomenine-treated gastric cancer cells. Moreover, overexpression of circTRPM7 upregulated the growth and metastasis of Sinomenine-treated gastric cancer cells. CircTRPM7 could sponge miR-145-5p, and miR-145-5p reversed the effect of circTRPM7 on the growth and metastasis of Sinomenine-treated gastric cancer cells. PBX3 was the target of miR-145-5p, and knockdown of PBX3 could restore the in-miR-145-5p promotion effect on the malignant behavior of Sinomenine-treated gastric cancer cells. To sum up, our data indicated that Sinomenine played an antitumor role in gastric cancer cells via circTRPM7/miR-145-5p/PBX3 axis.
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Affiliation(s)
- Jingwei Yan
- Department of Traditional Chinese Medicine, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China
| | - Jingqing Yang
- Department of Geriatric Medicine, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China
| | - Huifen Shen
- Department of Traditional Chinese Medicine, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China
| | - Rong Gao
- Department of Rheumatology and Immunology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China
| | - Shilong Lv
- Traditional Chinese Medicine, Weihai Health School, Weihai, China
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Song D, Ye Z, Chen F, Zhan L, Sun X. circFNDC3B promotes esophageal squamous cell carcinoma progression by targeting MYO5A via miR-370-3p/miR-136-5p. BMC Cancer 2023; 23:821. [PMID: 37667251 PMCID: PMC10476377 DOI: 10.1186/s12885-023-11314-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 08/18/2023] [Indexed: 09/06/2023] Open
Abstract
BACKGROUND Esophageal squamous cell carcinoma (ESCC) is a prevalent malignant tumor worldwide. Circular RNA (circRNA) is of great value in tumorigenesis progression. However, the mechanism of circFNDC3B in ESCC remains to be clarified. METHODS Firstly, the circular characteristics of circFNDC3B were evaluated by Actinomycin D and RNase R measurements. The functions of circFNDC3B in ESCC cells were examined by CCK-8, EdU and flow cytometry. Subsequently, the molecular mechanism of circFNDC3B was explained using luciferase reporter gene detection. Finally, we constructed xenograft model to prove the role of circFNDC3B in vivo. RESULTS Our study revealed that circFNDC3B was more stable than its linear RNA and prominently upregulated in ESCC. Functional findings suggested that silencing of circFNDC3B reduced the proliferation and enhanced apoptosis of ESCC cells in vitro. Meanwhile, knockdown of circFNDC3B attenuated tumor progression in vivo. Next, miR-370-3p/miR-136-5p was discovered to bind circFNDC3B. miR-370-3p/miR-136-5p reversed the promotive effect on cell proliferation and the inhibitory effect on cell apoptosis of circFNDC3B. MYO5A was a downstream target of miR-370-3p/miR-136-5p. CircFNDC3B served as a sponge for miR-370-3p/miR-136-5p and alleviated the prohibitory effect of miR-370-3p/miR-136-5p on MYO5A, which accelerated ESCC progression. CONCLUSION circFNDC3B positively adjusted the MYO5A expression via spongy miR-370-3p/miR-136-5p, hence achieving the cancer-promoting effect on ESCC. circFNDC3B was a prospective diagnosis marker for ESCC.
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Affiliation(s)
- Dan Song
- Department of Radiation Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, No.42, Baiziting, Nanjing, 210009, Jinagsu Province, China.
- Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou Road, Nanjing, 210029, Jiangsu, China.
| | - Ziqi Ye
- Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Fangyu Chen
- Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Liangliang Zhan
- Department of Radiation Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, No.42, Baiziting, Nanjing, 210009, Jinagsu Province, China
| | - Xinchen Sun
- Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou Road, Nanjing, 210029, Jiangsu, China.
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Yue W, Ye Y, Chen B, Wu D, Wang H, Hui G. CircRNA PDE3B regulates tumorigenicity via the miR-136-5p/MAP3K2 axis of esophageal squamous cell carcinoma. Histol Histopathol 2023; 38:1029-1041. [PMID: 36533720 DOI: 10.14670/hh-18-567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
BACKGROUND CircRNA has a covalently closed circular conformation and a stable structure. However, the exact role of circRNA in esophageal squamous cell carcinoma (ESCC) remains uncertain. The purpose of this study was to explore the role of hsa_circ_0000277 (circ_PDE3B) in ESCC. METHODS The expression levels of circ_PDE3B, miR-136-5p and mitogen-activated protein kinase kinase kinase 2 (MAP3K2) in ESCC tissues and cells were detected by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot. The proliferation ability of EC9706 and KYSE30 cells was detected by clonal formation, 5-ethynyl-2'-deoxyuridine (EdU) and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assays. Flow cytometry was used to detect the apoptosis rate of cells. Transwell assay was used to detect the invasion ability of EC9706 and KYSE3 cells. The relationship between miR-136-5p and circ_PDE3B or MAP3K2 was verified by dual-luciferase reporter assay and RNA pull-down, and the effect of circ_PDE3B on tumor growth in vivo was explored through tumor transplantation experiment. Immunohistochemistry (IHC) assay was used to detect MAP3K2 and Ki67 expression in mice tumor tissues. RESULTS The results showed that circ_PDE3B was highly expressed in ESCC tissues and cells. Downregulated circ_PDE3B expression in ESCC cells significantly reduced cell proliferation, migration and invasion. Circ_PDE3B served as a sponge for miR-136-5p, and miR-136-5p inhibition reversed the roles of circ_PDE3B knockdown in ESCC cells. MAP3K2 was a direct target of miR-136-5p, and miR-136-5p targeted MAP3K2 to inhibit the malignant behaviors of ESCC cells. Furthermore, circ_PDE3B regulated MAP3K2 expression by sponging miR-136-5p. Importantly, circ_PDE3B knockdown inhibited tumor growth in vivo. CONCLUSIONS In conclusion, circ_PDE3B acted as oncogenic circRNA in ESCC and accelerated ESCC progression by adsorption of miR-136-5p and activation of MAP3K2, supporting circ_PDE3B as a potential therapeutic target for ESCC.
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Affiliation(s)
- Wei Yue
- Department of Thoracic Surgery, Peking University Shenzhen Hospital, Shenzhen City, Guangdong, China
| | - Yiwang Ye
- Department of Thoracic Surgery, Peking University Shenzhen Hospital, Shenzhen City, Guangdong, China
| | - Baokun Chen
- Department of Thoracic Surgery, Peking University Shenzhen Hospital, Shenzhen City, Guangdong, China
| | - Da Wu
- Department of Thoracic Surgery, Peking University Shenzhen Hospital, Shenzhen City, Guangdong, China
| | - He Wang
- Department of Thoracic Surgery, Peking University Shenzhen Hospital, Shenzhen City, Guangdong, China
| | - Gang Hui
- Department of Thoracic Surgery, Peking University Shenzhen Hospital, Shenzhen City, Guangdong, China.
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Huang XJ, Wang Y, Wang HT, Liang ZF, Ji C, Li XX, Zhang LL, Ji RB, Xu WR, Jin JH, Qian H. Exosomal hsa_circ_000200 as a potential biomarker and metastasis enhancer of gastric cancer via miR-4659a/b-3p/HBEGF axis. Cancer Cell Int 2023; 23:151. [PMID: 37525152 PMCID: PMC10391853 DOI: 10.1186/s12935-023-02976-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Accepted: 06/26/2023] [Indexed: 08/02/2023] Open
Abstract
BACKGROUND Exosome, a component of liquid biopsy, loaded protein, DNA, RNA and lipid gradually emerges as biomarker in tumors. However, exosomal circRNAs as biomarker and function mechanism in gastric cancer (GC) are not well understood. METHODS Differentially expressed circRNAs in GC and healthy people were screened by database. The identification of hsa_circ_000200 was verified by RNase R and sequencing, and the expression of hsa_circ_000200 was evaluated using qRT-PCR. The biological function of hsa_circ_000200 in GC was verified in vitro. Western blot, RIP, RNA fluorescence in situ hybridization, and double luciferase assay were utilized to explore the potential mechanism of hsa_circ_000200. RESULTS Hsa_circ_000200 up-regulated in GC tissue, serum and serum exosomes. Hsa_circ_000200 in serum exosomes showed better diagnostic ability than that of tissues and serum. Combined with clinicopathological parameters, its level was related to invasion depth, TNM staging, and distal metastasis. Functionally, knockdown of hsa_circ_000200 inhibited GC cells proliferation, migration and invasion in vitro, while its overexpression played the opposite role. Importantly, exosomes with up-regulated hsa_circ_000200 promoted the proliferation and migration of co-cultured GC cells. Mechanistically, hsa_circ_000200 acted as a "ceRNA" for miR-4659a/b-3p to increase HBEGF and TGF-β/Smad expression, then promoted the development of GC. CONCLUSIONS Our findings suggest that hsa_circ_000200 promotes the progression of GC through hsa_circ_000200/miR-4659a/b-3p/HBEGF axis and affecting the expression of TGF-β/Smad. Serum exosomal hsa_circ_000200 may serve as a potential biomarker for GC.
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Affiliation(s)
- Xiao-Juan Huang
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Wujin Hospital Affiliated with Jiangsu University, 2 Yong Ning North Road, Chang Zhou, 213017, Jiangsu, China
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China
| | - Yan Wang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China
- Kunshan Hospital Affiliated with Jiangsu University, 91 Qianjin West Road, Kunshan, 215300, Jiangsu, China
| | - Hui-Ting Wang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China
| | - Zhao-Feng Liang
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Wujin Hospital Affiliated with Jiangsu University, 2 Yong Ning North Road, Chang Zhou, 213017, Jiangsu, China
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China
| | - Cheng Ji
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Wujin Hospital Affiliated with Jiangsu University, 2 Yong Ning North Road, Chang Zhou, 213017, Jiangsu, China
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China
| | - Xiao-Xi Li
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China
| | - Lei-Lei Zhang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China
| | - Run-Bi Ji
- The Laboratory Department, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, 212002, Jiangsu, China
| | - Wen-Rong Xu
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China
| | - Jian-Hua Jin
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Wujin Hospital Affiliated with Jiangsu University, 2 Yong Ning North Road, Chang Zhou, 213017, Jiangsu, China.
| | - Hui Qian
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Wujin Hospital Affiliated with Jiangsu University, 2 Yong Ning North Road, Chang Zhou, 213017, Jiangsu, China.
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China.
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Joshi N, Bhat F, Bellad A, Sathe G, Jain A, Chavan S, Sirdeshmukh R, Pandey A. Urinary Proteomics for Discovery of Gastric Cancer Biomarkers to Enable Precision Clinical Oncology. OMICS : A JOURNAL OF INTEGRATIVE BIOLOGY 2023; 27:361-371. [PMID: 37579183 PMCID: PMC10625469 DOI: 10.1089/omi.2023.0077] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/16/2023]
Abstract
For precision in clinical oncology practice, detection of tumor-derived peptides and proteins in urine offers an attractive and noninvasive alternative for diagnostic or screening purposes. In this study, we report comparative quantitative proteomic profiling of urine samples from patients with gastric cancer and healthy controls using tandem mass tags-based multiplexed mass spectrometry approach. We identified 1504 proteins, of which 246 were differentially expressed in gastric cancer cases. Notably, ephrin A1 (EFNA1), pepsinogen A3 (PGA3), sortilin 1 (SORT1), and vitronectin (VTN) were among the upregulated proteins, which are known to play crucial roles in the progression of gastric cancer. We also found other overexpressed proteins, including shisa family member 5 (SHISA5), mucin like 1 (MUCL1), and leukocyte cell derived chemotaxin 2 (LECT2), which had not previously been linked to gastric cancer. Using a novel approach for targeted proteomics, SureQuant, we validated changes in abundance of a subset of proteins discovered in this study. We confirmed the overexpression of vitronectin and sortilin 1 in an independent set of urine samples. Altogether, this study provides molecular candidates for biomarker development in gastric cancer, and the findings also support the promise of urinary proteomics for noninvasive diagnostics and personalized/precision medicine in the oncology clinic.
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Affiliation(s)
- Neha Joshi
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- Manipal Academy of Higher Education (MAHE), Manipal, India
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Firdous Bhat
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Anikha Bellad
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- Manipal Academy of Higher Education (MAHE), Manipal, India
| | - Gajanan Sathe
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- Manipal Academy of Higher Education (MAHE), Manipal, India
| | - Anu Jain
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Sandip Chavan
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Ravi Sirdeshmukh
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- Manipal Academy of Higher Education (MAHE), Manipal, India
| | - Akhilesh Pandey
- Manipal Academy of Higher Education (MAHE), Manipal, India
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
- Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA
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Sun Z, Chen X, Huang X, Wu Y, Shao L, Zhou S, Zheng Z, Lin Y, Chen S. Cuproptosis and Immune-Related Gene Signature Predicts Immunotherapy Response and Prognosis in Lung Adenocarcinoma. Life (Basel) 2023; 13:1583. [PMID: 37511958 PMCID: PMC10381686 DOI: 10.3390/life13071583] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 07/07/2023] [Accepted: 07/13/2023] [Indexed: 07/30/2023] Open
Abstract
Cuproptosis and associated immune-related genes (IRG) have been implicated in tumorigenesis and tumor progression. However, their effects on lung adenocarcinoma (LUAD) have not been elucidated. Therefore, we investigated the impact of cuproptosis-associated IRGs on the immunotherapy response and prognosis of LUAD using a bioinformatical approach and in vitro experiments analyzing clinical samples. Using the cuproptosis-associated IRG signature, we classified LUAD into two subtypes, cluster 1 and cluster 2, and identified three key cuproptosis-associated IRGs, NRAS, TRAV38-2DV8, and SORT1. These three genes were employed to establish a risk model and nomogram, and to classify the LUAD cohort into low- and high-risk subgroups. Biofunctional annotation revealed that cluster 2, remarkably downregulating epigenetic, stemness, and proliferation pathways activity, had a higher overall survival (OS) and immunoinfiltration abundance compared to cluster 1. Real-time quantitative PCR (RT-qPCR) validated the differential expression of these three genes in both subgroups. scRNA-seq demonstrated elevated expression of NRAS and SORT1 in macrophages. Immunity and oncogenic and stromal activation pathways were dramatically enriched in the low-risk subgroup, and patients in this subgroup responded better to immunotherapy. Our data suggest that the cuproptosis-associated IRG signature can be used to effectively predict the immunotherapy response and prognosis in LUAD. Our work provides enlightenment for immunotherapy response assessment, prognosis prediction, and the development of potential prognostic biomarkers for LUAD patients.
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Affiliation(s)
- Zihao Sun
- Department of Immuno-Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China
- Guangdong Provincial Engineering Research Center for Esophageal Cancer Precision Therapy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China
| | - Xiujing Chen
- Department of Immuno-Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China
- Guangdong Provincial Engineering Research Center for Esophageal Cancer Precision Therapy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China
| | - Xiaoning Huang
- Department of Immuno-Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China
- Guangdong Provincial Engineering Research Center for Esophageal Cancer Precision Therapy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China
| | - Yanfen Wu
- Department of Immuno-Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China
| | - Lijuan Shao
- Department of Immuno-Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China
- Key Laboratory of Cancer Immunotherapy of Guangdong Higher Education Institutes, Guangzhou 510080, China
| | - Suna Zhou
- Department of Immuno-Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China
- Guangdong Provincial Engineering Research Center for Esophageal Cancer Precision Therapy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China
| | - Zhu Zheng
- Department of Immuno-Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China
- Guangdong Provincial Engineering Research Center for Esophageal Cancer Precision Therapy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China
| | - Yiguang Lin
- Department of Immuno-Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China
- Guangdong Provincial Engineering Research Center for Esophageal Cancer Precision Therapy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China
- Key Laboratory of Cancer Immunotherapy of Guangdong Higher Education Institutes, Guangzhou 510080, China
- Research & Development Division, Guangzhou Anjie Biomedical Technology Co., Ltd., Guangzhou 510535, China
| | - Size Chen
- Department of Immuno-Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China
- Guangdong Provincial Engineering Research Center for Esophageal Cancer Precision Therapy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China
- Key Laboratory of Cancer Immunotherapy of Guangdong Higher Education Institutes, Guangzhou 510080, China
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Kong XX, Yang X, Jiang WJ, Zhu DM, Kong LB. The Long Non-Coding RNA AC006329.1 Facilitates Hepatocellular Carcinoma Progression and Metastasis by Regulating miR-127-5p/SHC3/ERK Axis. J Hepatocell Carcinoma 2023; 10:1085-1103. [PMID: 37483310 PMCID: PMC10361282 DOI: 10.2147/jhc.s415309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 07/03/2023] [Indexed: 07/25/2023] Open
Abstract
Purpose Hepatocellular carcinoma(HCC) is the most common type of liver cancer and the sixth largest common cancer worldwide. Although surgical resection, hepatic arterial chemoembolization, targeted drugs and immunotherapy are currently available, the mortality of advanced patients remains high. Therefore, new therapeutic targets are urgently needed. In recent years, many studies have found that The long non-coding RNA(lncRNA) has multiple functions in human tumors, including participating in epigenetic, transcriptional, post-transcriptional and translational regulation, and is closely related to the progression of HCC. The purpose of this study was to investigate the role of AC006329.1 in HCC progression and provide theoretical guidance for finding new targets. Patients and Methods AC006329.1 was screened out by transcriptome sequencing and quantitative real-time polymerase chain reaction (qRT-PCR). Then a series of functional tests in vivo and in vitro were conducted to investigate the effects of AC006329.1 on HCC progression and metastasis. Epithelial-mesenchymal transformation (EMT) of HCC was detected by Western blot and immunofluorescence staining. The targeted miRNA and downstream gene of AC006329.1 were predicted by databases and the pathway regulation axis eventually validated by dual luciferase reporter assays, qRT-PCR and WB. Results AC006329.1 was found high expressed in HCC tissues and cell lines by qRT-PCR. The prognosis of HCC patients with high expressed AC006329.1 was poor. In vitro and in vivo, overexpression of AC006329.1 can promote the progression, metastasis and EMT of HCC by acting as a sponge of miR-127-5p to increase the expression of SHC3. In addition, up-regulation of miR-127-5p or knockdown of SHC3 can both reverse the promoting effects of AC006329.1 on progression, metastasis and EMT of HCC. Finally, WB and qRT-PCR analysis was discovered that AC006329.1 can facilitate HCC progression, EMT and metastasis by competitively inhibiting miR-127-5p to activate SHC3/ERK signaling pathway. Conclusion These above experimental results confirmed that AC006329.1 can facilitate HCC progression, EMT and metastasis by acting as a competing endogenous RNA (ceRNA) to inhibit miR-127-5p and activate SHC3/ERK signaling pathway.
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Affiliation(s)
- Xiang Xu Kong
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, People’s Republic of China
| | - Xiao Yang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, People’s Republic of China
| | - Wang Jie Jiang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, People’s Republic of China
| | - De Ming Zhu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, People’s Republic of China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, 210000, People’s Republic of China
| | - Lian Bao Kong
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, People’s Republic of China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, 210000, People’s Republic of China
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Yang YJ, Xu XQ, Zhang YC, Hu PC, Yang WX. Establishment of a prognostic model related to tregs and natural killer cells infiltration in bladder cancer. World J Clin Cases 2023; 11:3444-3456. [PMID: 37383920 PMCID: PMC10294199 DOI: 10.12998/wjcc.v11.i15.3444] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 03/08/2023] [Accepted: 04/12/2023] [Indexed: 05/25/2023] Open
Abstract
BACKGROUND Regulatory T cells (Tregs) and natural killer (NK) cells play an essential role in the development of bladder urothelial carcinoma (BUC).
AIM To construct a prognosis-related model to judge the prognosis of patients with bladder cancer, meanwhile, predict the sensitivity of patients to chemotherapy and immunotherapy.
METHODS Bladder cancer information data was obtained from The Cancer Genome Atlas and GSE32894. The CIBERSORT was used to calculate the immune score of each sample. Weighted gene co-expression network analysis was used to find genes that will have the same or similar expression patterns. Subsequently, multivariate cox regression and lasso regression was used to further screen prognosis-related genes. The prrophetic package was used to predict phenotype from gene expression data, drug sensitivity of external cell line and predict clinical data.
RESULTS The stage and risk scores are independent prognostic factors in patients with BUC. Mutations in FGFR3 lead to an increase in Tregs percolation and affect the prognosis of the tumor, and additionally, EMP1, TCHH and CNTNAP3B in the model are mainly positively correlated with the expression of immune checkpoints, while CMTM8, SORT1 and IQSEC1 are negatively correlated with immune checkpoints and the high-risk group had higher sensitivity to chemotherapy drugs.
CONCLUSION Prognosis-related models of bladder tumor patients, based on Treg and NK cell percolation in tumor tissue. In addition to judging the prognosis of patients with bladder cancer, it can also predict the sensitivity of patients to chemotherapy and immunotherapy. At the same time, patients were divided into high and low risk groups based on this model, and differences in genetic mutations were found between the high and low risk groups.
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Affiliation(s)
- Yan-Jie Yang
- Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan 528308, Guangdong Province, China
| | - Xiao-Qing Xu
- The Graduate School, Tianjin Medical University, Tianjin 300041, China
| | - Yi-Chao Zhang
- The Graduate School, Qinghai University, Xi'ning 810000, Qinghai Province, China
| | - Peng-Cheng Hu
- Department of Ophthalmology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Wu-Xia Yang
- The Graduate School/Department of Traditional Chinese Medicine, Tianjin Medical University/Tianjin Medical University General Hospital, Tianjin 300041, China
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Li W, Wang Q, Lu J, Zhao B, Geng Y, Wu X, Chen X. Machine learning-based prognostic modeling of lysosome-related genes for predicting prognosis and immune status of patients with hepatocellular carcinoma. Front Immunol 2023; 14:1169256. [PMID: 37275878 PMCID: PMC10237352 DOI: 10.3389/fimmu.2023.1169256] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Accepted: 05/10/2023] [Indexed: 06/07/2023] Open
Abstract
Background Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. Lysosomes are organelles that play an important role in cancer progression by breaking down biomolecules. However, the molecular mechanisms of lysosome-related genes in HCC are not fully understood. Methods We downloaded HCC datasets from TCGA and GEO as well as lysosome-related gene sets from AIMGO. After univariate Cox screening of the set of lysosome-associated genes differentially expressed in HCC and normal tissues, risk models were built by machine learning. Model effects were assessed using the concordance index (C-index), Kaplan-Meier (K-M) and receiver operating characteristic curves (ROC). Additionally, we explored the biological function and immune microenvironment between the high- and low-risk groups, and analyzed the response of the high- and low-risk groups to immunotherapy responsiveness and chemotherapeutic agents. Finally, we explored the function of a key gene (RAMP3) at the cellular level. Results Univariate Cox yielded 46 differentially and prognostically significant lysosome-related genes, and risk models were constructed using eight genes (RAMP3, GPLD1, FABP5, CD68, CSPG4, SORT1, CSPG5, CSF3R) derived from machine learning. The risk model was a better predictor of clinical outcomes, with the higher risk group having worse clinical outcomes. There were significant differences in biological function, immune microenvironment, and responsiveness to immunotherapy and drug sensitivity between the high and low-risk groups. Finally, we found that RAMP3 inhibited the proliferation, migration, and invasion of HCC cells and correlated with the sensitivity of HCC cells to Idarubicin. Conclusion Lysosome-associated gene risk models built by machine learning can effectively predict patient prognosis and offer new prospects for chemotherapy and immunotherapy in HCC. In addition, cellular-level experiments suggest that RAMP3 may be a new target for the treatment of HCC.
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Affiliation(s)
- Wenhua Li
- Key Laboratory for Prevention and Treatment of High Morbidity in Central Asia, National Health and Health Commission, Shihezi, China
- Department of Immunology, Shihezi University School of Medicine, Shihezi, China
| | - Qianwen Wang
- Key Laboratory for Prevention and Treatment of High Morbidity in Central Asia, National Health and Health Commission, Shihezi, China
- Department of Immunology, Shihezi University School of Medicine, Shihezi, China
| | - Junxia Lu
- Key Laboratory for Prevention and Treatment of High Morbidity in Central Asia, National Health and Health Commission, Shihezi, China
- Department of Immunology, Shihezi University School of Medicine, Shihezi, China
| | - Bin Zhao
- Key Laboratory for Prevention and Treatment of High Morbidity in Central Asia, National Health and Health Commission, Shihezi, China
- Department of Immunology, Shihezi University School of Medicine, Shihezi, China
| | - Yuqing Geng
- Key Laboratory for Prevention and Treatment of High Morbidity in Central Asia, National Health and Health Commission, Shihezi, China
- Department of Immunology, Shihezi University School of Medicine, Shihezi, China
| | - Xiangwei Wu
- Key Laboratory for Prevention and Treatment of High Morbidity in Central Asia, National Health and Health Commission, Shihezi, China
- Department of Immunology, Shihezi University School of Medicine, Shihezi, China
- The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, China
| | - Xueling Chen
- Key Laboratory for Prevention and Treatment of High Morbidity in Central Asia, National Health and Health Commission, Shihezi, China
- Department of Immunology, Shihezi University School of Medicine, Shihezi, China
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Zheng W, Wang X, Yu Y, Ji C, Fang L. CircRNF10-DHX15 interaction suppressed breast cancer progression by antagonizing DHX15-NF-κB p65 positive feedback loop. Cell Mol Biol Lett 2023; 28:34. [PMID: 37101128 PMCID: PMC10131429 DOI: 10.1186/s11658-023-00448-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Accepted: 04/11/2023] [Indexed: 04/28/2023] Open
Abstract
BACKGROUND Breast cancer (BC) is a common threat to women. The continuous activation of nuclear factor kappa B (NF-κB) signaling pathway contributes to the development of BC. This study aimed to investigate the role of a circular RNA (circRNF10) in BC progression and regulating NF-κB signaling pathway. METHODS Bioinformatics analysis, RT-qPCR, subcellular fractionation, FISH, RNase R treatment, and actinomycin D assay were used to explore the expression and characteristics of circRNF10 in BC. The biological functions of circRNF10 in BC were analyzed by MTT assay, colony formation assay, wound healing assay, and Transwell assay. RNA pulldown and RIP assay were used to identify the interaction between circRNF10 and DEAH (Asp-Glu-Ala-His) box helicase 15 (DHX15). The impact of circRNF10-DHX15 interaction on NF-κB signaling pathway was explored by western blot, IF, and co-IP. Furthermore, dual-luciferase reporter assay, ChIP, and EMSA were performed to assess the effect of NF-κB p65 on DHX15 transcription. RESULTS CircRNF10 was downregulated in BC, and lower expression of circRNF10 was related to poor prognosis of patients with BC. CircRNF10 inhibited the proliferation and migration of BC. Mechanically, circRNF10-DHX15 interaction sequestered DHX15 from NF-κB p65, thereby inhibiting the activation of NF-κB signaling pathway. On the other hand, NF-κB p65 enhanced DHX15 transcription by binding to the promoter of DHX15. Altogether, circRNF10 impaired the DHX15-NF-κB p65 positive feedback loop and suppressed the progression of BC. CONCLUSION CircRNF10-DHX15 interaction suppressed the DHX15-NF-κB p65 positive feedback loop, thereby inhibiting BC progression. These findings provide new insights in the continuous activation of NF-κB signaling pathway and raised potential therapeutic approach for BC treatment.
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Affiliation(s)
- Wenfang Zheng
- Department of Breast and Thyroid Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, 301 Yanchangzhong Road, Shanghai, 200072, People's Republic of China
| | - Xuehui Wang
- Department of Breast and Thyroid Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, 301 Yanchangzhong Road, Shanghai, 200072, People's Republic of China
| | - Yunhe Yu
- Department of Breast and Thyroid Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, 301 Yanchangzhong Road, Shanghai, 200072, People's Republic of China
| | - Changle Ji
- Department of Breast and Thyroid Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, 301 Yanchangzhong Road, Shanghai, 200072, People's Republic of China
| | - Lin Fang
- Department of Breast and Thyroid Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, 301 Yanchangzhong Road, Shanghai, 200072, People's Republic of China.
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Lin XH, Li DP, Liu ZY, Zhang S, Tang WQ, Chen RX, Weng SQ, Tseng YJ, Xue RY, Dong L. Six immune-related promising biomarkers may promote hepatocellular carcinoma prognosis: a bioinformatics analysis and experimental validation. Cancer Cell Int 2023; 23:52. [PMID: 36959615 PMCID: PMC10035283 DOI: 10.1186/s12935-023-02888-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 02/23/2023] [Indexed: 03/25/2023] Open
Abstract
Background Abnormal miRNA and mRNA expression and dysregulated immune microenvironment have been found to frequently induce the progression of hepatocellular carcinoma (HCC) in recent reports. In particular, the immune-related competing endogenous RNAs (ceRNA) mechanism plays a crucial role in HCC progression. However, the underlying mechanisms remain unclear. Methods Differentially expressed immune-related genes were obtained from the Immport, GEO, and TCGA databases. The mRNA and protein expression levels in HCC tissues and adjacent normal tissues were confirmed, and we further investigated the methylation levels of these biomarkers to explore their function. Then, the TIMER and TISCH databases were used to assess the relationship between immune infiltration and hub genes. Survival analysis and univariate and multivariate Cox models were used to evaluate the association between hub genes and HCC diagnosis. Hub gene expression was experimentally validated in six HCC cell lines and 15 HCC samples using qRT-PCR and immunohistochemistry. The hub genes were uploaded to DSigDB for drug prediction enrichment analysis. Results We identified that patients with abnormal miRNAs (hsa-miR-125b-5p and hsa-miR-21-5p) and their targeted genes (NTF3, PSMD14, CD320, and SORT1) had a worse prognosis. Methylation analysis of miRNA-targeted genes suggested that alteration of methylation levels is also a factor in the induction of tumorigenesis. We also found that the development of HCC progression caused by miRNA-mRNA interactions may be closely correlated with the infiltration of immunocytes. Moreover, the GSEA, GO, and KEGG analysis suggested that several common immune-related biological processes and pathways were related to miRNA-targeted genes. The results of qRT-PCR, immunohistochemistry, and western blotting were consistent with our bioinformatics results, suggesting that abnormal miRNAs and their targeted genes may affect HCC progression. Conclusions Briefly, our study systematically describes the mechanisms of miRNA-mRNA interactions in HCC and predicts promising biomarkers that are associated with immune filtration for HCC progression. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-023-02888-9.
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Affiliation(s)
- Xia-Hui Lin
- grid.8547.e0000 0001 0125 2443Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
- grid.413087.90000 0004 1755 3939Shanghai Institute of Liver Disease, Shanghai, 200032 China
| | - Dong-ping Li
- grid.8547.e0000 0001 0125 2443Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
- grid.413087.90000 0004 1755 3939Shanghai Institute of Liver Disease, Shanghai, 200032 China
| | - Zhi-Yong Liu
- grid.8547.e0000 0001 0125 2443Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
- grid.413087.90000 0004 1755 3939Shanghai Institute of Liver Disease, Shanghai, 200032 China
| | - Si Zhang
- grid.8547.e0000 0001 0125 2443Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032 China
| | - Wen-qing Tang
- grid.8547.e0000 0001 0125 2443Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
- grid.413087.90000 0004 1755 3939Shanghai Institute of Liver Disease, Shanghai, 200032 China
| | - Rong-xin Chen
- grid.8547.e0000 0001 0125 2443Key Laboratory of Carcinogenesis and Cancer Invasion, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
| | - Shu-qiang Weng
- grid.8547.e0000 0001 0125 2443Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
- grid.413087.90000 0004 1755 3939Shanghai Institute of Liver Disease, Shanghai, 200032 China
| | - Yu-jen Tseng
- grid.8547.e0000 0001 0125 2443Department of Digestive Diseases, Huashan Hospital, Fudan University, 12 Wulumuqi Middle Road, Shanghai, 200040 China
| | - Ru-yi Xue
- grid.8547.e0000 0001 0125 2443Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
- grid.413087.90000 0004 1755 3939Shanghai Institute of Liver Disease, Shanghai, 200032 China
| | - Ling Dong
- grid.8547.e0000 0001 0125 2443Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
- grid.413087.90000 0004 1755 3939Shanghai Institute of Liver Disease, Shanghai, 200032 China
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Li Q, Kong F, Cong R, Ma J, Wang C, Ma X. PVT1/miR-136/Sox2/UPF1 axis regulates the malignant phenotypes of endometrial cancer stem cells. Cell Death Dis 2023; 14:177. [PMID: 36869031 PMCID: PMC9984375 DOI: 10.1038/s41419-023-05651-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 12/22/2022] [Accepted: 02/03/2023] [Indexed: 03/05/2023]
Abstract
Tumor stem cells (TSCs) are thought to contribute to the progression and maintenance of cancer. Previous studies have suggested that plasmacytoma variant translocation 1 (PVT1) has a tumor-promoting effect on endometrial cancer; however, its mechanism of action in endometrial cancer stem cells (ECSCs) is unknown. Here, we found that PVT1 was highly expressed in endometrial cancers and ECSCs, correlated with poor patient prognosis, promoted the malignant behavior and the stemness of endometrial cancer cells (ECCs) and ECSCs. In contrast, miR-136, which was lowly expressed in endometrial cancer and ECSCs, had the opposite effect, and knockdown miR-136 inhibited the anticancer effects of down-regulated PVT1. PVT1 affected miR-136 specifically binding the 3' UTR region of Sox2 by competitively "sponging" miR-136, thus positively saving Sox2. Sox2 promoted the malignant behavior and the stemness of ECCs and ECSCs, and overexpression Sox2 inhibited the anticancer effects of up-regulated miR-136. Sox2 can act as a transcription factor to positively regulate Up-frameshift protein 1 (UPF1) expression, thereby exerting a tumor-promoting effect on endometrial cancer. In nude mice, simultaneously downregulating PVT1 and upregulating miR-136 exerted the strongest antitumor effect. We demonstrate that the PVT1/miR-136/Sox2/UPF1 axis plays an important role in the progression and maintenance of endometrial cancer. The results suggest a novel target for endometrial cancer therapies.
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Affiliation(s)
- Qing Li
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, 39 Huaxiang Road, Tiexi District, Shenyang City, Liaoning Province, 110022, China
| | - Fanfei Kong
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, 39 Huaxiang Road, Tiexi District, Shenyang City, Liaoning Province, 110022, China
| | - Rong Cong
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, 39 Huaxiang Road, Tiexi District, Shenyang City, Liaoning Province, 110022, China
| | - Jian Ma
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, 39 Huaxiang Road, Tiexi District, Shenyang City, Liaoning Province, 110022, China
| | - Cuicui Wang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, 39 Huaxiang Road, Tiexi District, Shenyang City, Liaoning Province, 110022, China
| | - Xiaoxin Ma
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, 39 Huaxiang Road, Tiexi District, Shenyang City, Liaoning Province, 110022, China.
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Wang X, Zhang J, Cao G, Hua J, Shan G, Lin W. Emerging roles of circular RNAs in gastric cancer metastasis and drug resistance. J Exp Clin Cancer Res 2022; 41:218. [PMID: 35821160 PMCID: PMC9277821 DOI: 10.1186/s13046-022-02432-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 07/04/2022] [Indexed: 02/08/2023] Open
Abstract
Gastric cancer (GC) is an aggressive malignancy with a high mortality rate and poor prognosis, primarily caused by metastatic lesions. Improved understanding of GC metastasis at the molecular level yields meaningful insights into potential biomarkers and therapeutic targets. Covalently closed circular RNAs (circRNAs) have emerged as crucial regulators in diverse human cancers including GC. Furthermore, accumulating evidence has demonstrated that circRNAs exhibit the dysregulated patterns in GC and have emerged as crucial regulators in GC invasion and metastasis. However, systematic knowledge regarding the involvement of circRNAs in metastatic GC remains obscure. In this review, we outline the functional circRNAs related to GC metastasis and drug resistance and discuss their underlying mechanisms, providing a comprehensive delineation of circRNA functions on metastatic GC and shedding new light on future therapeutic interventions for GC metastases.
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Chen B, Hong Y, Gui R, Zheng H, Tian S, Zhai X, Xie X, Chen Q, Qian Q, Ren X, Fan L, Jiang C. N6-methyladenosine modification of circ_0003215 suppresses the pentose phosphate pathway and malignancy of colorectal cancer through the miR-663b/DLG4/G6PD axis. Cell Death Dis 2022; 13:804. [PMID: 36127319 PMCID: PMC9489788 DOI: 10.1038/s41419-022-05245-2] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 09/02/2022] [Accepted: 09/07/2022] [Indexed: 01/23/2023]
Abstract
Circular RNAs (circRNAs) are a recently discovered kind of regulatory RNAs that have emerged as critical biomarkers of various types of cancers. Metabolic reprogramming has gradually been identified as a distinct hallmark of cancer cells. The pentose phosphate pathway (PPP) plays an indispensable role in satisfying the bioenergetic and biosynthetic demands of cancer cells. However, little is known about the role of circRNAs and PPP in colorectal cancer (CRC). The novel circ_0003215 was identified at low levels in CRC and was negatively correlated with larger tumor size, higher TNM stage, and lymph node metastasis. The decreased level of circ_0003215 was resulted from the RNA degradation by m6A writer protein YTHDF2. A series of functional assays demonstrated that circ_0003215 inhibited cell proliferation, migration, invasion, and CRC tumor metastasis in vivo and in vitro. Moreover, circ_0003215 regulated the expression of DLG4 via sponging miR-663b, thereby inducing the metabolic reprogramming in CRC. Mechanismly, DLG4 inhibited the PPP through the K48-linked ubiquitination of glucose-6-phosphate dehydrogenase (G6PD). Taken together, we have identified m6A-modified circ_0003215 as a novel regulator of metabolic glucose reprogramming that inhibited the PPP and the malignant phenotype of CRC via the miR-663b/DLG4/G6PD axis.
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Affiliation(s)
- Baoxiang Chen
- Department of Colorectal and Anal Surgery, Zhongnan Hospital of Wuhan University, 430071, Wuhan, China
- Clinical Center of Intestinal and Colorectal Diseases of Hubei Province (Zhongnan Hospital of Wuhan University), 430071, Wuhan, China
- Hubei Key Laboratory of Intestinal and Colorectal Diseases (Zhongnan Hospital of Wuhan University), 430071, Wuhan, China
| | - Yuntian Hong
- Department of Colorectal and Anal Surgery, Zhongnan Hospital of Wuhan University, 430071, Wuhan, China
- Clinical Center of Intestinal and Colorectal Diseases of Hubei Province (Zhongnan Hospital of Wuhan University), 430071, Wuhan, China
- Hubei Key Laboratory of Intestinal and Colorectal Diseases (Zhongnan Hospital of Wuhan University), 430071, Wuhan, China
| | - Rui Gui
- Department of Infectious Diseases, Southwest Hospital, Third Military Medical University (Army Medical University), 400038, Chongqing, China
| | - Huabin Zheng
- CAS Key Laboratory of Special Pathogens and Biosafety, CAS Center for Influenza Research and Early Warning, Wuhan Institute of Virology, Chinese Academy of Sciences, 430064, Wuhan, China
| | - Shunhua Tian
- Department of Colorectal and Anal Surgery, Zhongnan Hospital of Wuhan University, 430071, Wuhan, China
- Clinical Center of Intestinal and Colorectal Diseases of Hubei Province (Zhongnan Hospital of Wuhan University), 430071, Wuhan, China
- Hubei Key Laboratory of Intestinal and Colorectal Diseases (Zhongnan Hospital of Wuhan University), 430071, Wuhan, China
| | - Xiang Zhai
- Department of Colorectal and Anal Surgery, Zhongnan Hospital of Wuhan University, 430071, Wuhan, China
- Clinical Center of Intestinal and Colorectal Diseases of Hubei Province (Zhongnan Hospital of Wuhan University), 430071, Wuhan, China
- Hubei Key Laboratory of Intestinal and Colorectal Diseases (Zhongnan Hospital of Wuhan University), 430071, Wuhan, China
| | - Xiaoyu Xie
- Department of Colorectal and Anal Surgery, Zhongnan Hospital of Wuhan University, 430071, Wuhan, China
- Clinical Center of Intestinal and Colorectal Diseases of Hubei Province (Zhongnan Hospital of Wuhan University), 430071, Wuhan, China
- Hubei Key Laboratory of Intestinal and Colorectal Diseases (Zhongnan Hospital of Wuhan University), 430071, Wuhan, China
| | - Quanjiao Chen
- CAS Key Laboratory of Special Pathogens and Biosafety, CAS Center for Influenza Research and Early Warning, Wuhan Institute of Virology, Chinese Academy of Sciences, 430064, Wuhan, China
| | - Qun Qian
- Department of Colorectal and Anal Surgery, Zhongnan Hospital of Wuhan University, 430071, Wuhan, China
- Clinical Center of Intestinal and Colorectal Diseases of Hubei Province (Zhongnan Hospital of Wuhan University), 430071, Wuhan, China
- Hubei Key Laboratory of Intestinal and Colorectal Diseases (Zhongnan Hospital of Wuhan University), 430071, Wuhan, China
| | - Xianghai Ren
- Department of Colorectal and Anal Surgery, Zhongnan Hospital of Wuhan University, 430071, Wuhan, China.
- Clinical Center of Intestinal and Colorectal Diseases of Hubei Province (Zhongnan Hospital of Wuhan University), 430071, Wuhan, China.
- Hubei Key Laboratory of Intestinal and Colorectal Diseases (Zhongnan Hospital of Wuhan University), 430071, Wuhan, China.
| | - Lifang Fan
- Department of Pathology, Zhongnan Hospital of Wuhan University, 430071, Wuhan, China.
| | - Congqing Jiang
- Department of Colorectal and Anal Surgery, Zhongnan Hospital of Wuhan University, 430071, Wuhan, China.
- Clinical Center of Intestinal and Colorectal Diseases of Hubei Province (Zhongnan Hospital of Wuhan University), 430071, Wuhan, China.
- Hubei Key Laboratory of Intestinal and Colorectal Diseases (Zhongnan Hospital of Wuhan University), 430071, Wuhan, China.
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Sortilin 1 Promotes Hepatocellular Carcinoma Cell Proliferation and Migration by Regulating Immune Cell Infiltration. JOURNAL OF ONCOLOGY 2022; 2022:6509028. [PMID: 35847356 PMCID: PMC9286884 DOI: 10.1155/2022/6509028] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 05/24/2022] [Indexed: 12/17/2022]
Abstract
Objectives Recent evidence suggests that Sort1 promotes carcinogenesis and tumor progression in multiple types of cancers. This study investigates the role of Sort1 in hepatocellular carcinoma (HCC). Methods The differentially expressed gene was screened through GEO and TCGA databases. The Sort1 gene was identified and its expression was then verified by TCGA and HCCDB (a database of hepatocellular carcinoma expression atlas) databases. The Human Protein Atlas database was used to assess the gene expression in tissues. The TCGA and KM-plotter databases were used to study the relationship between Sort1 and HCC. The correlation between Sort1 and immune cells was evaluated through the TIMER database. GO and KEGG enrichment analysis was used to investigate the possible mechanism. The role of Sort1 in cell proliferation and invasion of HCC was further explored through in vitro experiments. Result The differentially expressed molecule obtained from database screening was Sort1. Its expression was higher in cancer tissues than in paracancerous ones, and it was mainly located in the cytoplasm. The TCGA, KM-plotter databases, and our study data showed that low expression of Sort1 in HCC patients had better overall survival (OS), progression-free survival (PFI), and disease-specific survival (DSS). Further analysis indicated a significant correlation between Sort1 expression and immune cell infiltration. The gene set enrichment analysis (GSEA) analysis showed that Sort1 affected the biological events of HCC by participating in the WNT, TGF-BETA, JAK, STAT, and CALCIUM signaling pathways. In vitro, cytological experiments demonstrated reduced expression of PCNA, Ki-67, Vimentin, N-cadherin, and MMP-9 mRNA after knocking down Sort1, although E-cadherin expression was promoted. Overall, these processes reduced the ability of proliferation and invasion of HCC cells. Conclusion Downregulation of Sort1 can prolong the OS, PFI, and DSS of HCC patients. Furthermore, due to its link with immune cell infiltration, the Sort1 gene represents a potentially novel predictive biomarker of HCC. The growth of HCC can be significantly inhibited by interfering with Sort1; therefore, these results provide a potential target for developing anticancer strategies for HCC.
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Li Z, Xie Y, Xiao B, Guo J. The tumor suppressor function of hsa_circ_0006282 in gastric cancer through PTEN/AKT pathway. Int J Clin Oncol 2022; 27:1562-1569. [PMID: 35794253 DOI: 10.1007/s10147-022-02210-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 06/20/2022] [Indexed: 11/26/2022]
Abstract
BACKGROUND Circular RNAs (circRNAs) play key roles in carcinogenesis. However, the roles of circRNAs in gastric cancer are largely unknown. The aim of this study is to study the possible roles of hsa_circ_0006282 in gastric cancer. METHODS The hsa_circ_0006282 levels in gastric cancer cell lines, 85 gastritis tissues, and 103 paired gastric cancer tissues and non-tumor tissues were first detected by quantitative real-time reverse transcription-polymerase chain reaction. RNA interference and hsa_circ_0006282 expression plasmid were further used to manipulate hsa_circ_0006282 expression in gastric cancer. Finally, biological effects of hsa_circ_0006282 were analyzed by real-time cell analysis, flow cytometry, Transwell, cell cloning assay and Western blot analysis. RESULTS Hsa_circ_0006282 was down expressed in gastric cancer cells, gastritis tissues, and gastric cancer tissues. The abilities of cell proliferation, cell migration and resistance to apoptosis were enhanced after hsa_circ_0006282 was downregulated, while overexpression of hsa_circ_0006282 got opposite results. Besides, Western blot showed that the levels of protein kinase B (AKT) and cyclin-dependent kinase 2 (CDK2) were significantly increased and decreased after knockdown and up-regulation of hsa_circ_0006282, respectively, while phosphatase and tensin homolog deleted on chromosome ten (PTEN) was significantly opposite regulated. Finally, hsa_circ_0006282 promoted the expression of PTEN by sponging hsa-miR-136-5p. CONCLUSION By regulating the PTEN/AKT signaling pathway through competitively binding with hsa-miR-136-5p, hsa_circ_0006282 suppresses the growth of gastric cancer.
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Affiliation(s)
- Zhe Li
- Department of Gastroenterology, The Affiliated Hospital of Medical School, Ningbo University, Ningbo, 315020, China
| | - Yi Xie
- Department of Biochemistry and Molecular Biology, and Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo, 315211, China
| | - Bingxiu Xiao
- Department of Biochemistry and Molecular Biology, and Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo, 315211, China
| | - Junming Guo
- Department of Gastroenterology, The Affiliated Hospital of Medical School, Ningbo University, Ningbo, 315020, China.
- Department of Biochemistry and Molecular Biology, and Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo, 315211, China.
- Institute of Digestive Diseases of Ningbo University, Ningbo, 315020, China.
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miR-127-5p Targets JAM3 to Regulate Ferroptosis, Proliferation, and Metastasis in Malignant Meningioma Cells. DISEASE MARKERS 2022; 2022:6423237. [PMID: 35818586 PMCID: PMC9271006 DOI: 10.1155/2022/6423237] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 05/09/2022] [Accepted: 06/02/2022] [Indexed: 11/18/2022]
Abstract
Objective Meningiomas are one of the most common primary tumors of the central nervous system. Most of them are benign and can be cured by surgery, while a few meningiomas are malignant. Ferroptosis gene characteristics might be associated with drug therapy and survival in patients with clinically aggressive, unresectable meningiomas. This study explored the mechanism of differentially expressed miRNAs and ferroptosis in meningioma to provide a new reference to treat meningioma. Methods Bioinformatics analysis of differential miRNA profiles and functions in patients with meningioma was performed. The contents of lactate dehydrogenase (LDH), malondialdehyde (MDA), and Fe2+ were determined. Reactive oxygen species (ROS) values, as well as cell cycle changes, were analyzed by flow cytometry. The targets of miR-127-5p and JAM3 were detected by dual luciferase assays. Cell counting kit-8 (CCK8) and Transwell assays were used to analyze cell activity. Ki67 expression was analyzed by immunohistochemistry. Expression levels of miR-127-5p and JAM3 were analyzed by RT-qPCR. GPX4 expression was quantified by western blotting. Results miR-127-5p was expressed at low levels in IOMM-Lee cells, while JAM3 was highly expressed in IOMM-Lee cells. A dual luciferase assay demonstrated that miR-127-5p could target JAM3. Upregulation of miR-127-5p in IOMM-Lee cells resulted in cell cycle arrest and inhibition of cell activity. Upregulation of miR-127-5p increased LDH, MDA, and ROS levels and Fe2+ content and inhibited the expression of GPX4 protein. Upregulation of JAM3 reversed the results of miR-127-5p upregulation. Conclusion miR-127-5p regulated meningioma formation and ferroptosis through JAM3, providing insights for the development of new treatments for meningioma.
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Zhang Z, Sun C, Zheng Y, Gong Y. circFCHO2 promotes gastric cancer progression by activating the JAK1/STAT3 pathway via sponging miR-194-5p. Cell Cycle 2022; 21:2145-2164. [PMID: 35708677 DOI: 10.1080/15384101.2022.2087280] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
circFCHO2 has been revealed to be overexpressed in gastric cancer (GC) patients. This article identified the function of circFCHO2 on GC progression. The expression of circFCHO2, miR-194-5p and JAK1 in 30 GC patients and cells was monitored by quantitative reverse transcription-polymerase chain reaction. circFCHO2 localization in GC cells was monitored by RNA fluorescence in situ hybridization. Cell counting kit-8 assay, 5-ethynyl-2-deoxyuridine staining, transwell experiment, tube formation and sphere formation experiments were applied to detect GC cell proliferation, invasion, angiogenesis and cancer stem cell characteristics. Dual-luciferase reporter gene assay, RNA pull down assay and RNA immunoprecipitation experiment were utilized to research the binding between two genes. In vivo tumorigenesis and lung metastasis were studied using nude mice. Immunohistochemistry and hematoxylin-eosin staining were conducted. Protein expression was assessed by Western blot. Serum exosomes of GC patients and healthy participants were isolated. circFCHO2 up-modulation in GC patients was related to poor outcome. circFCHO2 was located in the cytoplasm of GC cells. circFCHO2 silencing weakened the proliferation, invasion, angiogenesis and stem cell characteristics of GC cells. miR-194-5p knockdown counteracted this effect. circFCHO2 activated the JAK1/STAT3 pathway by sponging miR-194-5p. miR-194-5p overexpression attenuated the malignant phenotypes of GC cells. JAK1 overexpression abrogated this effect. circFCHO2 silencing weakened GC cells growth and lung metastasis in vivo. circFCHO2 was up-modulated in serum exosomes of GC patients. circFCHO2 was an oncogene in GC by activating the JAK1/STAT3 pathway via sponging miR-194-5p. circFCHO2 might be a novel target and diagnostic marker for GC.
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Affiliation(s)
- Zhe Zhang
- Department of Geriatrics, the Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Chengying Sun
- Department of Geriatrics, the Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yan Zheng
- Department of Gastroenterology, the Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yanying Gong
- Department of Gastroenterology, the Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
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Zhang Y, Zhang X, Xu Y, Fang S, Ji Y, Lu L, Xu W, Qian H, Liang ZF. Circular RNA and Its Roles in the Occurrence, Development, Diagnosis of Cancer. Front Oncol 2022; 12:845703. [PMID: 35463362 PMCID: PMC9021756 DOI: 10.3389/fonc.2022.845703] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 03/14/2022] [Indexed: 12/19/2022] Open
Abstract
Circular RNAs (circRNAs) are non-coding single-stranded covalently closed circular RNA, mainly produced by reverse splicing of exons of precursor mRNAs (pre-mRNAs). The characteristics of high abundance, strong specificity, and good stability of circRNAs have been discovered. A large number of studies have reported its various functions and mechanisms in biological events, such as the occurrence and development of cancer. In this review, we focus on the classification, characterization, biogenesis, functions of circRNAs, and the latest advances in cancer research. The development of circRNAs as biomarkers in cancer diagnosis and treatment also provides new ideas for studying circRNAs research.
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Affiliation(s)
- Yue Zhang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Xinyi Zhang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Yumeng Xu
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Shikun Fang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Ying Ji
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Ling Lu
- Child Healthcare Department, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Wenrong Xu
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Hui Qian
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Zhao Feng Liang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
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Zhang B, Li Q, Song Z, Ren L, Gu Y, Feng C, Wang J, Liu T. hsa_circ_0000285 facilitates thyroid cancer progression by regulating miR-127-5p/CDH2. J Clin Lab Anal 2022; 36:e24421. [PMID: 35447001 PMCID: PMC9279989 DOI: 10.1002/jcla.24421] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 03/28/2022] [Accepted: 03/30/2022] [Indexed: 01/08/2023] Open
Abstract
Thyroid cancer (THCA) is a leading endocrine cancer and becomes the fifth most commonly diagnosed malignancy in females. It is confirmed that circular RNAs (circRNAs) perform regulatory potencies in the pathological progress of THCA. Our purpose was to certify the trait of hsa_circ_0000285 (circ_0000285) and investigate its modulatory mechanism in THCA progression. We identified the expression profile of hsa_circ_0000285 in THCA by conducting qRT-PCR assay. Therewith, the potential of hsa_circ_0000285 in THCA development was determined with a set of functional experiments, including CCK-8, wound healing assay, Western blot, and xenograft model. The molecular mechanism underlying hsa_circ_0000285 was investigated with bioinformatic analysis, RIP and dual-luciferase reporter experiments. As opposed to normal samples and cells, hsa_circ_0000285 level was overtly increased in THCA specimens and cells. The downregulation of hsa_circ_0000285 weakened the proliferative and migratory capacity of THCA cells and promoted cell apoptosis. In addition, hsa_circ_0000285 silence suppressed the tumor growth of xenograft model mice in vivo. Notably, we demonstrated that hsa_circ_0000285 might target miR-127-5p/CDH2 axis in THCA. Afterward, our findings manifested that miR-127-5p attenuation blocked the function of hsa_circ_0000285 depletion in THCA cells. In the final step, CDH2 was proven to mediate the repressive potency of miR-127-5p in the malignant behaviors of THCA. Mechanistically, hsa_circ_0000285 induced the development of THCA via functioning as a competing endogenous RNA (ceRNA) of miR-127-5p to enhance CDH2 expression, which provided a new perspective for THCA therapy.
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Affiliation(s)
- Bowei Zhang
- Department of Vascular and Thyroid Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Qiaoling Li
- Department of Medical Cosmetology, Chengdu Second People's Hospital, Chengdu, China
| | - Zhe Song
- Department of Vascular and Thyroid Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Li Ren
- Department of Vascular and Thyroid Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Yi Gu
- Department of Vascular and Thyroid Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Chao Feng
- Department of Vascular and Thyroid Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Jinju Wang
- Department of Vascular and Thyroid Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Tong Liu
- Department of Vascular and Thyroid Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
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Wang L, Yang X, Zhou F, Sun X, Li S. Circular RNA UBAP2 facilitates the cisplatin resistance of triple-negative breast cancer via microRNA-300/anti-silencing function 1B histone chaperone/PI3K/AKT/mTOR axis. Bioengineered 2022; 13:7197-7208. [PMID: 35263216 PMCID: PMC8973968 DOI: 10.1080/21655979.2022.2036894] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Circular RNAs (CircRNAs) have attracted increasing attention in the diagnosis and treatment of human cancers. CircUBAP2 has been identified to promote the progression of triple-negative breast cancer (TNBC), but the function of circUBAP2 in the cisplatin (DDP) resistance of TNBC remains obscure. Our investigation showed that circUBAP2 was significantly upregulated in DDP-resistant TNBC and TNBC sensitivity to DDP could be enhanced by silencing of circUBAP2. Moreover, circUBAP2 was revealed to be a ceRNA for miR-300 to upregulate the expression of anti-silencing function 1B histone chaperone (ASF1B). The effect of circUBAP2/miR-300/ASF1B axis on DDP resistance of TNBC was evaluated by rescue experiments, which demonstrated that circUBAP2 inhibited TNBC sensitivity to DDP through miR-300/ASF1B axis. Furthermore, it was discovered that ASF1B activated PI3K/AKT/mTOR signaling to facilitate the DDP resistance of TNBC cells. In summary, this research revealed a novel regulatory mechanism that circUBAP2 functioned as ceRNA of miR-300 to upregulate ASF1B, which further triggered the PI3K/AKT/mTOR (PAM) signaling to enhance the DDP resistance of TNBC.
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Affiliation(s)
- Leiming Wang
- Department of General Surgery, The Affiliated Shuyang Hospital of Xuzhou Medical University, Suqian City, Jiangsu Province 223600, China
| | - Xi Yang
- Department of General Surgery, The Affiliated Shuyang Hospital of Xuzhou Medical University, Suqian City, Jiangsu Province 223600, China
| | - Fei Zhou
- Department of General Surgery, The Affiliated Shuyang Hospital of Xuzhou Medical University, Suqian City, Jiangsu Province 223600, China
| | - Xuesi Sun
- Department of General Surgery, The Affiliated Shuyang Hospital of Xuzhou Medical University, Suqian City, Jiangsu Province 223600, China
| | - Shulin Li
- Department of General Surgery, The Affiliated Shuyang Hospital of Xuzhou Medical University, Suqian City, Jiangsu Province 223600, China
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Sortilin 1 regulates hepatocellular carcinoma progression by activating the PI3K/AKT signaling. Hum Exp Toxicol 2022; 41:9603271221140111. [DOI: 10.1177/09603271221140111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Background Sortilin 1 (SORT1) has been reported as an oncogene in several human tumors. Nonetheless, the biological functions of SORT1 in hepatocellular carcinoma (HCC) remain poorly understood. Methods Western blotting was employed for the determination of protein expression. Hepatocellular carcinoma cell viability, apoptosis, migration, and invasion were measured via CCK-8, flow cytometry, wound healing, and Transwell assays. Results Sortilin 1 was upregulated in HCC and closely associated with unsatisfactory outcomes of HCC patients. Furthermore, in vitro and in vivo assays revealed that SORT1 knockdown significantly diminished HCC cell proliferation and metastasis but accelerated HCC cell apoptosis; moreover, SORT1 depletion also restrained the growth of xenografted HCC tumors. Mechanistically, SORT1 activated PI3K/AKT signaling in HCC cells, thereby promoting the malignant behaviors of HCC cells. Conclusion This study demonstrated that SORT1 might promote HCC progression by activating PI3K/AKT signaling, indicating that SORT1 might be a promising target and biomarker for HCC treatment and prognosis.
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Huang P, Xu M, Han H, Zhao X, Li MD, Yang Z. Integrative Analysis of Epigenome and Transcriptome Data Reveals Aberrantly Methylated Promoters and Enhancers in Hepatocellular Carcinoma. Front Oncol 2021; 11:769390. [PMID: 34858848 PMCID: PMC8631276 DOI: 10.3389/fonc.2021.769390] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 10/14/2021] [Indexed: 12/15/2022] Open
Abstract
DNA methylation is a key transcription regulator, whose aberration was ubiquitous and important in most cancers including hepatocellular carcinoma (HCC). Whole-genome bisulfite sequencing (WGBS) was conducted for comparison of DNA methylation in tumor and adjacent tissues from 33 HCC patients, accompanying RNA-seq to determine differentially methylated region-associated, differentially expressed genes (DMR-DEGs), which were independently replicated in the TCGA-LIHC cohort and experimentally validated via 5-aza-2-deoxycytidine (5-azadC) demethylation. A total of 9,867,700 CpG sites showed significantly differential methylation in HCC. Integrations of mRNA-seq, histone ChIP-seq, and WGBS data identified 611 high-confidence DMR-DEGs. Enrichment analysis demonstrated activation of multiple molecular pathways related to cell cycle and DNA repair, accompanying repression of several critical metabolism pathways such as tyrosine and monocarboxylic acid metabolism. In TCGA-LIHC, we replicated about 53% of identified DMR-DEGs and highlighted the prognostic significance of combinations of methylation and expression of nine DMR-DEGs, which were more efficient prognostic biomarkers than considering either type of data alone. Finally, we validated 22/23 (95.7%) DMR-DEGs in 5-azadC-treated LO2 and/or HepG2 cells. In conclusion, integration of epigenome and transcriptome data depicted activation of multiple pivotal cell cycle-related pathways and repression of several metabolic pathways triggered by aberrant DNA methylation of promoters and enhancers in HCC.
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Affiliation(s)
- Peng Huang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Mengxiang Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Haijun Han
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xinyi Zhao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ming D Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Research Center for Air Pollution and Health, Zhejiang University, Hangzhou, China
| | - Zhongli Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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