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1
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Sun HT. Helicobacter pylori-related serum indicators: Cutting-edge advances to enhance the efficacy of gastric cancer screening. World J Gastrointest Oncol 2025; 17:100739. [PMID: 40092953 PMCID: PMC11866254 DOI: 10.4251/wjgo.v17.i3.100739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 12/08/2024] [Accepted: 01/03/2025] [Indexed: 02/14/2025] Open
Abstract
Helicobacter pylori (H. pylori) infection induces pathological changes via chronic inflammation and virulence factors, thereby increasing the risk of gastric cancer development. Compared with invasive examination methods, H. pylori-related serum indicators are cost-effective and valuable for the early detection of gastric cancer (GC); however, large-scale clinical validation and sufficient understanding of the specific molecular mechanisms involved are lacking. Therefore, a comprehensive review and analysis of recent advances in this field is necessary. In this review, we systematically analyze the relationship between H. pylori and GC and discuss the application of new molecular biomarkers in GC screening. We also summarize the screening potential and application of anti-H. pylori immunoglobulin G and virulence factor-related serum antibodies for identifying GC risk. These indicators provide early warning of infection and enhance screening accuracy. Additionally, we discuss the potential combination of multiple screening indicators for the comprehensive analysis and development of emerging testing methods to improve the accuracy and efficiency of GC screening. Although this review may lack sufficient evidence due to limitations in existing studies, including small sample sizes, regional variations, and inconsistent testing methods, it contributes to advancing personalized precision medicine in high-risk populations and developing GC screening strategies.
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Affiliation(s)
- Hao-Tian Sun
- Cancer Institute, University College London, London WC1E 6BT, United Kingdom
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2
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Qian L, Wang L, Chen H, Wang S, Hou Y, Xu L, Xia Y, Xu M, Huang X. Hsa_circ_0001756 drives gastric cancer glycolysis by increasing the expression and stability of PGK1 mRNA. Front Immunol 2025; 16:1511247. [PMID: 40051638 PMCID: PMC11882586 DOI: 10.3389/fimmu.2025.1511247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Accepted: 01/29/2025] [Indexed: 03/09/2025] Open
Abstract
Introduction Strategies for preventing high glycolysis in tumour cells are urgently needed. CircRNAs (circRNAs) play important roles in glycolysis. However, the mechanism underlying the effects of hsa_circ_0001756 in gastric cancer (GC) remains unclear. Methods In this study, we detected the expression of hsa_circ_0001756 in GC tissues and cells using quantitative real-time polymerase chain reaction (qRT PCR). Construct a silencing and overexpression vector to validate the role of hsa_circ_0001756 in GC. Pulldown and RIP experiments were conducted to verify the identification of miRNA and protein binding to hsa_circ_0001756. Results The expression level of hsa_circ_0001756 in GC tissues and cells is significantly upregulated. The expression level of hsa_circ_0001756 is closely related to TNM stage and tumour size in patients with GC. The proliferation and migration of hsa_circ_0001756-expressing cells in vitro were assessed by functional experiments. Hsa_circ_0001756 was found to not only promote the expression and stability of PGK1 by binding with polypyrimidine tract-binding protein 1 (PTBP1) but also promote glycolysis through the miR-185-3P/PGK1 pathway. We found that the regulatory relationships of competing endogenous RNA (ceRNA) and RNA-binding proteins (RBPs) with hsa_circ_0001756may affect glycolysis in GC. Conclusion This study provides a theoretical basis for designing drugs that target molecules related to energy metabolism in tumours and provides a new strategy for the clinical treatment of GC.
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Affiliation(s)
- Long Qian
- Department of Gastrointestinal Surgery, The First Affiliated Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- General Surgery Department, Wuhu Hospital of Traditional Chinese Medicine, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China
| | - Luman Wang
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Hao Chen
- Department of Oncology, Wuhu Conch Hospital, Wuhu, Anhui, China
| | - Song Wang
- Department of Gastrointestinal Surgery, The First Affiliated Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China
| | - Yinfen Hou
- Department of Medical Examination Center, The First Affiliated Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
| | - Li Xu
- Department of Gastrointestinal Surgery, The First Affiliated Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China
| | - Yabin Xia
- Department of Gastrointestinal Surgery, The First Affiliated Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China
| | - Maoqi Xu
- General Surgery Department, Anhui Wannan Rehabilitation Hospital, The Fifth People’s Hospital of Wuhu, Wuhu, Anhui, China
| | - Xiaoxu Huang
- Department of Gastrointestinal Surgery, The First Affiliated Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China
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3
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Christodoulidis G, Koumarelas KE, Kouliou MN, Thodou E, Samara M. Gastric Cancer in the Era of Epigenetics. Int J Mol Sci 2024; 25:3381. [PMID: 38542354 PMCID: PMC10970362 DOI: 10.3390/ijms25063381] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 03/12/2024] [Accepted: 03/13/2024] [Indexed: 11/11/2024] Open
Abstract
Gastric cancer (GC) remains a significant contributor to cancer-related mortality. Novel high-throughput techniques have enlightened the epigenetic mechanisms governing gene-expression regulation. Epigenetic characteristics contribute to molecular taxonomy and give rise to cancer-specific epigenetic patterns. Helicobacter pylori (Hp) infection has an impact on aberrant DNA methylation either through its pathogenic CagA protein or by inducing chronic inflammation. The hypomethylation of specific repetitive elements generates an epigenetic field effect early in tumorigenesis. Epstein-Barr virus (EBV) infection triggers DNA methylation by dysregulating DNA methyltransferases (DNMT) enzyme activity, while persistent Hp-EBV co-infection leads to aggressive tumor behavior. Distinct histone modifications are also responsible for oncogene upregulation and tumor-suppressor gene silencing in gastric carcinomas. While histone methylation and acetylation processes have been extensively studied, other less prevalent alterations contribute to the development and migration of gastric cancer via a complex network of interactions. Enzymes, such as Nicotinamide N-methyltransferase (NNMT), which is involved in tumor's metabolic reprogramming, interact with methyltransferases and modify gene expression. Non-coding RNA molecules, including long non-coding RNAs, circular RNAs, and miRNAs serve as epigenetic regulators contributing to GC development, metastasis, poor outcomes and therapy resistance. Serum RNA molecules hold the potential to serve as non-invasive biomarkers for diagnostic, prognostic or therapeutic applications. Gastric fluids represent a valuable source to identify potential biomarkers with diagnostic use in terms of liquid biopsy. Ongoing clinical trials are currently evaluating the efficacy of next-generation epigenetic drugs, displaying promising outcomes. Various approaches including multiple miRNA inhibitors or targeted nanoparticles carrying epigenetic drugs are being designed to enhance existing treatment efficacy and overcome treatment resistance.
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Affiliation(s)
- Grigorios Christodoulidis
- Department of General Surgery, University Hospital of Larissa, University of Thessaly, Biopolis Campus, 41110 Larissa, Greece; (G.C.); (K.-E.K.); (M.-N.K.)
| | - Konstantinos-Eleftherios Koumarelas
- Department of General Surgery, University Hospital of Larissa, University of Thessaly, Biopolis Campus, 41110 Larissa, Greece; (G.C.); (K.-E.K.); (M.-N.K.)
| | - Marina-Nektaria Kouliou
- Department of General Surgery, University Hospital of Larissa, University of Thessaly, Biopolis Campus, 41110 Larissa, Greece; (G.C.); (K.-E.K.); (M.-N.K.)
| | - Eleni Thodou
- Department of Pathology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis Campus, 41110 Larissa, Greece;
| | - Maria Samara
- Department of Pathology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis Campus, 41110 Larissa, Greece;
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4
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Orășeanu A, Brisc MC, Maghiar OA, Popa H, Brisc CM, Șolea SF, Maghiar TA, Brisc C. Landscape of Innovative Methods for Early Diagnosis of Gastric Cancer: A Systematic Review. Diagnostics (Basel) 2023; 13:3608. [PMID: 38132192 PMCID: PMC10742893 DOI: 10.3390/diagnostics13243608] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 11/28/2023] [Accepted: 12/01/2023] [Indexed: 12/23/2023] Open
Abstract
From a global perspective, gastric cancer (GC) persists as a significant healthcare issue. In the Western world, the majority of cases are discovered at late stages, when the treatment is generally unsuccessful. There are no organized screening programs outside of Asia (Japan and Republic of Korea). Traditional diagnosis techniques (such as upper endoscopy), conventional tumor markers (CEA, CA19-9, and CA72-4), radiographic imaging, and CT scanning all have drawbacks. The gold standard for the earliest detection of cancer and related premalignant lesions is still endoscopy with a proper biopsy follow-up. Since there are currently no clinically approved biomarkers for the early diagnosis of GC, the identification of non-invasive biomarkers is expected to help improve the prognosis and survival rate of these patients. The search for new screening biomarkers is currently underway. These include genetic biomarkers, such as circulating tumor cells, microRNAs, and exosomes, as well as metabolic biomarkers obtained from biofluids. Meanwhile, cutting-edge high-resolution endoscopic technologies are demonstrating promising outcomes in the visual diagnosis of mucosal lesions with the aid of linked color imaging and machine learning models. Following the PRISMA guidelines, this study examined the articles in databases such as PubMed, resulting in 167 included articles. This review discusses the currently available and emerging methods for diagnosing GC early on, as well as new developments in the endoscopic detection of early lesions of the stomach.
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Affiliation(s)
- Alexandra Orășeanu
- Clinic of Gastroenterology, Bihor Clinical County Emergency Hospital, 410169 Oradea, Romania; (A.O.); (S.F.Ș.)
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania; (O.A.M.); (T.A.M.); (C.B.)
| | | | - Octavian Adrian Maghiar
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania; (O.A.M.); (T.A.M.); (C.B.)
- Faculty of Medicine and Pharmacy, University of Oradea, 410068 Oradea, Romania;
| | - Horia Popa
- Clinical Emergency Hospital “Prof. Dr. Agrippa Ionescu”, 011356 Bucharest, Romania;
| | - Ciprian Mihai Brisc
- Faculty of Medicine and Pharmacy, University of Oradea, 410068 Oradea, Romania;
| | - Sabina Florina Șolea
- Clinic of Gastroenterology, Bihor Clinical County Emergency Hospital, 410169 Oradea, Romania; (A.O.); (S.F.Ș.)
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania; (O.A.M.); (T.A.M.); (C.B.)
| | - Teodor Andrei Maghiar
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania; (O.A.M.); (T.A.M.); (C.B.)
- Faculty of Medicine and Pharmacy, University of Oradea, 410068 Oradea, Romania;
| | - Ciprian Brisc
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania; (O.A.M.); (T.A.M.); (C.B.)
- Faculty of Medicine and Pharmacy, University of Oradea, 410068 Oradea, Romania;
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5
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Izraely S, Ben-Menachem S, Malka S, Sagi-Assif O, Bustos MA, Adir O, Meshel T, Chelladurai M, Ryu S, Ramos RI, Pasmanik-Chor M, Hoon DSB, Witz IP. The Vicious Cycle of Melanoma-Microglia Crosstalk: Inter-Melanoma Variations in the Brain-Metastasis-Promoting IL-6/JAK/STAT3 Signaling Pathway. Cells 2023; 12:1513. [PMID: 37296634 PMCID: PMC10253015 DOI: 10.3390/cells12111513] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 05/17/2023] [Accepted: 05/23/2023] [Indexed: 06/12/2023] Open
Abstract
Previous studies from our lab demonstrated that the crosstalk between brain-metastasizing melanoma cells and microglia, the macrophage-like cells of the central nervous system, fuels progression to metastasis. In the present study, an in-depth investigation of melanoma-microglia interactions elucidated a pro-metastatic molecular mechanism that drives a vicious melanoma-brain-metastasis cycle. We employed RNA-Sequencing, HTG miRNA whole transcriptome assay, and reverse phase protein arrays (RPPA) to analyze the impact of melanoma-microglia interactions on sustainability and progression of four different human brain-metastasizing melanoma cell lines. Microglia cells exposed to melanoma-derived IL-6 exhibited upregulated levels of STAT3 phosphorylation and SOCS3 expression, which, in turn, promoted melanoma cell viability and metastatic potential. IL-6/STAT3 pathway inhibitors diminished the pro-metastatic functions of microglia and reduced melanoma progression. SOCS3 overexpression in microglia cells evoked microglial support in melanoma brain metastasis by increasing melanoma cell migration and proliferation. Different melanomas exhibited heterogeneity in their microglia-activating capacity as well as in their response to microglia-derived signals. In spite of this reality and based on the results of the present study, we concluded that the activation of the IL-6/STAT3/SOCS3 pathway in microglia is a major mechanism by which reciprocal melanoma-microglia signaling engineers the interacting microglia to reinforce the progression of melanoma brain metastasis. This mechanism may operate differently in different melanomas.
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Affiliation(s)
- Sivan Izraely
- The Shmunis School of Biomedicine and Cancer Research, The George S. Wise Faculty of Life Science, Tel Aviv University, Tel Aviv 6997801, Israel; (S.I.)
| | - Shlomit Ben-Menachem
- The Shmunis School of Biomedicine and Cancer Research, The George S. Wise Faculty of Life Science, Tel Aviv University, Tel Aviv 6997801, Israel; (S.I.)
| | - Sapir Malka
- The Shmunis School of Biomedicine and Cancer Research, The George S. Wise Faculty of Life Science, Tel Aviv University, Tel Aviv 6997801, Israel; (S.I.)
| | - Orit Sagi-Assif
- The Shmunis School of Biomedicine and Cancer Research, The George S. Wise Faculty of Life Science, Tel Aviv University, Tel Aviv 6997801, Israel; (S.I.)
| | - Matias A. Bustos
- Department of Translational Molecular Medicine, Saint John’s Cancer Institute, Providence Saint John’s Health Center, Santa Monica, CA 90404, USA
| | - Orit Adir
- The Shmunis School of Biomedicine and Cancer Research, The George S. Wise Faculty of Life Science, Tel Aviv University, Tel Aviv 6997801, Israel; (S.I.)
| | - Tsipi Meshel
- The Shmunis School of Biomedicine and Cancer Research, The George S. Wise Faculty of Life Science, Tel Aviv University, Tel Aviv 6997801, Israel; (S.I.)
| | - Maharrish Chelladurai
- The Shmunis School of Biomedicine and Cancer Research, The George S. Wise Faculty of Life Science, Tel Aviv University, Tel Aviv 6997801, Israel; (S.I.)
| | - Suyeon Ryu
- Department of Genome Sequencing, Saint John’s Cancer Institute, Providence Saint John’s Health Center, Santa Monica, CA 90404, USA
| | - Romela I. Ramos
- Department of Translational Molecular Medicine, Saint John’s Cancer Institute, Providence Saint John’s Health Center, Santa Monica, CA 90404, USA
| | - Metsada Pasmanik-Chor
- Bioinformatics Unit, The George S. Wise Faculty of Life Science, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Dave S. B. Hoon
- Department of Translational Molecular Medicine, Saint John’s Cancer Institute, Providence Saint John’s Health Center, Santa Monica, CA 90404, USA
| | - Isaac P. Witz
- The Shmunis School of Biomedicine and Cancer Research, The George S. Wise Faculty of Life Science, Tel Aviv University, Tel Aviv 6997801, Israel; (S.I.)
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6
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Yan W, Chen Y, Hu G, Shi T, Liu X, Li J, Sun L, Qian F, Chen W. MiR-200/183 family-mediated module biomarker for gastric cancer progression: an AI-assisted bioinformatics method with experimental functional survey. J Transl Med 2023; 21:163. [PMID: 36864416 PMCID: PMC9983275 DOI: 10.1186/s12967-023-04010-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 02/18/2023] [Indexed: 03/04/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is a major cancer burden throughout the world with a high mortality rate. The performance of current predictive and prognostic factors is still limited. Integrated analysis is required for accurate cancer progression predictive biomarker and prognostic biomarkers that help to guide therapy. METHODS An AI-assisted bioinformatics method that combines transcriptomic data and microRNA regulations were used to identify a key miRNA-mediated network module in GC progression. To reveal the module's function, we performed the gene expression analysis in 20 clinical samples by qRT-PCR, prognosis analysis by multi-variable Cox regression model, progression prediction by support vector machine, and in vitro studies to elaborate the roles in GC cells migration and invasion. RESULTS A robust microRNA regulated network module was identified to characterize GC progression, which consisted of seven miR-200/183 family members, five mRNAs and two long non-coding RNAs H19 and CLLU1. Their expression patterns and expression correlation patterns were consistent in public dataset and our cohort. Our findings suggest a two-fold biological potential of the module: GC patients with high-risk score exhibited a poor prognosis (p-value < 0.05) and the model achieved AUCs of 0.90 to predict GC progression in our cohort. In vitro cellular analyses shown that the module could influence the invasion and migration of GC cells. CONCLUSIONS Our strategy which combines AI-assisted bioinformatics method with experimental and clinical validation suggested that the miR-200/183 family-mediated network module as a "pluripotent module", which could be potential marker for GC progression.
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Affiliation(s)
- Wenying Yan
- Department of Bioinformatics, School of Biology and Basic Medical Sciences, Suzhou Medical College of Soochow University, 199 Renai Road, Suzhou, 215123, China. .,Center for Systems Biology, Soochow University, 199 Renai Road, Suzhou, 215123, China.
| | - Yuqi Chen
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, 215006, China
| | - Guang Hu
- Department of Bioinformatics, School of Biology and Basic Medical Sciences, Suzhou Medical College of Soochow University, 199 Renai Road, Suzhou, 215123, China.,Center for Systems Biology, Soochow University, 199 Renai Road, Suzhou, 215123, China
| | - Tongguo Shi
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, 215021, China.,Suzhou Key Laboratory for Tumor Immunology of Digestive Tract, The First Affiliated Hospital of Soochow University, Suzhou, 215021, China.,Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, 215021, China.,Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, 215021, China
| | - Xingyi Liu
- Department of Bioinformatics, School of Biology and Basic Medical Sciences, Suzhou Medical College of Soochow University, 199 Renai Road, Suzhou, 215123, China
| | - Juntao Li
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, 215006, China
| | - Linqing Sun
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, 215006, China
| | - Fuliang Qian
- Center for Systems Biology, Soochow University, 199 Renai Road, Suzhou, 215123, China. .,Medical Center of Soochow University, Suzhou, 215000, China.
| | - Weichang Chen
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, 215006, China. .,Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, 215021, China. .,Suzhou Key Laboratory for Tumor Immunology of Digestive Tract, The First Affiliated Hospital of Soochow University, Suzhou, 215021, China. .,Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, 215021, China. .,Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, 215021, China.
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7
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Vo D, Ghosh P, Sahoo D. Artificial intelligence-guided discovery of gastric cancer continuum. Gastric Cancer 2023; 26:286-297. [PMID: 36692601 PMCID: PMC9871434 DOI: 10.1007/s10120-022-01360-3] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 12/19/2022] [Indexed: 01/25/2023]
Abstract
BACKGROUND Detailed understanding of pre-, early and late neoplastic states in gastric cancer helps develop better models of risk of progression to gastric cancers (GCs) and medical treatment to intercept such progression. METHODS We built a Boolean implication network of gastric cancer and deployed machine learning algorithms to develop predictive models of known pre-neoplastic states, e.g., atrophic gastritis, intestinal metaplasia (IM) and low- to high-grade intestinal neoplasia (L/HGIN), and GC. Our approach exploits the presence of asymmetric Boolean implication relationships that are likely to be invariant across almost all gastric cancer datasets. Invariant asymmetric Boolean implication relationships can decipher fundamental time-series underlying the biological data. Pursuing this method, we developed a healthy mucosa → GC continuum model based on this approach. RESULTS Our model performed better against publicly available models for distinguishing healthy versus GC samples. Although not trained on IM and L/HGIN datasets, the model could identify the risk of progression to GC via the metaplasia → dysplasia → neoplasia cascade in patient samples. The model could rank all publicly available mouse models for their ability to best recapitulate the gene expression patterns during human GC initiation and progression. CONCLUSIONS A Boolean implication network enabled the identification of hitherto undefined continuum states during GC initiation. The developed model could now serve as a starting point for rationalizing candidate therapeutic targets to intercept GC progression.
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Affiliation(s)
- Daniella Vo
- Department of Pediatrics, University of California San Diego, 9500 Gilman Drive, MC 0703, Leichtag Building 132, La Jolla, CA, 92093-0703, USA
| | - Pradipta Ghosh
- Moores Cancer Center, University of California San Diego, La Jolla, USA
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, USA
- Department of Medicine, University of California San Diego, La Jolla, USA
| | - Debashis Sahoo
- Department of Pediatrics, University of California San Diego, 9500 Gilman Drive, MC 0703, Leichtag Building 132, La Jolla, CA, 92093-0703, USA.
- Moores Cancer Center, University of California San Diego, La Jolla, USA.
- Department of Computer Science and Engineering, Jacob's School of Engineering, University of California San Diego, La Jolla, USA.
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8
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Jiang T, Mei L, Yang X, Sun T, Wang Z, Ji Y. Biomarkers of gastric cancer: current advancement. Heliyon 2022; 8:e10899. [PMID: 36247151 PMCID: PMC9561735 DOI: 10.1016/j.heliyon.2022.e10899] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 07/22/2022] [Accepted: 09/28/2022] [Indexed: 11/06/2022] Open
Abstract
Gastric cancer (GC) is one of the most prevalent malignant types worldwide, especially in East Asia. Due to its frequently advanced stage at diagnosis, the mortality from GC is high and the prognosis is still unsatisfactory. Thus, early detection using effective screening approaches is vital to decrease the morbidity and mortality of GC. Interestingly, biomarkers can be used for diagnosis, prediction of sensitivity to treatment, and prognosis in GC. The potential biomarkers detectable in liquid biopsies such as circulating tumor cells (CTCs), long non-coding RNAs (lncRNAs), cell-free DNA (cfDNA), microRNAs, and exosomes reveal numerous information regarding the early prediction and the outcomes for GC patients. Additionally, using the novel serum biomarkers has opened up new opportunities for diagnosing and monitoring patients with GC. This review mainly summarizes the novel progress and approaches in GC biomarkers, which could be potentially used for early diagnosis and therapy monitoring. Meanwhile, we also discussed the advantages, disadvantages, and future perspectives of GC biomarkers.
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Affiliation(s)
- Tiantian Jiang
- Department of General Surgery, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Lin Mei
- Scientific Research Center and Precision Medical Institute, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Xiao Yang
- Scientific Research Center and Precision Medical Institute, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Tingkai Sun
- Department of General Surgery, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Zhidong Wang
- Department of General Surgery, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Yuanyuan Ji
- Scientific Research Center and Precision Medical Institute, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
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9
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Dawson RE, Deswaerte V, West AC, Tang K, West AJ, Balic JJ, Gearing LJ, Saad MI, Yu L, Wu Y, Bhathal PS, Kumar B, Chakrabarti JT, Zavros Y, Oshima H, Klinman DM, Oshima M, Tan P, Jenkins BJ. STAT3-mediated upregulation of the AIM2 DNA sensor links innate immunity with cell migration to promote epithelial tumourigenesis. Gut 2022; 71:1515-1531. [PMID: 34489308 DOI: 10.1136/gutjnl-2020-323916] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 08/27/2021] [Indexed: 01/26/2023]
Abstract
OBJECTIVE The absent in melanoma 2 (AIM2) cytosolic pattern recognition receptor and DNA sensor promotes the pathogenesis of autoimmune and chronic inflammatory diseases via caspase-1-containing inflammasome complexes. However, the role of AIM2 in cancer is ill-defined. DESIGN The expression of AIM2 and its clinical significance was assessed in human gastric cancer (GC) patient cohorts. Genetic or therapeutic manipulation of AIM2 expression and activity was performed in the genetically engineered gp130 F/F spontaneous GC mouse model, as well as human GC cell line xenografts. The biological role and mechanism of action of AIM2 in gastric tumourigenesis, including its involvement in inflammasome activity and functional interaction with microtubule-associated end-binding protein 1 (EB1), was determined in vitro and in vivo. RESULTS AIM2 expression is upregulated by interleukin-11 cytokine-mediated activation of the oncogenic latent transcription factor STAT3 in the tumour epithelium of GC mouse models and patients with GC. Genetic and therapeutic targeting of AIM2 in gp130 F/F mice suppressed tumourigenesis. Conversely, AIM2 overexpression augmented the tumour load of human GC cell line xenografts. The protumourigenic function of AIM2 was independent of inflammasome activity and inflammation. Rather, in vivo and in vitro AIM2 physically interacted with EB1 to promote epithelial cell migration and tumourigenesis. Furthermore, upregulated expression of AIM2 and EB1 in the tumour epithelium of patients with GC was independently associated with poor patient survival. CONCLUSION AIM2 can play a driver role in epithelial carcinogenesis by linking cytokine-STAT3 signalling, innate immunity and epithelial cell migration, independent of inflammasome activation.
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Affiliation(s)
- Ruby E Dawson
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Virginie Deswaerte
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Alison C West
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Ke Tang
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Alice J West
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Jesse J Balic
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Linden J Gearing
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Mohamed I Saad
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Liang Yu
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Yonghui Wu
- Cellular and Molecular Research, National Cancer Centre of Singapore, Singapore
| | - Prithi S Bhathal
- Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Beena Kumar
- Department of Anatomical Pathology, Monash Health, Clayton, Victoria, Australia
| | - Jayati T Chakrabarti
- Department of Cellular and Molecular Medicine, College of Medicine, University of Arizona, Tucson, Arizona, USA
| | - Yana Zavros
- Department of Cellular and Molecular Medicine, College of Medicine, University of Arizona, Tucson, Arizona, USA
| | - Hiroko Oshima
- Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Dennis M Klinman
- Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Masanobu Oshima
- Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Patrick Tan
- Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore.,Genome Institute of Singapore, Singapore.,Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Brendan J Jenkins
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia .,Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
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10
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Cui H, Li H, Wu H, Du F, Xie X, Zeng S, Zhang Z, Dong K, Shang L, Jing C, Li L. A novel 3'tRNA-derived fragment tRF-Val promotes proliferation and inhibits apoptosis by targeting EEF1A1 in gastric cancer. Cell Death Dis 2022; 13:471. [PMID: 35585048 PMCID: PMC9117658 DOI: 10.1038/s41419-022-04930-6] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 05/03/2022] [Accepted: 05/09/2022] [Indexed: 12/14/2022]
Abstract
At present, it is commonly believed that tRFs and tiRNAs are formed by the specific and selective shear of tRNAs under certain pressure stimulation, rather than by random degradation of tRNA. tRFs and tiRNAs have been reported to contribute to the biological process of a variety of human cancers. However, the evidence for the mechanisms of tRFs and tiRNAs in the occurrence and development of gastric cancer (GC) is still insufficient. Here, we aimed to explore the carcinogenic roles of tRFs and tiRNAs in GC with RNA-sequencing technique, and found a novel 3'tRNA-derived fragment tRF-Val was significantly upregulated in GC tissues and cell lines. tRF-Val expression was positively correlated with tumor size and the depth of tumor invasion in GC tissues. Functionally, tRF-Val promoted proliferation and invasion, and inhibited apoptosis in GC cells. Mechanistically, tRF-Val directly bound to the chaperone molecule EEF1A1, mediated its transport into the nucleus and promoted its interaction with MDM2 (a specific p53 E3 ubiquitin ligase), thus inhibiting the downstream molecular pathway of p53 and promoting GC progression. These findings provided a new potential therapeutic target for GC and a new explanation for the occurrence of GC.
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Affiliation(s)
- Huaiping Cui
- grid.27255.370000 0004 1761 1174Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, 250021 Jinan, Shandong China ,grid.460018.b0000 0004 1769 9639Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021 Jinan, Shandong China ,grid.460018.b0000 0004 1769 9639Shandong Provincial Laboratory of Translational Medicine Engineering for Digestive Tumors, Shandong Provincial Hospital, 250021 Jinan, Shandong China
| | - Han Li
- grid.452422.70000 0004 0604 7301Department of Gastrointestinal Surgery, the First Affiliated Hospital of Shandong First Medical University, Shandong Provincial Qianfoshan Hospital, 250013 Jinan, Shandong China
| | - Hao Wu
- grid.27255.370000 0004 1761 1174Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, 250021 Jinan, Shandong China
| | - Fengying Du
- grid.27255.370000 0004 1761 1174Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, 250021 Jinan, Shandong China
| | - Xiaozhou Xie
- grid.460018.b0000 0004 1769 9639Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021 Jinan, Shandong China
| | - Shujie Zeng
- grid.27255.370000 0004 1761 1174Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, 250021 Jinan, Shandong China
| | - Zihao Zhang
- grid.27255.370000 0004 1761 1174Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, 250021 Jinan, Shandong China
| | - Kangdi Dong
- grid.460018.b0000 0004 1769 9639Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021 Jinan, Shandong China
| | - Liang Shang
- grid.27255.370000 0004 1761 1174Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, 250021 Jinan, Shandong China ,grid.460018.b0000 0004 1769 9639Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021 Jinan, Shandong China ,grid.460018.b0000 0004 1769 9639Shandong Provincial Laboratory of Translational Medicine Engineering for Digestive Tumors, Shandong Provincial Hospital, 250021 Jinan, Shandong China
| | - Changqing Jing
- grid.27255.370000 0004 1761 1174Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, 250021 Jinan, Shandong China ,grid.460018.b0000 0004 1769 9639Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021 Jinan, Shandong China ,grid.460018.b0000 0004 1769 9639Shandong Provincial Laboratory of Translational Medicine Engineering for Digestive Tumors, Shandong Provincial Hospital, 250021 Jinan, Shandong China
| | - Leping Li
- grid.27255.370000 0004 1761 1174Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, 250021 Jinan, Shandong China ,grid.460018.b0000 0004 1769 9639Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021 Jinan, Shandong China ,grid.460018.b0000 0004 1769 9639Shandong Provincial Laboratory of Translational Medicine Engineering for Digestive Tumors, Shandong Provincial Hospital, 250021 Jinan, Shandong China
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11
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Alhayyani S, McLeod L, West AC, Balic JJ, Hodges C, Yu L, Smith JA, Prodanovic Z, Bozinovski S, Kumar B, Ruwanpura SM, Saad MI, Jenkins BJ. Oncogenic dependency on STAT3 serine phosphorylation in KRAS mutant lung cancer. Oncogene 2022; 41:809-823. [PMID: 34857889 DOI: 10.1038/s41388-021-02134-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 11/15/2021] [Accepted: 11/23/2021] [Indexed: 02/07/2023]
Abstract
The oncogenic potential of the latent transcription factor signal transducer and activator of transcription (STAT)3 in many human cancers, including lung cancer, has been largely attributed to its nuclear activity as a tyrosine-phosphorylated (pY705 site) transcription factor. By contrast, an alternate mitochondrial pool of serine phosphorylated (pS727 site) STAT3 has been shown to promote tumourigenesis by regulating metabolic processes, although this has been reported in only a restricted number of mutant RAS-addicted neoplasms. Therefore, the involvement of STAT3 serine phosphorylation in the pathogenesis of most cancer types, including mutant KRAS lung adenocarcinoma (LAC), is unknown. Here, we demonstrate that LAC is suppressed in oncogenic KrasG12D-driven mouse models engineered for pS727-STAT3 deficiency. The proliferative potential of the transformed KrasG12D lung epithelium, and mutant KRAS human LAC cells, was significantly reduced upon pS727-STAT3 deficiency. Notably, we uncover the multifaceted capacity of constitutive pS727-STAT3 to metabolically reprogramme LAC cells towards a hyper-proliferative state by regulating nuclear and mitochondrial (mt) gene transcription, the latter via the mtDNA transcription factor, TFAM. Collectively, our findings reveal an obligate requirement for the transcriptional activity of pS727-STAT3 in mutant KRAS-driven LAC with potential to guide future therapeutic targeting approaches.
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Affiliation(s)
- Sultan Alhayyani
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, 3168, Australia
- Department of Molecular and Translational Science, School of Clinical Sciences, Monash University, Clayton, Victoria, 3168, Australia
- Department of Chemistry, College of Sciences and Arts, King Abdulaziz University, Rabigh, Saudi Arabia
| | - Louise McLeod
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, 3168, Australia
- Department of Molecular and Translational Science, School of Clinical Sciences, Monash University, Clayton, Victoria, 3168, Australia
| | - Alison C West
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, 3168, Australia
- Department of Molecular and Translational Science, School of Clinical Sciences, Monash University, Clayton, Victoria, 3168, Australia
| | - Jesse J Balic
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, 3168, Australia
- Department of Molecular and Translational Science, School of Clinical Sciences, Monash University, Clayton, Victoria, 3168, Australia
| | - Christopher Hodges
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, 3168, Australia
- Department of Molecular and Translational Science, School of Clinical Sciences, Monash University, Clayton, Victoria, 3168, Australia
| | - Liang Yu
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, 3168, Australia
- Department of Molecular and Translational Science, School of Clinical Sciences, Monash University, Clayton, Victoria, 3168, Australia
| | - Julian A Smith
- Department of Surgery, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, 3168, Australia
- Department of Cardiothoracic Surgery, Monash Health, Clayton, Victoria, 3168, Australia
| | | | - Steven Bozinovski
- School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, 3082, Australia
| | - Beena Kumar
- Department of Anatomical Pathology, Monash Health, Clayton, Victoria, 3168, Australia
| | - Saleela M Ruwanpura
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, 3168, Australia
- Department of Molecular and Translational Science, School of Clinical Sciences, Monash University, Clayton, Victoria, 3168, Australia
| | - Mohamed I Saad
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, 3168, Australia
- Department of Molecular and Translational Science, School of Clinical Sciences, Monash University, Clayton, Victoria, 3168, Australia
| | - Brendan J Jenkins
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, 3168, Australia.
- Department of Molecular and Translational Science, School of Clinical Sciences, Monash University, Clayton, Victoria, 3168, Australia.
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12
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Tang SY, Zhou PJ, Meng Y, Zeng FR, Deng GT. Gastric cancer: An epigenetic view. World J Gastrointest Oncol 2022; 14:90-109. [PMID: 35116105 PMCID: PMC8790429 DOI: 10.4251/wjgo.v14.i1.90] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/17/2021] [Accepted: 12/23/2021] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) poses a serious threat worldwide with unfavorable prognosis mainly due to late diagnosis and limited therapies. Therefore, precise molecular classification and search for potential targets are required for diagnosis and treatment, as GC is complicated and heterogeneous in nature. Accumulating evidence indicates that epigenetics plays a vital role in gastric carcinogenesis and progression, including histone modifications, DNA methylation and non-coding RNAs. Epigenetic biomarkers and drugs are currently under intensive evaluations to ensure efficient clinical utility in GC. In this review, key epigenetic alterations and related functions and mechanisms are summarized in GC. We focus on integration of existing epigenetic findings in GC for the bench-to-bedside translation of some pivotal epigenetic alterations into clinical practice and also describe the vacant field waiting for investigation.
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Affiliation(s)
- Si-Yuan Tang
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Pei-Jun Zhou
- Cancer Research Institute, School of Basic Medicine Science, Central South University, School of Basic Medicine Science, Central South University 410008, Hunan Province, China
| | - Yu Meng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Fu-Rong Zeng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Guang-Tong Deng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
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13
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Sajjadi-Dokht M, Merza Mohamad TA, Rahman HS, Maashi MS, Danshina S, Shomali N, Solali S, Marofi F, Zeinalzadeh E, Akbari M, Adili A, Aslaminabad R, Hagh MF, Jarahian M. MicroRNAs and JAK/STAT3 signaling: A new promising therapeutic axis in blood cancers. Genes Dis 2021; 9:849-867. [PMID: 35685482 PMCID: PMC9170603 DOI: 10.1016/j.gendis.2021.10.009] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 09/16/2021] [Accepted: 10/22/2021] [Indexed: 11/27/2022] Open
Abstract
Blood disorders include a wide spectrum of blood-associated malignancies resulting from inherited or acquired defects. The ineffectiveness of existing therapies against blood disorders arises from different reasons, one of which is drug resistance, so different types of leukemia may show different responses to treatment. Leukemia occurs for a variety of genetic and acquired reasons, leading to uncontrolled proliferation in one or more cell lines. Regarding the genetic defects, oncogene signal transducer and activator of transcription (STAT) family transcription factor, especially STAT3, play an essential role in hematological disorders onset and progress upon mutations, dysfunction, or hyperactivity. Besides, microRNAs, as biological molecules, has been shown to play a dual role in either tumorigenesis and tumor suppression in various cancers. Besides, a strong association between STAT3 and miRNA has been reported. For example, miRNAs can regulate STAT3 via targeting its upstream mediators such as IL6, IL9, and JAKs or directly binding to the STAT3 gene. On the other hand, STAT3 can regulate miRNAs. In this review study, we aimed to determine the role of either microRNAs and STAT3 along with their effect on one another's activity and function in hematological malignancies.
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14
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Complete loss of miR-200 family induces EMT associated cellular senescence in gastric cancer. Oncogene 2021; 41:26-36. [PMID: 34667277 PMCID: PMC8724006 DOI: 10.1038/s41388-021-02067-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 09/17/2021] [Accepted: 10/06/2021] [Indexed: 01/10/2023]
Abstract
The EMT (epithelial-to-mesenchymal-transition) subtype of gastric cancer (GC) is associated with poor treatment responses and unfavorable clinical outcomes. Despite the broad physiological roles of the micro-RNA (miR)-200 family, they largely serve to maintain the overall epithelial phenotype. However, during late-stage gastric tumorigenesis, members of the miR-200 family are markedly suppressed, resulting in the transition to the mesenchymal state and the acquisition of invasive properties. As such, the miR-200 family represents a robust molecular marker of EMT, and subsequently, disease severity and prognosis. Most reports have studied the effect of single miR-200 family member knockdown. Here, we employ a multiplex CRISPR/Cas9 system to generate a complete miR-200 family knockout (FKO) to investigate their collective and summative role in regulating key cellular processes during GC pathogenesis. Genetic deletion of all miR-200s in the human GC cell lines induced potent morphological alterations, G1/S cell cycle arrest, increased senescence-associated β-galactosidase (SA-β−Gal) activity, and aberrant metabolism, collectively resembling the senescent phenotype. Coupling RNA-seq data with publicly available datasets, we revealed a clear separation of senescent and non-senescent states amongst FKO cells and control cells, respectively. Further analysis identified key senescence-associated secretory phenotype (SASP) components in FKO cells and a positive feedback loop for maintenance of the senescent state controlled by activation of TGF-β and TNF-α pathways. Finally, we showed that miR-200 FKO associated senescence in cancer epithelial cells significantly recruited stromal cells in the tumor microenvironment. Our work has identified a new role of miR-200 family members which function as an integrated unit serving to link senescence with EMT, two major conserved biological processes.
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15
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Huang X, Liu F, Guan H, Jiang Z, Wei P, Luo Y, Jia Q. Effects of endoscopic submucosal dissection on post-operative early treatment effectiveness and serum TAT-2 and GP73 expression levels in patients with early gastric cancer. Exp Ther Med 2021; 22:806. [PMID: 34093762 PMCID: PMC8170670 DOI: 10.3892/etm.2021.10238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Accepted: 10/06/2020] [Indexed: 12/24/2022] Open
Abstract
The present study aimed to explore the effectiveness of endoscopic submucosal dissection (ESD) in the treatment of early gastric cancer (EGC) and its effect on serum tumor-associated trypsin-2 (TAT-2) and Golgi protein 73 (GP73) expression levels to provide a reference for the treatment of EGC. TAT-2 is a proteolytic target enzyme for tumor-associated trypsin inhibitor that has been previously reported to enhance invasion by promoting extracellular matrix degradation. GP73 is a novel type II Golgi membrane protein of unknown function that is expressed in the hepatocytes of patients with adult giant-cell hepatitis. A total of 161 patients with EGC treated at our hospital from April 2013 to February 2014 were selected as the study subjects. Among these, 86 patients underwent ESD (group A) and the remaining 75 underwent endoscopic mucosal resection (group B). Treatment effectiveness, incidence of complications and adverse reactions, operation time, intraoperative blood loss and length of hospital stay, as well as serum TAT-2 and GP73 expression levels, were compared between the two groups. The treatment effectiveness was significantly higher in group A than in group B (P<0.05). However, there was no significant inter-group difference in terms of incidence of complications/adverse reactions (P>0.05). After treatment, serum TAT-2 expression levels decreased in both groups (P<0.05) and serum TAT-2 expression levels were lower in group A than in group B (P<0.05). Furthermore, serum GP73 expression levels were significantly elevated in both groups (P<0.05). Kaplan-Meier survival analysis indicated no significant inter-group difference in the 5-year survival rate (P>0.05). In conclusion, ESD had a good therapeutic effect on EGC and is able to decrease serum TAT-2 expression levels and increase serum GP73 expression levels. The present study was registered into the Chinese Trials Registry (registration no. NCT02157534).
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Affiliation(s)
- Xue Huang
- Department of Gastroenterology, The Eighth Affiliated Hospital of Guangxi Medical University, Guigang, Guangxi 537100, P.R. China
| | - Fujian Liu
- Department of Gastroenterology, The Eighth Affiliated Hospital of Guangxi Medical University, Guigang, Guangxi 537100, P.R. China
| | - Hang Guan
- Department of Gastroenterology, The Eighth Affiliated Hospital of Guangxi Medical University, Guigang, Guangxi 537100, P.R. China
| | - Zhiyong Jiang
- Department of Gastroenterology, The Eighth Affiliated Hospital of Guangxi Medical University, Guigang, Guangxi 537100, P.R. China
| | - Peng Wei
- Department of Respiratory and Critical Care Medicine, The Eighth Affiliated Hospital of Guangxi Medical University, Guigang, Guangxi 537100, P.R. China
| | - Yifeng Luo
- Department of Intensive Care Unit, The Eighth Affiliated Hospital of Guangxi Medical University, Guigang, Guangxi 537100, P.R. China
| | - Qiuhong Jia
- Department of Gastroenterology, The Eighth Affiliated Hospital of Guangxi Medical University, Guigang, Guangxi 537100, P.R. China
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16
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Abstract
Gastric cancer (GC) is one of the most common malignant tumors. The mechanism of how GC develops is vague, and therapies are inefficient. The function of microRNAs (miRNAs) in tumorigenesis has attracted the attention from many scientists. During the development of GC, miRNAs function in the regulation of different phenotypes, such as proliferation, apoptosis, invasion and metastasis, drug sensitivity and resistance, and stem-cell-like properties. MiRNAs were evaluated for use in diagnostic and prognostic predictions and exhibited considerable accuracy. Although many problems exist for the application of therapy, current studies showed the antitumor effects of miRNAs. This paper reviews recent advances in miRNA mechanisms in the development of GC and the potential use of miRNAs in the diagnosis and treatment of GC.
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17
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Wen B, Zhu R, Jin H, Zhao K. Differential expression and role of miR-200 family in multiple tumors. Anal Biochem 2021; 626:114243. [PMID: 33964251 DOI: 10.1016/j.ab.2021.114243] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 04/23/2021] [Accepted: 05/01/2021] [Indexed: 01/02/2023]
Abstract
microRNA (miRNA) can maintain the homeostasis of the human by participating in the regulation of cell proliferation, apoptosis, differentiation, and metabolism. During the entire stage of tumorigenesis, miRNA can maintain the heterogeneity of cancer stem cells by regulating the formation and metastasis of the tumor, which leads to chemotherapy resistance. miR-200 family consists of five members, which can regulate the proliferation, invasion, and migration of cancer cells by inhibiting the transcription of downstream genes (including zinc finger E-box binding homeobox 1 and 2, E-cadherin, N-cadherin, transforming growth factor-β, and cancer stem cell related-proteins). Meanwhile, Long non-coding RNA can bind to miR-200s to regulate the proliferation and apoptosis of cancer cells. Besides, the expression of the miR-200 family can affect the mechanism of chemotherapy resistance.
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Affiliation(s)
- Bin Wen
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563000, PR China
| | - Rong Zhu
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563000, PR China
| | - Hai Jin
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563000, PR China
| | - Kui Zhao
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563000, PR China.
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18
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Fang R, Lu Q, Xu B. hsa‑miR‑5580‑3p inhibits oral cancer cell viability, proliferation and migration by suppressing LAMC2. Mol Med Rep 2021; 23:453. [PMID: 33880581 PMCID: PMC8072311 DOI: 10.3892/mmr.2021.12092] [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: 02/28/2020] [Accepted: 03/16/2021] [Indexed: 11/09/2022] Open
Abstract
The present study aimed to explore whether and how microRNA-5580-3p (miR-5580-3p) affected oral cancer (OC) cell phenotypes via regulation of laminin subunit γ2 (LAMC2). Bioinformatics analysis was used to identify miR-5580-3p/LAMC2, a novel interactome that, to the best of our knowledge, has not been studied previously in OC. In the present study, the expression levels of miR-5580-3p and LAMC2 were detected by reverse transcription-quantitative PCR, while the protein expression levels of LAMC2 were identified using western blotting. To determine the effects of miR-5580-3p and LAMC2 in OC, a number of experiments, including Cell Counting Kit-8, 5-bromo-2′-deoxyuridine cell proliferation and wound healing migration assays, were performed using OC SCC-4 and Cal-27 cell lines. Additionally, luciferase reporter assays were employed to examine the interaction between miR-5580-3p and LAMC2 mRNA. The results demonstrated that miR-5580-3p expression was downregulated, while LAMC2 expression was upregulated in OC tissues and cell lines. In addition to the observation that miR-5580-3p promoted the malignant phenotypes of OC, it was also revealed that miR-5580-3p inhibited OC cell viability, proliferation and migration by suppressing LAMC2. Therefore, the present study suggested that miR-5580-3p and LAMC2 may be potential biomarkers and therapeutic targets for OC diagnosis and therapies in the future.
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Affiliation(s)
- Rong Fang
- Department of Gastroenterology, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430033, P.R. China
| | - Qian Lu
- Department of Stomatology, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430015, P.R. China
| | - Bo Xu
- Department of Gastroenterology, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430033, P.R. China
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19
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Abstract
IL-6 is involved both in immune responses and in inflammation, hematopoiesis, bone metabolism and embryonic development. IL-6 plays roles in chronic inflammation (closely related to chronic inflammatory diseases, autoimmune diseases and cancer) and even in the cytokine storm of corona virus disease 2019 (COVID-19). Acute inflammation during the immune response and wound healing is a well-controlled response, whereas chronic inflammation and the cytokine storm are uncontrolled inflammatory responses. Non-immune and immune cells, cytokines such as IL-1β, IL-6 and tumor necrosis factor alpha (TNFα) and transcription factors nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) play central roles in inflammation. Synergistic interactions between NF-κB and STAT3 induce the hyper-activation of NF-κB followed by the production of various inflammatory cytokines. Because IL-6 is an NF-κB target, simultaneous activation of NF-κB and STAT3 in non-immune cells triggers a positive feedback loop of NF-κB activation by the IL-6-STAT3 axis. This positive feedback loop is called the IL-6 amplifier (IL-6 Amp) and is a key player in the local initiation model, which states that local initiators, such as senescence, obesity, stressors, infection, injury and smoking, trigger diseases by promoting interactions between non-immune cells and immune cells. This model counters dogma that holds that autoimmunity and oncogenesis are triggered by the breakdown of tissue-specific immune tolerance and oncogenic mutations, respectively. The IL-6 Amp is activated by a variety of local initiators, demonstrating that the IL-6-STAT3 axis is a critical target for treating diseases.
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Affiliation(s)
- Toshio Hirano
- National Institutes for Quantum and Radiological Science and Technology, Anagawa, Inage-ku, Chiba, Japan
- Division of Molecular Psychoimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
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20
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Pan H, Ding Y, Jiang Y, Wang X, Rao J, Zhang X, Yu H, Hou Q, Li T. LncRNA LIFR-AS1 promotes proliferation and invasion of gastric cancer cell via miR-29a-3p/COL1A2 axis. Cancer Cell Int 2021; 21:7. [PMID: 33407453 PMCID: PMC7789183 DOI: 10.1186/s12935-020-01644-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Accepted: 11/09/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND LncRNA was known to be closely associated with the progression of human tumors. The role of lncRNA LIFR-AS1 in the pathogenesis and progression of gastric tumor is still unclear. The aim of this study was to investigate the function of LIFR-AS1 and the underlying mechanism in the pathogenesis and progression of gastric cancer. METHODS QRT-PCR was used to evaluate the expression of LIFR-AS1, miR-29a-3p and COL1A2 in gastric tumor tissues and cells. Western blotting was used to evaluate the protein expression of COL1A2 in gastric tumor cells. CCK-8 assay, transwell assay and flow cytometry were used to evaluate the roles of LIFR-AS1, miR-29a-3p and COL1A2 in cell proliferation, invasion, migration and apoptosis. The relationship among LIFR-AS1, miR-29a-3p and COL1A2 was assessed by bioinformatics analyses and luciferase reporter assay. RESULTS The expression levels of LIFR-AS1 were significantly increased in gastric tumor tissues and cells, while the expression levels of miR-29a-3p were decreased. The expression of miR-29a-3p was negatively correlated with the expression of LIFR-AS1 in gastric cancer tumor tissues. Knocking down of LIFR-AS1 inhibited proliferation, invasion and migration of gastric tumor cells, and induced apoptosis of gastric tumor cells. Bioinformatics analyses and integrated experiments revealed that LIFR-AS1 elevated the expression of COL1A2 through sponging miR-29a-3p, which further resulted in the progression of gastric tumor. CONCLUSION LIFR-AS1 plays an important role as a competing endogenous RNA in gastric tumor pathogenesis and may be a potential target for the diagnosis and treatment of gastric tumor.
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Affiliation(s)
- Haiyan Pan
- School of Public Health, Guangdong Medical University, Dongguan, 523808, Guangdong, People's Republic of China
| | - Yuanlin Ding
- School of Public Health, Guangdong Medical University, Dongguan, 523808, Guangdong, People's Republic of China
| | - Yugang Jiang
- Department of gastrointestinal Surgery, Shandong Provincial Hospital, Jinan, 250021, Shandong, People's Republic of China
| | - Xingjie Wang
- School of Public Health, Guangdong Medical University, Dongguan, 523808, Guangdong, People's Republic of China
| | - Jiawei Rao
- School of Public Health, Guangdong Medical University, Dongguan, 523808, Guangdong, People's Republic of China
| | - Xingshan Zhang
- School of Public Health, Guangdong Medical University, Dongguan, 523808, Guangdong, People's Republic of China
| | - Haibing Yu
- School of Public Health, Guangdong Medical University, Dongguan, 523808, Guangdong, People's Republic of China
| | - Qinghua Hou
- College of Ocean and Meteorology, Guangdong Ocean University, Zhanjiang, 524088, Guangdong, People's Republic of China
| | - Tao Li
- Department of Chemotherapy, The People's Hospital of Gaozhou, Gaozhou, 525200, Guangdong, People's Republic of China.
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21
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Peng J, Liu F, Zheng H, Wu Q, Liu S. IncRNA ZFAS1 contributes to the radioresistance of nasopharyngeal carcinoma cells by sponging hsa-miR-7-5p to upregulate ENO2. Cell Cycle 2020; 20:126-141. [PMID: 33342344 DOI: 10.1080/15384101.2020.1864128] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Previous research revealed that lncRNA ZFAS1 could promote nasopharyngeal carcinoma (NPC) by inhibiting its downstream target axis. However, the association between ZFAS1 and radioresistant NPC cells is unclear. This study aimed to explore the roles of ZFAS1 in the radioresistance of NPC. Bioinformatics analysis was conducted to identify the significant factors (ENO2 and miR-7-5p) that contributed to the radioresistance of NPC cells. After performing qRT-PCR analysis, we found that the expression of ZFAS1 and ENO2 was upregulated in NPC cells but that the miR-7-5p expression was downregulated in the same samples. Apart from that, we noticed that ZFAS1 inhibition enhanced the sensitivity of NPC cells to radiation therapy by repressing cell proliferation and promoting cell apoptosis. Subsequently, we found that ZFAS1 could sponge miR-7-5p to upregulate ENO2, which was the target of miR-7-5p. Experimental results also indicated that the suppression of miR-7-5p inhibited the sensitivity of NPC cells to radiation therapy, thereby suppressing ENO2 expression. Overall, our findings suggested that ZFAS1 contributed to the radioresistance of NPC cells by regulating the miR-7-5p/ENO2 axis and that ZFAS1 might be a potential therapeutic target for addressing the radioresistance of NPC cells.
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Affiliation(s)
- Jiaojiao Peng
- Department of Otolaryngology, Head and Neck Surgery, West China Hospital, Sichuan University , Sichuan, China
| | - Feng Liu
- Department of Otolaryngology, Head and Neck Surgery, West China Hospital, Sichuan University , Sichuan, China
| | - Hong Zheng
- Department of Otolaryngology, Head and Neck Surgery, West China Hospital, Sichuan University , Sichuan, China
| | - Qi Wu
- Department of Otolaryngology, Head and Neck Surgery, West China Hospital, Sichuan University , Sichuan, China
| | - Shixi Liu
- Department of Otolaryngology, Head and Neck Surgery, West China Hospital, Sichuan University , Sichuan, China
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22
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张 丽, 白 俊, 胡 雅, 周 丹, 郑 荃, 尹 崇, 牟 青, 李 洪. [MiR-204 inhibits invasion and metastasis of breast cancer cells by targeted regulation of HNRNPA2B1]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2020; 40:869-875. [PMID: 32895200 PMCID: PMC7321266 DOI: 10.12122/j.issn.1673-4254.2020.06.15] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Indexed: 12/14/2022]
Abstract
OBJECTIVE To investigate the effect of miR-204 on the invasion and metastasis of breast cancer by targeted regulation of HNRNPA2B1. METHODS The bioinformatics database was used to obtain data of the expressions of miR-204 in breast cancer patients and the survival rate of the patients. RT-qPCR was used to detect the expression of miR-204 in breast cancer cell lines. The expression vector GV369-miR-204 was used to overexpress miR-204 in MDA-MB-231 cells. Transwell assay was performed to detect the effect of miR-204 on the migration and invasion ability of the breast cancer cells. The key genes (hub genes) of miR-204 were determined by bioinformatics method. A dual luciferase assay was used to analyze the targeting relationship between miR-204 and HNRNPA2B1. The expression of HNRNPA2B1 in MDA-MB-231 cells after miR-204 overexpression was detected by Western blotting, and Transwell assay was used to examine the changes in the cell invasion ability. RESULTS The expression of miR-204 was decreased in both breast cancer tissues, and was significantly lower in breast cancer MDA-MB-231 cells than in MCF-10A cells (P < 0.05). The decreased expression of miR-204 was associated with poorer prognosis of breast cancer patients (P < 0.05). Upregulation of miR-204 in MDA-MB-231 cells significantly inhibited the invasion and migration of the cells (P < 0.05). Analysis of the data from the Starbase revealed that the expression of miR-204-5p was negatively correlated with the expression of HNRNPA2B1, and the expression of HNRNPA2B1 was increased in breast cancer patients (P < 0.05) in association with a poorer prognosis of the patients (P < 0.05). Dual luciferase assay demonstrated that miR-204 could bind to HNRNPA2B1 in a target-specific manner. Western blotting and Transwell assay showed that miR-204 significant inhibited the migration and invasion ability of breast cancer cells by targeting HNRNPA2B1 (P < 0.05). CONCLUSIONS miR-204 expression is decreased in breast cancer tissues and cells, and its overexpression can inhibit the invasion and metastasis of breast cancer cells by targeted regulation of HNRNPA2B1.
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Affiliation(s)
- 丽萍 张
- 潍坊医学院 病理学教研室, 山东 潍坊 261053Department of Pathology, Weifang Medical University, Weifang 261053, China
| | - 俊 白
- 潍坊医学院 病理学教研室, 山东 潍坊 261053Department of Pathology, Weifang Medical University, Weifang 261053, China
| | - 雅琼 胡
- 潍坊医学院 病理学教研室, 山东 潍坊 261053Department of Pathology, Weifang Medical University, Weifang 261053, China
| | - 丹丹 周
- 潍坊医学院 病理学教研室, 山东 潍坊 261053Department of Pathology, Weifang Medical University, Weifang 261053, China
| | - 荃 郑
- 潍坊医学院 病理学教研室, 山东 潍坊 261053Department of Pathology, Weifang Medical University, Weifang 261053, China
| | - 崇高 尹
- 潍坊医学院 护理学院, 山东 潍坊 261053College of Nursing, Weifang Medical University, Weifang 261053, China
| | - 青杰 牟
- 潍坊医学院 临床医学院, 山东 潍坊 261053Clinical Medical College, Weifang Medical University, Weifang 261053, China
| | - 洪利 李
- 潍坊医学院 医学研究实验中心, 山东 潍坊 261053Medicine Research Center, Weifang Medical University, Weifang 261053, China
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23
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STAT3 Pathway in Gastric Cancer: Signaling, Therapeutic Targeting and Future Prospects. BIOLOGY 2020; 9:biology9060126. [PMID: 32545648 PMCID: PMC7345582 DOI: 10.3390/biology9060126] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 06/02/2020] [Accepted: 06/04/2020] [Indexed: 12/11/2022]
Abstract
Molecular signaling pathways play a significant role in the regulation of biological mechanisms, and their abnormal expression can provide the conditions for cancer development. The signal transducer and activator of transcription 3 (STAT3) is a key member of the STAT proteins and its oncogene role in cancer has been shown. STAT3 is able to promote the proliferation and invasion of cancer cells and induces chemoresistance. Different downstream targets of STAT3 have been identified in cancer and it has also been shown that microRNA (miR), long non-coding RNA (lncRNA) and other molecular pathways are able to function as upstream mediators of STAT3 in cancer. In the present review, we focus on the role and regulation of STAT3 in gastric cancer (GC). miRs and lncRNAs are considered as potential upstream mediators of STAT3 and they are able to affect STAT3 expression in exerting their oncogene or onco-suppressor role in GC cells. Anti-tumor compounds suppress the STAT3 signaling pathway to restrict the proliferation and malignant behavior of GC cells. Other molecular pathways, such as sirtuin, stathmin and so on, can act as upstream mediators of STAT3 in GC. Notably, the components of the tumor microenvironment that are capable of targeting STAT3 in GC, such as fibroblasts and macrophages, are discussed in this review. Finally, we demonstrate that STAT3 can target oncogene factors to enhance the proliferation and metastasis of GC cells.
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24
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Saad MI, Alhayyani S, McLeod L, Yu L, Alanazi M, Deswaerte V, Tang K, Jarde T, Smith JA, Prodanovic Z, Tate MD, Balic JJ, Watkins DN, Cain JE, Bozinovski S, Algar E, Kohmoto T, Ebi H, Ferlin W, Garbers C, Ruwanpura S, Sagi I, Rose-John S, Jenkins BJ. ADAM17 selectively activates the IL-6 trans-signaling/ERK MAPK axis in KRAS-addicted lung cancer. EMBO Mol Med 2020; 11:emmm.201809976. [PMID: 30833304 PMCID: PMC6460353 DOI: 10.15252/emmm.201809976] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Oncogenic KRAS mutations are major drivers of lung adenocarcinoma (LAC), yet the direct therapeutic targeting of KRAS has been problematic. Here, we reveal an obligate requirement by oncogenic KRAS for the ADAM17 protease in LAC In genetically engineered and xenograft (human cell line and patient-derived) Kras G12D-driven LAC models, the specific blockade of ADAM17, including with a non-toxic prodomain inhibitor, suppressed tumor burden by reducing cellular proliferation. The pro-tumorigenic activity of ADAM17 was dependent upon its threonine phosphorylation by p38 MAPK, along with the preferential shedding of the ADAM17 substrate, IL-6R, to release soluble IL-6R that drives IL-6 trans-signaling via the ERK1/2 MAPK pathway. The requirement for ADAM17 in Kras G12D-driven LAC was independent of bone marrow-derived immune cells. Furthermore, in KRAS mutant human LAC, there was a significant positive correlation between augmented phospho-ADAM17 levels, observed primarily in epithelial rather than immune cells, and activation of ERK and p38 MAPK pathways. Collectively, these findings identify ADAM17 as a druggable target for oncogenic KRAS-driven LAC and provide the rationale to employ ADAM17-based therapeutic strategies for targeting KRAS mutant cancers.
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Affiliation(s)
- Mohamed I Saad
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Vic., Australia.,Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Vic., Australia
| | - Sultan Alhayyani
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Vic., Australia.,Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Vic., Australia
| | - Louise McLeod
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Vic., Australia.,Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Vic., Australia
| | - Liang Yu
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Vic., Australia.,Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Vic., Australia
| | - Mohammad Alanazi
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Vic., Australia.,Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Vic., Australia
| | - Virginie Deswaerte
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Vic., Australia.,Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Vic., Australia
| | - Ke Tang
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Vic., Australia.,Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Vic., Australia
| | - Thierry Jarde
- Cancer Program, Monash Biomedicine Discovery Institute, Clayton, Vic., Australia.,Department of Anatomy and Developmental Biology, Monash University, Clayton, Vic., Australia.,Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Vic., Australia
| | - Julian A Smith
- Department of Surgery, School of Clinical Sciences at Monash Health, Monash University, Clayton, Vic., Australia.,Department of Cardiothoracic Surgery, Monash Health, Clayton, Vic., Australia
| | | | - Michelle D Tate
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Vic., Australia.,Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Vic., Australia
| | - Jesse J Balic
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Vic., Australia.,Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Vic., Australia
| | - D Neil Watkins
- The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
| | - Jason E Cain
- Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Vic., Australia.,Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Vic., Australia
| | - Steven Bozinovski
- School of Health and Biomedical Sciences, RMIT University, Bundoora, Vic., Australia
| | - Elizabeth Algar
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Vic., Australia.,Genetics and Molecular Pathology Laboratory, Monash Health, Clayton, Vic., Australia
| | - Tomohiro Kohmoto
- Department of Human Genetics, Tokushima University Graduate School of Medicine, Tokushima, Japan.,Division of Molecular Genetics, Aichi Cancer Center Research Institute, Nagoya, Japan
| | - Hiromichi Ebi
- Division of Molecular Therapeutics, Aichi Cancer Center Research Institute, Nagoya, Japan.,Division of Advanced Cancer Therapeutics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | | | - Christoph Garbers
- Department of Pathology, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany
| | - Saleela Ruwanpura
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Vic., Australia.,Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Vic., Australia
| | - Irit Sagi
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
| | - Stefan Rose-John
- Institute of Biochemistry, Christian-Albrechts-University, Kiel, Germany
| | - Brendan J Jenkins
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Vic., Australia .,Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Vic., Australia
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25
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Kozak J, Jonak K, Maciejewski R. The function of miR-200 family in oxidative stress response evoked in cancer chemotherapy and radiotherapy. Biomed Pharmacother 2020; 125:110037. [PMID: 32187964 DOI: 10.1016/j.biopha.2020.110037] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 02/14/2020] [Accepted: 02/17/2020] [Indexed: 12/14/2022] Open
Abstract
Since the beginning of the discovery of microRNAs (miRs), these molecules have attracted highly progressive attention due to their powerful regulatory roles in a broad spectrum of biological processes, including proliferation, differentiation, apoptosis and carcinogenesis. With regard to carcinogenesis, the miRs regulatory potency has been associated with cancer onset, progression, metastasis, diagnosis and therapeutic response. In this review we discuss the impact of miR-200 family on drug resistance development during anti-cancer therapy. Developing resistance to chemotherapeutic drugs as well as radiotherapy are major clinical obstacles in the successful therapeutic strategies to cancer treatment. Acquired cancer chemoresistance is a multifactorial phenomenon involving such factors as tumor type, tumor stage, cellular reactive oxygen species (ROS) level or ROS-responsive miRs profile. ROS level could influence the miRs expression level, which changes the cellular profile of the content of miRs. Such significant changes in the cellular miRs profile generate subsequent biological effects through the regulation of their target genes. This review outlines the interactions between ROS and miR-200 family in different kinds of cancers in response to chemotherapy.
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Affiliation(s)
- Joanna Kozak
- Department of Normal Anatomy, Medical University of Lublin, 20-090 Lublin, Poland.
| | - Katarzyna Jonak
- Interfaculty Centre for Didactics, Department of Foreign Languages, Medical University of Lublin, 20-081 Lublin, Poland
| | - Ryszard Maciejewski
- Department of Normal Anatomy, Medical University of Lublin, 20-090 Lublin, Poland
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26
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Chen J, Liu H, Chen J, Sun B, Wu J, Du C. PLXNC1 Enhances Carcinogenesis Through Transcriptional Activation of IL6ST in Gastric Cancer. Front Oncol 2020; 10:33. [PMID: 32117710 PMCID: PMC7010712 DOI: 10.3389/fonc.2020.00033] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 01/09/2020] [Indexed: 01/12/2023] Open
Abstract
Background: Transcriptional factors (TFs) are responsible for orchestrating gene transcription during cancer progression. However, their roles in gastric cancer (GC) remain unclear. Methods: We analyzed the differential expressions of TFs and, using GC cells and tissues, investigated plexin C1 (PLXNC1) RNA levels, as well as PLXNC1's clinical relevance and functional mechanisms. The molecular function of PLXNC1 was evaluated in vitro and in vivo. Kaplan-Meier curves and the log-rank test were used to analyze overall survival (OS) and disease-free survival (DFS). Results: PLXNC1 was frequently up-regulated in GC and associated with poor prognosis. The expression level of PLXNC1 could serve as an independent biomarker to predict a patient's overall survival. Notably, knockdown of PLXNC1 significantly abolished GC cell proliferation, and migration, and overexpression of PLXNC1 accelerated carcinogenesis in GC. The gene set enrichment analysis (GSEA) indicated that high-expression of PLXNC1 was positively correlated with the activation of epithelial-mesenchymal transition (EMT), TNF-α, and IL-6/STAT3 signaling pathways. PLXNC1 promoted proliferation and migration of GC cells through transcriptional activation of the interleukin 6 signal transducer (IL6ST), which could rescue the malignant behavior of PLXNC1-deficient GC cells. Conclusions: Our study demonstrated that the PLXNC1 plays an oncogenic role in GC patients. The PLXNC1-IL6ST axis represents a novel potential therapeutic target for GC.
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Affiliation(s)
- Jie Chen
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
| | - Haining Liu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jinggui Chen
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
| | - Bo Sun
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
| | - Jianghong Wu
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
| | - Chunyan Du
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
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27
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Yuan K, Ye J, Liu Z, Ren Y, He W, Xu J, He Y, Yuan Y. Complement C3 overexpression activates JAK2/STAT3 pathway and correlates with gastric cancer progression. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:9. [PMID: 31928530 PMCID: PMC6956509 DOI: 10.1186/s13046-019-1514-3] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Accepted: 12/22/2019] [Indexed: 12/21/2022]
Abstract
Background Localized C3 deposition is a well-known factor of inflammation. However, its role in oncoprogression of gastric cancer (GC) remains obscured. This study aims to explore the prognostic value of C3 deposition and to elucidate the mechanism of C3-related oncoprogression for GC. Methods From August to December 2013, 106 GC patients were prospectively included. The regional expression of C3 and other effectors in gastric tissues were detected by WB, IHC, qRT-PCR and other tests. The correlation of localized C3 deposition and oncologic outcomes was determined by 5-year survival significance. Human GC and normal epithelial cell lines were employed to detect a relationship between C3 and STAT3 signaling pathway in vitro experiments. Results C3 and C3a expression were markedly enhanced in GC tissues at both mRNA and protein levels compared with those in paired nontumorous tissues. According to IHC C3 score, 65 (61.3%) and 41 (38.7%) patients had high and low C3 deposition, respectively. C3 deposition was negatively correlated with plasma levels of C3 and C3a (both P < 0.001) and positively correlated with pathological T and TNM stages (both P < 0.001). High C3 deposition was identified as an independent prognostic factor of poor 5-year overall survival (P = 0.045). In vitro C3 administration remarkably enhanced p-JAK2/p-STAT3 expression in GC cell lines but caused a reduction of such activation when pre-incubated with a C3 blocker. Importantly, C3 failed to activate such signaling in cells pre-treated with a JAK2 inhibitor. Conclusions Localized C3 deposition in the tumor microenvironment is a relevant immune signature for predicting prognosis of GC. It may aberrantly activate JAK2/STAT3 pathway allowing oncoprogression. Trial registration ClinicalTrials.gov, NCT02425930, Registered 1st August 2013.
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Affiliation(s)
- Kaitao Yuan
- Center of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.,Center of Gastric cancer, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Jinning Ye
- Center of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.,Center of Gastric cancer, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Zhenguo Liu
- Department of Thoracic Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Yufeng Ren
- Department of Radiation Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Weiling He
- Center of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China. .,Center of Gastric cancer, Sun Yat-sen University, Guangzhou, People's Republic of China.
| | - Jianbo Xu
- Center of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China. .,Center of Gastric cancer, Sun Yat-sen University, Guangzhou, People's Republic of China.
| | - Yulong He
- Center of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China. .,Center of Gastric cancer, Sun Yat-sen University, Guangzhou, People's Republic of China.
| | - Yujie Yuan
- Center of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China. .,Center of Gastric cancer, Sun Yat-sen University, Guangzhou, People's Republic of China.
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28
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Liu L, Tian YC, Mao G, Zhang YG, Han L. MiR-675 is frequently overexpressed in gastric cancer and enhances cell proliferation and invasion via targeting a potent anti-tumor gene PITX1. Cell Signal 2019; 62:109352. [DOI: 10.1016/j.cellsig.2019.109352] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 06/21/2019] [Accepted: 06/27/2019] [Indexed: 12/29/2022]
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29
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Rojas-Sanchez G, Cotzomi-Ortega I, Pazos-Salazar NG, Reyes-Leyva J, Maycotte P. Autophagy and Its Relationship to Epithelial to Mesenchymal Transition: When Autophagy Inhibition for Cancer Therapy Turns Counterproductive. BIOLOGY 2019; 8:biology8040071. [PMID: 31554173 PMCID: PMC6956138 DOI: 10.3390/biology8040071] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 09/14/2019] [Accepted: 09/20/2019] [Indexed: 02/06/2023]
Abstract
The manipulation of autophagy for cancer therapy has gained recent interest in clinical settings. Although inhibition of autophagy is currently being used in clinical trials for the treatment of several malignancies, autophagy has been shown to have diverse implications for normal cell homeostasis, cancer cell survival, and signaling to cells in the tumor microenvironment. Among these implications and of relevance for cancer therapy, the autophagic process is known to be involved in the regulation of protein secretion, in tumor cell immunogenicity, and in the regulation of epithelial-to-mesenchymal transition (EMT), a critical step in the process of cancer cell invasion. In this work, we have reviewed recent evidence linking autophagy to the regulation of EMT in cancer and normal epithelial cells, and have discussed important implications for the manipulation of autophagy during cancer therapy.
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Affiliation(s)
- Guadalupe Rojas-Sanchez
- Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, Ciudad Universitaria, Puebla 72570, Mexico.
- Centro de Investigación Biomédica de Oriente (CIBIOR), Instituto Mexicano del Seguro Social (IMSS), Km 4.5 Carretera Atlixco-Metepec HGZ5, Puebla 74360, Mexico.
| | - Israel Cotzomi-Ortega
- Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, Ciudad Universitaria, Puebla 72570, Mexico.
- Centro de Investigación Biomédica de Oriente (CIBIOR), Instituto Mexicano del Seguro Social (IMSS), Km 4.5 Carretera Atlixco-Metepec HGZ5, Puebla 74360, Mexico.
| | - Nidia G Pazos-Salazar
- Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, Ciudad Universitaria, Puebla 72570, Mexico.
| | - Julio Reyes-Leyva
- Centro de Investigación Biomédica de Oriente (CIBIOR), Instituto Mexicano del Seguro Social (IMSS), Km 4.5 Carretera Atlixco-Metepec HGZ5, Puebla 74360, Mexico.
| | - Paola Maycotte
- Consejo Nacional de Ciencia y Tecnología (CONACYT)-CIBIOR, IMSS, Puebla 74360, Mexico.
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30
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Balic JJ, Garama DJ, Saad MI, Yu L, West AC, West AJ, Livis T, Bhathal PS, Gough DJ, Jenkins BJ. Serine-Phosphorylated STAT3 Promotes Tumorigenesis via Modulation of RNA Polymerase Transcriptional Activity. Cancer Res 2019; 79:5272-5287. [PMID: 31481496 DOI: 10.1158/0008-5472.can-19-0974] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 07/24/2019] [Accepted: 08/28/2019] [Indexed: 11/16/2022]
Abstract
Deregulated activation of the latent oncogenic transcription factor STAT3 in many human epithelial malignancies, including gastric cancer, has invariably been associated with its canonical tyrosine phosphorylation and enhanced transcriptional activity. By contrast, serine phosphorylation (pS) of STAT3 can augment its nuclear transcriptional activity and promote essential mitochondrial functions, yet the role of pS-STAT3 among epithelial cancers is ill-defined. Here, we reveal that genetic ablation of pS-STAT3 in the gp130 F/F spontaneous gastric cancer mouse model and human gastric cancer cell line xenografts abrogated tumor growth that coincided with reduced proliferative potential of the tumor epithelium. Microarray gene expression profiling demonstrated that the suppressed gastric tumorigenesis in pS-STAT3-deficient gp130 F/F mice associated with reduced transcriptional activity of STAT3-regulated gene networks implicated in cell proliferation and migration, inflammation, and angiogenesis, but not mitochondrial function or metabolism. Notably, the protumorigenic activity of pS-STAT3 aligned with its capacity to primarily augment RNA polymerase II-mediated transcriptional elongation, but not initiation, of STAT3 target genes. Furthermore, by using a combinatorial in vitro and in vivo proteomics approach based on the rapid immunoprecipitation mass spectrometry of endogenous protein (RIME) assay, we identified RuvB-like AAA ATPase 1 (RUVBL1/Pontin) and enhancer of rudimentary homolog (ERH) as interacting partners of pS-STAT3 that are pivotal for its transcriptional activity on STAT3 target genes. Collectively, these findings uncover a hitherto unknown transcriptional role and obligate requirement for pS-STAT3 in gastric cancer that could be extrapolated to other STAT3-driven cancers. SIGNIFICANCE: These findings reveal a new transcriptional role and mandatory requirement for constitutive STAT3 serine phosphorylation in gastric cancer.
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Affiliation(s)
- Jesse J Balic
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Daniel J Garama
- Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.,Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia
| | - Mohamed I Saad
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Liang Yu
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Alison C West
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Alice J West
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Thaleia Livis
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Prithi S Bhathal
- Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Daniel J Gough
- Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia. .,Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia
| | - Brendan J Jenkins
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia. .,Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
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31
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Gao C, Cai X, Fu Q, Yang N, Song L, Su B, Tan F, Liu B, Li C. Dynamics of MiRNA Transcriptome in Turbot (Scophthalmus maximus L.) Intestine Following Vibrio anguillarum Infection. MARINE BIOTECHNOLOGY (NEW YORK, N.Y.) 2019; 21:550-564. [PMID: 31111338 DOI: 10.1007/s10126-019-09903-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 04/26/2019] [Indexed: 06/09/2023]
Abstract
MicroRNAs (miRNAs) are a group of small non-coding RNAs, which could bind to the 3'-untranslated regions of their target mRNAs to regulate gene expression in various biological processes, including immune-regulated signaling pathways. Turbot (Scophthalmus maximus L.), an important commercial fish species in China, has been suffering with Vibrio anguillarum infection resulted in dramatic economic loss. Therefore, we investigated the expression profiles of miRNAs, as well as the immune-related miRNA-mRNA pairs in turbot intestine at 1 h, 4 h, and 12 h following V. anguillarum infection. As a result, 266 predicted novel miRNAs and 283 conserved miRNAs belonging to 92 miRNA families were detected. A total of 44 miRNAs were differentially expressed in the intestine following V. anguillarum infection. Following prediction, the potential target genes of differentially expressed miRNAs were grouped into a wide range of functional categories, including immune defense/evasion, inflammatory responses, RIG-I signaling pathway, and Toll-like receptor signaling pathway. Moreover, we selected 15 differentially expressed immune genes and their related differentially expressed miRNAs to construct an interaction network for V. anguillarum infection in turbot. These results suggested that in teleost, as in higher vertebrates, miRNAs prominently contribute to immune responses, protecting the host against infection. In addition, this is the first report of comprehensive identification of turbot miRNAs being differentially regulated in the intestine related to V. anguillarum infection. Our results provided an opportunity for further understanding of the molecular mechanisms of miRNA regulation in turbot host-pathogen interactions.
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Affiliation(s)
- Chengbin Gao
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China
| | - Xin Cai
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China
| | - Qiang Fu
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China
| | - Ning Yang
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China
| | - Lin Song
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China
| | - Baofeng Su
- School of Fisheries, Aquaculture and Aquatic Sciences, Auburn University, Auburn, AL, 36849, USA
| | - Fenghua Tan
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China
| | - Baining Liu
- Menaul School Qingdao, Qingdao, 266200, China
| | - Chao Li
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China.
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32
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Interplay between STAT3, Cell Adhesion Molecules and Angiogenesis-Related Parameters in Gastric Carcinoma. Does STAT3 Really Have a Prognostic Value? ACTA ACUST UNITED AC 2019; 55:medicina55060300. [PMID: 31234597 PMCID: PMC6630606 DOI: 10.3390/medicina55060300] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 06/17/2019] [Accepted: 06/21/2019] [Indexed: 12/24/2022]
Abstract
Background and objectives: Gastric cancer (GC) is one of the deadliest malignancies, with the underlying pathophysiological mechanisms still not completely understood. In this study, we aimed to investigate the signal transducer and activator of transcription 3 (STAT3) moleculeconnection with the pathological features of GCs, and the expression of cell adhesive molecules (E-cadherin and β-catenin) and angiogenesis-related factors (vascular endothelial growth factor (VEGF), HIF1α, and CD31)). Materials and Methods: This study comprised 136 cases of GCs with data related to the patients’ demographic characteristics (age, gender) and pathological features (tumor location, gross type, Laurens’ type of GC, histological differentiation, invasion depth, lymphovascular invasion and the presence of metastases) which were correlated with STAT3 expression. Additionally, STAT3 expression and the expression of adhesive molecules and angiogenesis-related factors were studied by immunohistochemical methods. Results: The expression of STAT3 was found to be significantly associated with the occurrence of poorly differentiated GCs in the lower portion of the stomach and with the presence of distant metastases. Interestingly, none of the investigated parameters related to cell adhesion or to angiogenesis were found to be related to the expression of STAT3. Conclusions: The lack of significant differences between the studied STAT3 expression and some of the molecules associated with different cancer features might be due to the characteristics of the studied population sample associated with the origin, heterogeneity, and cancer pathophysiological background. Nonetheless, the results of our study suggest that STAT3 could be a useful marker for the presence of distant GC metastases, which further indicates that STAT3 action might involve some other signaling molecules/pathways that warrant further elucidation.
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Wu G, Zheng H, Xu J, Guo Y, Zheng G, Ma C, Hao S, Liu X, Chen H, Wei S, Song X, Wang X. miR-429 suppresses cell growth and induces apoptosis of human thyroid cancer cell by targeting ZEB1. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2019; 47:548-554. [PMID: 30849921 DOI: 10.1080/21691401.2018.1564320] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Thyroid cancer is now the most common endocrine malignancy and the effect of miR-429 in the development of thyroid cancer still need to be further investigated. The expression level of miR-429 was quantified by qPCR in both clinical samples and cultured cell lines. MTT, flow cytometry, migration analyses and Matrigel invasion assays were conducted to test the proliferation, apoptosis, migration and invasion of MiR-429 transfection in thyroid cancer cell lines. Luciferase activity assay and western blot were conducted to detect the direct effect of miR-429 on Zinc finger E-box-binding homeobox 1 (ZEB1) expression. In this study, it was found that miR-429 was frequently decreased in thyroid cancer tissues and cell lines. Transfection of miR-429 in thyroid cancer cell lines substantially suppressed cell proliferation, migration and invasion. Besides, miR-429 up-regulation would induce apoptosis in different cell lines. ZEB1 was identified as a direct target of miR-429 and miR-429 transfection could inhibit ZEB1 by direct binding to its 3'-untranslated region (3'-UTR). In conclusion, these data indicated that miR-429 could act as a tumour suppressor miRNA and contribute to the development and progression and metastasis of thyroid cancer.
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Affiliation(s)
- Guochang Wu
- a Department of Thyroid Surgery , The Affiliated Yantai Yuhuangding Hospital of Qingdao University , Yantai , China
| | - Haitao Zheng
- a Department of Thyroid Surgery , The Affiliated Yantai Yuhuangding Hospital of Qingdao University , Yantai , China
| | - Jie Xu
- a Department of Thyroid Surgery , The Affiliated Yantai Yuhuangding Hospital of Qingdao University , Yantai , China
| | - Yawen Guo
- a Department of Thyroid Surgery , The Affiliated Yantai Yuhuangding Hospital of Qingdao University , Yantai , China
| | - Guibin Zheng
- a Department of Thyroid Surgery , The Affiliated Yantai Yuhuangding Hospital of Qingdao University , Yantai , China
| | - Ci Ma
- a Department of Thyroid Surgery , The Affiliated Yantai Yuhuangding Hospital of Qingdao University , Yantai , China
| | - Shaolong Hao
- a Department of Thyroid Surgery , The Affiliated Yantai Yuhuangding Hospital of Qingdao University , Yantai , China
| | - Xincheng Liu
- a Department of Thyroid Surgery , The Affiliated Yantai Yuhuangding Hospital of Qingdao University , Yantai , China
| | - Huanjie Chen
- a Department of Thyroid Surgery , The Affiliated Yantai Yuhuangding Hospital of Qingdao University , Yantai , China
| | - Shujian Wei
- a Department of Thyroid Surgery , The Affiliated Yantai Yuhuangding Hospital of Qingdao University , Yantai , China
| | - Xicheng Song
- b Department of Otolaryngology-Head and Neck Surgery , The Affiliated Yantai Yuhuangding Hospital of Qingdao University , Yantai , China
| | - Xiaojie Wang
- a Department of Thyroid Surgery , The Affiliated Yantai Yuhuangding Hospital of Qingdao University , Yantai , China
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Liu YD, Yu L, Ying L, Balic J, Gao H, Deng NT, West A, Yan F, Ji CB, Gough D, Tan P, Jenkins BJ, Li JK. Toll-like receptor 2 regulates metabolic reprogramming in gastric cancer via superoxide dismutase 2. Int J Cancer 2019; 144:3056-3069. [PMID: 30536754 PMCID: PMC6590666 DOI: 10.1002/ijc.32060] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Revised: 11/07/2018] [Accepted: 11/13/2018] [Indexed: 01/05/2023]
Abstract
Toll-like receptors (TLRs) play critical roles in host defense after recognition of conserved microbial- and host-derived components, and their dysregulation is a common feature of various inflammation-associated cancers, including gastric cancer (GC). Despite the recent recognition that metabolic reprogramming is a hallmark of cancer, the molecular effectors of altered metabolism during tumorigenesis remain unclear. Here, using bioenergetics function assays on human GC cells, we reveal that ligand-induced activation of TLR2, predominantly through TLR1/2 heterodimer, augments both oxidative phosphorylation (OXPHOS) and glycolysis, with a bias toward glycolytic activity. Notably, DNA microarray-based expression profiling of human cancer cells stimulated with TLR2 ligands demonstrated significant enrichment of gene-sets for oncogenic pathways previously implicated in metabolic regulation, including reactive oxygen species (ROS), p53 and Myc. Moreover, the redox gene encoding the manganese-dependent mitochondrial enzyme, superoxide dismutase (SOD)2, was strongly induced at the mRNA and protein levels by multiple signaling pathways downstream of TLR2, namely JAK-STAT3, JNK MAPK and NF-κB. Furthermore, siRNA-mediated suppression of SOD2 ameliorated the TLR2-induced metabolic shift in human GC cancer cells. Importantly, patient-derived tissue microarrays and bioinformatics interrogation of clinical datasets indicated that upregulated expression of TLR2 and SOD2 were significantly correlated in human GC, and the TLR2-SOD2 axis was associated with multiple clinical parameters of advanced stage disease, including distant metastasis, microvascular invasion and stage, as well as poor survival. Collectively, our findings reveal a novel TLR2-SOD2 axis as a potential biomarker for therapy and prognosis in cancer.
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Affiliation(s)
- You Dong Liu
- Department of General SurgeryShanghai General Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
- Centre for Innate Immunity and Infectious DiseasesHudson Institute of Medical ResearchClaytonVICAustralia
| | - Liang Yu
- Department of General SurgeryShanghai General Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
- Centre for Innate Immunity and Infectious DiseasesHudson Institute of Medical ResearchClaytonVICAustralia
- Department of Molecular Translational Science, Faculty of MedicineNursing and Health Sciences, Monash UniversityClaytonVICAustralia
| | - Le Ying
- Department of Molecular Translational Science, Faculty of MedicineNursing and Health Sciences, Monash UniversityClaytonVICAustralia
- Centre for Cancer ResearchHudson Institute of Medical ResearchClaytonVICAustralia
| | - Jesse Balic
- Centre for Innate Immunity and Infectious DiseasesHudson Institute of Medical ResearchClaytonVICAustralia
- Department of Molecular Translational Science, Faculty of MedicineNursing and Health Sciences, Monash UniversityClaytonVICAustralia
| | - Hugh Gao
- Centre for Innate Immunity and Infectious DiseasesHudson Institute of Medical ResearchClaytonVICAustralia
- Department of Molecular Translational Science, Faculty of MedicineNursing and Health Sciences, Monash UniversityClaytonVICAustralia
| | - Nian Tao Deng
- Tumour Progression Cancer DivisionGarvan Institute of Medical ResearchDarlinghurstNSWAustralia
| | - Alison West
- Centre for Innate Immunity and Infectious DiseasesHudson Institute of Medical ResearchClaytonVICAustralia
- Department of Molecular Translational Science, Faculty of MedicineNursing and Health Sciences, Monash UniversityClaytonVICAustralia
| | - Feng Yan
- Australian Centre for Blood DiseasesMonash UniversityMelbourneVICAustralia
| | - Cheng Bo Ji
- Department of General SurgeryShanghai General Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
- Centre for Innate Immunity and Infectious DiseasesHudson Institute of Medical ResearchClaytonVICAustralia
- Department of Molecular Translational Science, Faculty of MedicineNursing and Health Sciences, Monash UniversityClaytonVICAustralia
| | - Daniel Gough
- Department of Molecular Translational Science, Faculty of MedicineNursing and Health Sciences, Monash UniversityClaytonVICAustralia
- Centre for Cancer ResearchHudson Institute of Medical ResearchClaytonVICAustralia
| | - Patrick Tan
- Genome Institute of SingaporeSingaporeSingapore
- Cancer and Stem Cell BiologyDuke‐NUS Medical SchoolSingaporeSingapore
- Cancer Science Institute of SingaporeNational University of SingaporeSingaporeSingapore
| | - Brendan J. Jenkins
- Centre for Innate Immunity and Infectious DiseasesHudson Institute of Medical ResearchClaytonVICAustralia
- Department of Molecular Translational Science, Faculty of MedicineNursing and Health Sciences, Monash UniversityClaytonVICAustralia
| | - Ji Kun Li
- Department of General SurgeryShanghai General Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
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Shi Y, Huang X, Chen G, Wang Y, Liu Y, Xu W, Tang S, Guleng B, Liu J, Ren J. miR-632 promotes gastric cancer progression by accelerating angiogenesis in a TFF1-dependent manner. BMC Cancer 2019; 19:14. [PMID: 30612555 PMCID: PMC6322242 DOI: 10.1186/s12885-018-5247-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2018] [Accepted: 12/26/2018] [Indexed: 12/12/2022] Open
Abstract
Background Gastric cancer (GC) is a common malignant disease worldwide. Aberrant miRNAs expression contributes to malignant cells behaviour, and in preclinical research, miRNA targeting has shown potential for improving GC therapy. Our present study demonstrated that miR-632 promotes GC progression in a trefoil factor 1 (TFF1)-dependent manner. Methods We collected GC tissues and serum samples to detect miR-632 expression using real-time PCR. A dual-luciferase reporter assay was used to identify whether miR-632 directly regulates TFF1 expression. Tube formation and endothelial cell recruitment assays were performed with or without miR-632 treatment. Western blot and in situ hybridization assays were performed to detect angiogenesis and endothelial recruitment markers that are affected by miR-632. Results Our results showed that miR-632 is highly expressed in GC tissue and serum and negatively associated with TFF1 in GC. miR-632 improves tube formation and endothelial cell recruitment by negatively regulating TFF1 in GC cells. Recombinant TFF1 reversed miR-632-mediated angiogenesis. TFF1 is a target gene of miR-632. Conclusions Our study demonstrated that miR-632 promotes GC progression by accelerating angiogenesis in a TFF1-dependent manner. Targeting of miR-632 may be a potential therapeutic approach for GC patients. Electronic supplementary material The online version of this article (10.1186/s12885-018-5247-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Ying Shi
- Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, 510630, People's Republic of China. .,The First Clinical Medical College, Jinan University, Guangzhou, 510630, People's Republic of China.
| | - Xiaoxiao Huang
- Department of Gastroenterology, Zhongshan Hospital, Xiamen University, Xiamen, 361004, People's Republic of China
| | - Guobin Chen
- Xiamen branch, Zhongshan hospital, Fudan University, Xiamen, 361015, People's Republic of China
| | - Ying Wang
- Xiamen branch, Zhongshan hospital, Fudan University, Xiamen, 361015, People's Republic of China
| | - Yuansheng Liu
- Department of Gastroenterology, Zhongshan Hospital, Xiamen University, Xiamen, 361004, People's Republic of China
| | - Wei Xu
- Department of Gastroenterology, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, People's Republic of China
| | - Shaohui Tang
- Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, 510630, People's Republic of China.,The First Clinical Medical College, Jinan University, Guangzhou, 510630, People's Republic of China
| | - Bayasi Guleng
- Department of Gastroenterology, Zhongshan Hospital, Xiamen University, Xiamen, 361004, People's Republic of China
| | - Jingjing Liu
- Department of Gastroenterology, Zhongshan Hospital, Xiamen University, Xiamen, 361004, People's Republic of China.
| | - Jianlin Ren
- Department of Gastroenterology, Zhongshan Hospital, Xiamen University, Xiamen, 361004, People's Republic of China.
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Tang CT, Liang Q, Yang L, Lin XL, Wu S, Chen Y, Zhang XT, Gao YJ, Ge ZZ. RAB31 Targeted by MiR-30c-2-3p Regulates the GLI1 Signaling Pathway, Affecting Gastric Cancer Cell Proliferation and Apoptosis. Front Oncol 2018; 8:554. [PMID: 30534536 PMCID: PMC6275292 DOI: 10.3389/fonc.2018.00554] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 11/08/2018] [Indexed: 12/13/2022] Open
Abstract
Background: Gastric cancer (GC), one of the most common cancers worldwide, is highly malignant and fatal. Ras-related protein in brain 31 (RAB31), a member of the RAB family of oncogenes, participates in the process of carcinogenesis and cancer development; however, its role in GC progression is unknown. Methods: In our study, 90 pairs of tissue microarrays were used to measure the levels of RAB31 protein by immunochemistry, and 22 pairs of fresh tissue were used to measure the levels of RAB31 mRNA by quantitative PCR. We also investigated the effects of RAB31 on tumor growth both in vitro and in vivo. Results: RAB31 was overexpressed in GC tissues, and its overexpression predicted poor survival in patients. In a nude mouse model, depletion of RAB31 inhibited tumor growth. In vitro, silencing of RAB31 suppressed cell viability, promoted cell cycle arrest, enhanced apoptosis, and affected the expression of cell cycle and apoptotic proteins; these effects were mediated by glioma-associated oncogene homolog 1 (GLI1). Co-immunoprecipitation and immunofluorescence assays confirmed that RAB31 interacted with GLI1. In addition, luciferase reporter assays and Western blotting showed that microRNA-30c-2-3p modulated the RAB31/GLI1 pathway by targeting the 3′-untranslated region of RAB31. Conclusions: Collectively, these data show that RAB31 is regulated by microRNA-30c-2-3p, and functions as an oncogene in GC tumorigenesis and development by interacting with GLI1. Therefore, targeting the miR-30c-2-3p/RAB31/GLI1 axis may be a therapeutic intervention for gastric cancer.
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Affiliation(s)
- Chao-Tao Tang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qian Liang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Li Yang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiao-Lu Lin
- Department of Digestive Endoscopy, Provincial Clinic Medical College, Fujian Medical University, Fujian Provincial Hospital, Fuzhou, China
| | - Shan Wu
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yong Chen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xin-Tian Zhang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yun-Jie Gao
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zhi-Zheng Ge
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Tao P, Feng J, Li Q, Liu W, Yang L, Zhao X, Ni H, Xia P. Expression of miR-664 and miR-184 on proliferation, apoptosis and migration of osteosarcoma cells. Oncol Lett 2018; 17:1791-1797. [PMID: 30675239 PMCID: PMC6341773 DOI: 10.3892/ol.2018.9739] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Accepted: 11/01/2018] [Indexed: 12/15/2022] Open
Abstract
The expression of micro-ribonucleic acid miR-664 and miR-184 on the biological characteristics of osteosarcoma (OS) SOSP-9607 cells was investigated. Eighteen surgical specimens of OS and 18 normal tissue specimens were collected. The expression of miR-664 and miR-184 was detected via fluorescence reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The OS cell line SOSP-9607 was selected as the object of study, and miR-664 blank group, miR-664 mimic group, miR-664 inhibitor group, miR-184 blank group, miR-184 mimic group and miR-184 inhibitor group were established through transfection. Changes in apoptosis were detected via flow cytometry, the cell proliferation capacity was detected via Cell Counting Kit-8 assay, and the cell migration was observed via wound healing assay. In cancer tissues of OS patients, the relative expression of miR-664 and miR-184 was significantly higher than that in para-carcinoma tissues (P<0.05). The cell growth in miR-664 inhibitor group was obviously decreased compared with those in miR-664 blank and mimic groups (P<0.05). There were differences in the cell migration capacity among groups (P<0.01), and the cell scratch areas in miR-664 and miR-184 mimic groups were significantly decreased compared with those in miR-664 and miR-184 blank groups (P<0.05), while they were significantly increased in miR-664 and miR-184 inhibitor groups compared with those in miR-664 and miR-184 blank and mimic groups (P<0.05, P<0.01). There were differences in the apoptosis rate among groups (P<0.01) and apoptosis in miR-664 and miR-184 inhibitor groups was remarkably increased compared with those in miR-664 and miR-184 blank and mimic groups (P<0.05). Downregulating the expression of miR-664 and miR-184 may promote apoptosis, inhibit the proliferation and reduce the migration capacity of SOSP-9607 cells. Therefore, miR-664 and miR-184 may provide a theoretical basis for the target selection in clinical targeted therapy and drug development for OS.
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Affiliation(s)
- Pengfei Tao
- Department of Spine Surgery, Wuhan No. 1 Hospital, Wuhan, Hubei 430022, P.R. China
| | - Jing Feng
- Department of Spine Surgery, Wuhan No. 1 Hospital, Wuhan, Hubei 430022, P.R. China
| | - Qiong Li
- Department of Radiology, Taihe Hospital Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Wei Liu
- Department of Spine Surgery, Wuhan No. 1 Hospital, Wuhan, Hubei 430022, P.R. China
| | - Lin Yang
- Department of Spine Surgery, Wuhan No. 1 Hospital, Wuhan, Hubei 430022, P.R. China
| | - Xiaolong Zhao
- Department of Spine Surgery, Wuhan No. 1 Hospital, Wuhan, Hubei 430022, P.R. China
| | - Huan Ni
- Department of Spine Surgery, Wuhan No. 1 Hospital, Wuhan, Hubei 430022, P.R. China
| | - Ping Xia
- Department of Spine Surgery, Wuhan No. 1 Hospital, Wuhan, Hubei 430022, P.R. China
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HIF-1α-induced miR-23a∼27a∼24 cluster promotes colorectal cancer progression via reprogramming metabolism. Cancer Lett 2018; 440-441:211-222. [PMID: 30393198 DOI: 10.1016/j.canlet.2018.10.025] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Revised: 10/01/2018] [Accepted: 10/16/2018] [Indexed: 12/30/2022]
Abstract
Tumor cells switch metabolic profile from oxidative phosphorylation to glycolysis in a hypoxic environment for survival and proliferation. The mechanisms governing this metabolic switch, however, remain incompletely understood. Here, we show that three miRNAs in the miR-23a∼27a∼24 cluster, miR-23a, miR-27a and miR-24, are the most upregulated miRNA cluster in colorectal cancer (CRC) under hypoxia. Gain- and loss-of-function assays, a human glucose metabolism array and gene pathway analyses confirm that HIF-1α-induced miR-23a∼27a∼24 cluster collectively regulate glucose metabolic network through regulating various metabolic pathways and targeting multiple tricarboxylic acid cycle (TCA)-related genes. In specific, miR-24/VHL/HIF-1α in CRC form a double-negative feedback loop, which in turn, promotes the cellular transition to the 'high HIF-1α/miR-24 and low VHL' state and facilitates cell survival. Our findings reveal that the miR-23a∼27a∼24 cluster is critical regulator switching CRC metabolism from oxidative phosphorylation to glycolysis, and controlling their expression can suppress colorectal cancer progression.
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Jones SA, Jenkins BJ. Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer. Nat Rev Immunol 2018; 18:773-789. [DOI: 10.1038/s41577-018-0066-7] [Citation(s) in RCA: 722] [Impact Index Per Article: 103.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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