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1
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Dong F, Zhou J, Wu Y, Gao Z, Li W, Song Z. MicroRNAs in pancreatic cancer drug resistance: mechanisms and therapeutic potential. Front Cell Dev Biol 2025; 12:1499111. [PMID: 39882259 PMCID: PMC11774998 DOI: 10.3389/fcell.2024.1499111] [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: 09/20/2024] [Accepted: 12/30/2024] [Indexed: 01/31/2025] Open
Abstract
Pancreatic cancer (PC) remains one of the most lethal malignancies, primarily due to its intrinsic resistance to conventional therapies. MicroRNAs (miRNAs), key regulators of gene expression, have been identified as crucial modulators of drug resistance mechanisms in this cancer type. This review synthesizes recent advancements in our understanding of how miRNAs influence treatment efficacy in PC. We have thoroughly summarized and discussed the complex role of miRNA in mediating drug resistance in PC treatment. By highlighting specific miRNAs that are implicated in drug resistance pathways, we provide insights into their functional mechanisms and interactions with key molecular targets. We also explore the potential of miRNA-based strategies as novel therapeutic approaches and diagnostic tools to overcome resistance and improve patient outcomes. Despite promising developments, challenges such as specificity, stability, and effective delivery of miRNA-based therapeutics remain. This review aims to offer a critical perspective on current research and propose future directions for leveraging miRNA-based interventions in the fight against PC.
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Affiliation(s)
- Fangying Dong
- Emergency Department, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Jing Zhou
- Department of Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Yijie Wu
- Department of general practice, Taozhuang Branch of the First People’s Hospital of Jiashan, Jiaxing, Zhejiang, China
| | - Zhaofeng Gao
- Department of Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Weiwei Li
- Emergency Department, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Zhengwei Song
- Department of Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
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2
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An Y, Gao D, He Y, Ge N, Guo J, Sun S, Wang C, Yang F. Guarding against digestive-system cancers: Unveiling the role of Chk2 as a potential therapeutic target. Genes Dis 2025; 12:101191. [PMID: 39524544 PMCID: PMC11550749 DOI: 10.1016/j.gendis.2023.101191] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Revised: 11/08/2023] [Accepted: 11/19/2023] [Indexed: 11/16/2024] Open
Abstract
Digestive-system cancers represent major threats to human health; however, the mechanisms underlying tumorigenesis and radiochemotherapy resistance have remained elusive. Therefore, an urgent need exists for identifying key drivers of digestive system tumorigenesis and novel targeted therapeutics. The checkpoint kinase 2 (Chk2) regulates cell-cycle progression, and Chk2 dysregulation or Chk2 mutations can lead to the development of various cancers, which makes Chk2 an important research topic. This review summarizes the roles of Chk2 in DNA-damage responses, cell-cycle regulation, autophagy, and homeostasis maintenance. We describe relationships between tumorigenesis and cell-cycle dysregulation induced by Chk2 mutations. In addition, we summarize evidence indicating that Chk2 can serve as a novel therapeutic target, based on its contributions to radiochemotherapy-resistance reversion and progress made in developing antitumor agents against Chk2. The prevailing evidence supports the conclusion that further research on Chk2 will provide a deeper understanding of digestive-system tumorigenesis and should suggest novel therapeutic targets.
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Affiliation(s)
- Yucheng An
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
| | - Duolun Gao
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
| | - Yanjie He
- Department of Surgery, New York University School of Medicine and NYU-Langone Medical Center, New York, NY 10016, USA
| | - Nan Ge
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
| | - Jintao Guo
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
| | - Siyu Sun
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
| | - Caixia Wang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
| | - Fan Yang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
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3
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Feng DQ, Zhang W, Wang W, Liu G. Smart flared-nanokites with ultra-high fluorescence enhancement for multiplexing virus DNA biosensing. SENSORS AND ACTUATORS B: CHEMICAL 2023; 387:133813. [DOI: 10.1016/j.snb.2023.133813] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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4
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Hou J, Yang Y, Gao H, Ouyang T, Liu Q, Ding R, Kan H. Systematic investigation of the clinical significance and prognostic value of the CBXs in esophageal cancer. Medicine (Baltimore) 2022; 101:e30888. [PMID: 36221371 PMCID: PMC9542684 DOI: 10.1097/md.0000000000030888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 09/01/2022] [Indexed: 11/05/2022] Open
Abstract
Esophageal cancer (ESCA), one of the most aggressive malignant tumors, has been announced to be the ninth most common cancer and the sixth leading cause of cancer-related death in the world. Chromobox family members (CBXs) are important epigenetic regulators which are related with the transcription of target genes. The role of CBXs in carcinomas has been reported in many studies. However, the function and prognostic value of different CBXs in ESCA are still largely unknown. In this article, we first performed differential expression analysis through several methods including Oncomine and Gene Expression Profiling Interactive Analysis. The results led us to determine the differential expression of CBXs in pan-cancer, especially ESCA. Then we evaluated the prognostic value of different CBX messenger RNA (mRNA) expression in patients with ESCA through the Kaplan-Meier plotter and the Human Protein Atlas database. In addition, we used cBioPortal to explore all genetic alterations and mutations in the CBXs in ESCA. Simultaneously, the correlation between its expression and the level of immune infiltration of ESCA was visualized by TIMER. Finally, the biological function of CBXs in ESCA is obtained through Biological Enrichment Analysis including gene ontology and Kyoto Encyclopedia of Genes and Genomes. The expression levels of CBX3/4/5 and CBX8 in ESCA tissues increased significantly and the expression level of CBX7 decreased through differential expression analysis. Additionally, CBX1 is significantly related to the clinical cancer stage and disease-free survival of ESCA patients. The high mRNA expression of CBX4 is related to the short overall survival of patients with esophageal squamous cell carcinoma, and the high mRNA expression of CBX3/7/8 is related to the short overall survival of patients with esophageal adenocarcinoma, indicating that CBX1/3/4/7/8 may be a potential prognostic biomarker for the survival of ESCA patients. Besides, the expression of CBXs is significantly related to the infiltration of a variety of immune cells, including six types of CD4-positive T-lymphocytes, macrophages, neutrophils, bursindependentlymphocyte, CD8-positive T-lymphocytes cells and dendritic cells in ESCA. Moreover, we found that CBXs are mainly associated with the inhibition of cell cycle and apoptosis pathway. Further, enrichment analysis indicated that CBXs and correlated genes were enriched in mismatch repair, DNA replication, cancer pathways, and spliceosomes. Our research may provide new insights into the choice of prognosis biomarkers of the CBXs in ESCA.
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Affiliation(s)
- Jun Hou
- School of Medical Informatics Engineering, Anhui University of Chinese Medicine, Hefei, China
| | - Yinfeng Yang
- School of Medical Informatics Engineering, Anhui University of Chinese Medicine, Hefei, China
- Anhui Computer Application Research Institute of Chinese Medicine, China Academy of Chinese Medical Sciences, Hefei, China
| | - Honglei Gao
- School of Medical Informatics Engineering, Anhui University of Chinese Medicine, Hefei, China
| | - Ting Ouyang
- School of Medical Informatics Engineering, Anhui University of Chinese Medicine, Hefei, China
| | - Qiwei Liu
- School of Medical Informatics Engineering, Anhui University of Chinese Medicine, Hefei, China
| | - Ran Ding
- School of Medical Informatics Engineering, Anhui University of Chinese Medicine, Hefei, China
| | - Hongxing Kan
- School of Medical Informatics Engineering, Anhui University of Chinese Medicine, Hefei, China
- Anhui Computer Application Research Institute of Chinese Medicine, China Academy of Chinese Medical Sciences, Hefei, China
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5
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Zhang Y, Huang S, Yang G, Zou L, Huang X, Liu S. The Role of miRNAs during Endoplasmic Reticulum Stress Induced Apoptosis in Digestive Cancer. J Cancer 2021; 12:6787-6795. [PMID: 34659567 PMCID: PMC8517994 DOI: 10.7150/jca.62352] [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: 05/05/2021] [Accepted: 09/18/2021] [Indexed: 11/10/2022] Open
Abstract
Digestive cancer is one of the leading causes of cancer mortality in the world. Despite a number of studies being conducted, the exact mechanism for treating digestive cancer has not yet been fully understood. To survive, digestive cancer cells are subjected to various internal and external adverse factors, such as hypoxia, nutritional deficiencies or drug toxicity, resulting in accumulation of misfolded and unfolded protein in endoplasmic reticulum (ER) lumen further leading to ER stress and the unfolded protein response (UPR). During the last years, studies on the relationship between ER stress and microRNAs (miRNAs) has burst on the scene. miRNAs are non-coding RNAs with a length of 21~22nucleotides involved in post-transcriptional regulation of gene expression, which could be regarded as oncomiRs (tumor inducers) and tumor suppressors regulating cancer cell proliferation, invasion, and apoptosis by differently affecting the expression of genes related to cancer cell signaling. Therefore, investigating the interaction between ER stress and miRNAs is crucial for developing effective cancer treatment and prevention strategies. In this review, we mainly discuss miRNAs focusing on its regulation, role in ER stress induced apoptosis in Digestive cancer, expound the underlying mechanism, thus provides a theoretical foundation for finding new therapeutic targets of digestive cancer.
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Affiliation(s)
- Yujing Zhang
- Key Laboratory of Molecular Epidemiology of Hunan Province, School of Medicine, Hunan Normal University, Changsha, 410081, China.,Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education, Hunan Normal University, Changsha, 410081, China
| | - Shuai Huang
- Key Laboratory of Molecular Epidemiology of Hunan Province, School of Medicine, Hunan Normal University, Changsha, 410081, China.,Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education, Hunan Normal University, Changsha, 410081, China
| | - Gang Yang
- Key Laboratory of Molecular Epidemiology of Hunan Province, School of Medicine, Hunan Normal University, Changsha, 410081, China.,Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education, Hunan Normal University, Changsha, 410081, China
| | - Lianhong Zou
- Hunan Provincial Institute of Emergency Medicine, Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal University, Changsha, 410015, China
| | - Xin Huang
- Key Laboratory of Molecular Epidemiology of Hunan Province, School of Medicine, Hunan Normal University, Changsha, 410081, China.,Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education, Hunan Normal University, Changsha, 410081, China
| | - Sulai Liu
- Department of Hepatobiliary Surgery, Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal University, Changsha, 410015, China
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6
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Wang P, Zheng D, Qi H, Gao Q. Thioredoxin-interacting protein is a favored target of miR-125b, promoting metastasis and progression of pancreatic cancer via the HIF1α pathway. J Biochem Mol Toxicol 2021; 35:e22782. [PMID: 33896068 DOI: 10.1002/jbt.22782] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 02/02/2021] [Accepted: 03/24/2021] [Indexed: 12/21/2022]
Abstract
MicroRNAs (miRs) are vital in the development of pancreatic cancer (PC) targeting several cellular processes. This study was aimed at evaluating the function of miR-125b and the mechanism involved in PC. Cell migration, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), and Bromodeoxyuridine/5-bromo-2'-deoxyuridine (BrdU) study was done to establish the migration capability, cell viability, and cell proliferation, respectively. Binding sites for miR-125b were recognized by luciferase assay, and the expression of protein by Western blot and immunofluorescence assay. In vivo study was done by BALB/c nude xenograft mice for evaluating the function of miR-125b. The study showed that expression of miR-125b was elevated in PC cells and tissues and was correlated to proliferation and migration of cells. Also, overexpression of miR-125b encouraged migration, metastasis, and proliferation of BxPC-3 cells, and suppression reversed it. We also noticed that thioredoxin-interacting protein (TXNIP) was the potential target of miR-125b. The outcomes also suggested that miR-125b governed the expression of TXNIP inversely via directly attaching to the three prime untranslated region (3'-UTR) activating hypoxia-inducible factor 1α (HIF1α). Looking into the relation between HIF1α and TXNIP, we discovered that TXNIP caused the degradation and export of HIF1α by making a complex with it. The miR-125b-TXNIP-HIF1α pathway may serve as a useful strategy for diagnosing and treating PC.
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Affiliation(s)
- Pengli Wang
- Department of Gastroenterology, Xinxiang Central Hospital, Xinxiang, Henan, China
| | - Dan Zheng
- Department of Endocrinology, Xinxiang Central Hospital, Xinxiang, Henan, China
| | - Hongyang Qi
- Department of Gastroenterology, Xinxiang Central Hospital, Xinxiang, Henan, China
| | - Qi Gao
- Department of Gastroenterology, Xinxiang Central Hospital, Xinxiang, Henan, China
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7
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Wang P, Zheng D, Qi H, Gao Q. miR-125b enhances metastasis and progression of cancer via the TXNIP and HIF1α pathway in pancreatic cancer. Cancer Biomark 2021; 31:27-38. [PMID: 33749639 DOI: 10.3233/cbm-203112] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND MicroRNAs (miRNAs) play potential role in the development of various types of cancer conditions including pancreatic cancer (PC) targeting several cellular processes. Present study was aimed to evaluate function of miR-125b and the mechanism involved in PC. METHODS Cell migration, MTT and BrdU study was done to establish the migration capability, cell viability and cell proliferation respectively. Binding sites for miR-125b were recognized by luciferase assay, expression of protein by western blot and immunofluorescence assay. In vivo study was done by BALB/c nude xenograft mice for evaluating the function of miR-125b. RESULTS The study showed that expression of miR-125b was elevated in PC cells and tissues, and was correlated to proliferation and migration of cells. Also, over-expression of miR-125b encouraged migration, metastasis and proliferation of BxPC-3 cells, the suppression reversed it. We also noticed that thioredoxin-interacting protein (TXNIP) was the potential target of miR-125b. The outcomes also suggested that miR-125b governed the expression of TXNIP inversely via directly attaching to the 3'-UTR activating hypoxia-inducible factor 1α (HIF1α). Looking into the relation between HIF1α and TXNIP, we discovered that TXNIP caused the degradation and export of HIF1α by making a complex with it. CONCLUSION The miR-125b-TXNIP-HIF1α pathway may serve useful strategy for diagnosing and treating PC.
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Affiliation(s)
- Pengli Wang
- Department of Gastroenterology, Xinxiang Central Hospital, Xinxiang, Henan, China
| | - Dan Zheng
- Department of Endocrinology, Xinxiang Central Hospital, Xinxiang, Henan, China
| | - Hongyang Qi
- Department of Gastroenterology, Xinxiang Central Hospital, Xinxiang, Henan, China
| | - Qi Gao
- Department of Gastroenterology, Xinxiang Central Hospital, Xinxiang, Henan, China
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Yamamoto H, Watanabe Y, Sato Y, Maehata T, Itoh F. Non-Invasive Early Molecular Detection of Gastric Cancers. Cancers (Basel) 2020; 12:E2880. [PMID: 33036473 PMCID: PMC7600616 DOI: 10.3390/cancers12102880] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 09/29/2020] [Accepted: 10/04/2020] [Indexed: 12/14/2022] Open
Abstract
Gastric cancer (GC) is a significant source of global cancer death with a high mortality rate, because the majority of patients with GC are diagnosed at a late stage, with limited therapeutic choices and poor outcomes. Therefore, development of minimally invasive or noninvasive biomarkers which are specific to GC is crucially needed. The latest advancements in the understanding of GC molecular landscapes and molecular biological methods have accelerated attempts to diagnose GC at an early stage. Body fluids, including peripheral blood, saliva, gastric juice/wash, urine, and others, can be a source of biomarkers, offering new methods for the early detection of GC. Liquid biopsy-based methods using circulating sources of cancer nucleic acids could also be considered as alternative strategies. Moreover, investigating gastric juices/washes could represent an alternative for the detection of GC via invasive biopsy. This review summarizes recently reported biomarkers based on DNA methylation, microRNA, long noncoding RNA, circular RNA, or extracellular vesicles (exosomes) for the detection of GC. Although the majority of studies have been conducted to detect these alterations in advanced-stage GC and only a few in population studies or early-stage GC, some biomarkers are potentially valuable for the development of novel approaches for an early noninvasive detection of GC.
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Affiliation(s)
- Hiroyuki Yamamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan; (Y.W.); (Y.S.); (T.M.); (F.I.)
| | - Yoshiyuki Watanabe
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan; (Y.W.); (Y.S.); (T.M.); (F.I.)
- Department of Internal Medicine, Kawasaki Rinko General Hospital, Kawasaki 210-0806, Japan
| | - Yoshinori Sato
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan; (Y.W.); (Y.S.); (T.M.); (F.I.)
| | - Tadateru Maehata
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan; (Y.W.); (Y.S.); (T.M.); (F.I.)
| | - Fumio Itoh
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan; (Y.W.); (Y.S.); (T.M.); (F.I.)
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Tanase C, Gheorghisan-Galateanu AA, Popescu ID, Mihai S, Codrici E, Albulescu R, Hinescu ME. CD36 and CD97 in Pancreatic Cancer versus Other Malignancies. Int J Mol Sci 2020; 21:5656. [PMID: 32781778 PMCID: PMC7460590 DOI: 10.3390/ijms21165656] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 07/31/2020] [Accepted: 08/04/2020] [Indexed: 02/06/2023] Open
Abstract
Starting from the recent identification of CD36 and CD97 as a novel marker combination of fibroblast quiescence in lung during fibrosis, we aimed to survey the literature in search for facts about the separate (or concomitant) expression of clusters of differentiation CD36 and CD97 in either tumor- or pancreatic-cancer-associated cells. Here, we provide an account of the current knowledge on the diversity of the cellular functions of CD36 and CD97 and explore their potential (common) contributions to key cellular events in oncogenesis or metastasis development. Emphasis is placed on quiescence as an underexplored mechanism and/or potential target in therapy. Furthermore, we discuss intricate signaling mechanisms and networks involving CD36 and CD97 that may regulate different subpopulations of tumor-associated cells, such as cancer-associated fibroblasts, adipocyte-associated fibroblasts, tumor-associated macrophages, or neutrophils, during aggressive pancreatic cancer. The coexistence of quiescence and activated states in cancer-associated cell subtypes during pancreatic cancer should be better documented, in different histological forms. Remodeling of the local microenvironment may also change the balance between growth and dormant state. Taking advantage of the reported data in different other tissue types, we explore the possibility to induce quiescence (similar to that observed in normal cells), as a therapeutic option to delay the currently observed clinical outcome.
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Affiliation(s)
- Cristiana Tanase
- Victor Babeș National Institute of Pathology, 99-101 Splaiul Independentei, 050096 Bucharest, Romania; (I.D.P.); (S.M.); (E.C.); (R.A.); (M.E.H.)
- Faculty of Medicine, Titu Maiorescu University, 001863 Bucharest, Romania
| | - Ancuta-Augustina Gheorghisan-Galateanu
- Department of Cellular and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, 8 Eroilor Sanitari Str., 050474 Bucharest, Romania;
- ‘C.I. Parhon’ National Institute of Endocrinology, 001863 Bucharest, Romania
| | - Ionela Daniela Popescu
- Victor Babeș National Institute of Pathology, 99-101 Splaiul Independentei, 050096 Bucharest, Romania; (I.D.P.); (S.M.); (E.C.); (R.A.); (M.E.H.)
| | - Simona Mihai
- Victor Babeș National Institute of Pathology, 99-101 Splaiul Independentei, 050096 Bucharest, Romania; (I.D.P.); (S.M.); (E.C.); (R.A.); (M.E.H.)
| | - Elena Codrici
- Victor Babeș National Institute of Pathology, 99-101 Splaiul Independentei, 050096 Bucharest, Romania; (I.D.P.); (S.M.); (E.C.); (R.A.); (M.E.H.)
| | - Radu Albulescu
- Victor Babeș National Institute of Pathology, 99-101 Splaiul Independentei, 050096 Bucharest, Romania; (I.D.P.); (S.M.); (E.C.); (R.A.); (M.E.H.)
- National Institute for Chemical Pharmaceutical R&D, 001863 Bucharest, Romania
| | - Mihail Eugen Hinescu
- Victor Babeș National Institute of Pathology, 99-101 Splaiul Independentei, 050096 Bucharest, Romania; (I.D.P.); (S.M.); (E.C.); (R.A.); (M.E.H.)
- Department of Cellular and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, 8 Eroilor Sanitari Str., 050474 Bucharest, Romania;
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10
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Neagu M, Constantin C, Cretoiu SM, Zurac S. miRNAs in the Diagnosis and Prognosis of Skin Cancer. Front Cell Dev Biol 2020; 8:71. [PMID: 32185171 PMCID: PMC7058916 DOI: 10.3389/fcell.2020.00071] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 01/27/2020] [Indexed: 12/16/2022] Open
Abstract
Skin cancer is, at present, the most common type of malignancy in the Caucasian population. Its incidence has increased rapidly in the last decade for both melanoma and non-melanoma skin cancer. Differential expression profiles of microRNAs (miRNAs) have been reported for a variety of different cancers, including skin cancers. Since miRNAs’ discovery as regulators of gene expression, their importance grew in the field of oncology. miRNAs can post-transcriptionally regulate gene expression, tumor initiation, development progression, and aggressiveness. Nowadays, these short regulatory RNAs are perceived as one of the epigenetic markers for the identification of new diagnostic and/or prognostic molecular markers. Moreover, as miRNAs can drive tumorigenesis, they might eventually represent new therapy targets. Some miRNAs are pleiotropic, such as miR-214, which was found deregulated in several other tumors besides skin cancers. Some others are specific for one or more skin cancer types, like miR-21 and miR-221 for cutaneous melanoma and cutaneous squamous carcinoma or miR-155 for melanoma and cutaneous lymphoma. The goal of this review was to summarize some of the main miRNA detection technologies that are used to evaluate miRNAs in tissues and body fluids. Furthermore, their quantification limits, conformity, and robustness are discussed. Aberrant miRNA expression is analyzed for cutaneous melanoma, cutaneous squamous cell carcinoma (CSCC), skin lymphomas, cutaneous lymphoma, and Merkel cell carcinoma (MCC). In this type of disease, miRNAs are described as potential biomarkers to diagnose early lesion and/or early metastatic disease. In the future, whether in tissue or circulating in body fluids, miRNAs will gain their place in skin cancer diagnosis, prognosis, and future therapeutic targets.
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Affiliation(s)
- Monica Neagu
- Immunology Laboratory, "Victor Babeş" National Institute of Pathology, Bucharest, Romania.,Doctoral School, Faculty of Biology, University of Bucharest, Bucharest, Romania.,Department of Pathology, Colentina Clinical Hospital, Bucharest, Romania
| | - Carolina Constantin
- Immunology Laboratory, "Victor Babeş" National Institute of Pathology, Bucharest, Romania.,Department of Pathology, Colentina Clinical Hospital, Bucharest, Romania
| | - Sanda Maria Cretoiu
- Division of Cell and Molecular Biology and Histology, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania
| | - Sabina Zurac
- Department of Pathology, Colentina Clinical Hospital, Bucharest, Romania.,Department of Pathology, Faculty of Dental Medicine, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania
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Tian Y, Zhang L, Wang H, Ji W, Zhang Z, Zhang Y, Yang Z, Cao Z, Zhang S, Chang J. Intelligent Detection Platform for Simultaneous Detection of Multiple MiRNAs Based on Smartphone. ACS Sens 2019; 4:1873-1880. [PMID: 31259533 DOI: 10.1021/acssensors.9b00752] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
As a marker of malignant tumors, miRNA is closely related to the occurrence and metastasis of tumors. How to achieve rapid and sensitive real-time detection is important for clinical prevention and treatment of cancer. In this study, an intelligent detection platform based on smartphone image processing technology made point-of-care testing a reality. This new smart approach could detect multiple targets simultaneously and sensitively. Hydrogel microparticles of different coding modes (shapes, numbers) were prepared by flow lithography to detect different miRNAs. After sandwich immunoassays, different shapes of hydrogels showed different fluorescence intensities depending on their targets. Images were captured by a smartphone and then analyzed by image recognition processing software installed on the smartphone. The concentration of miRNA was obtained within 10 s. The entire reaction process did not exceed 2 h. This intelligent and portable detection platform for miRNAs was reliable and the limit of detection reached the femtomole level. This work provided a demonstration of intelligent, portable, real-time detection of tumor markers.
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Affiliation(s)
| | | | | | | | | | | | - Zhengchun Yang
- School of Electrical and Electronic Engineering, Tianjin Key Laboratory of Film Electronic & Communication Devices, Tianjin University of Technology, Tianjin 300384, China
| | - Zongsheng Cao
- School of Electrical and Electronic Engineering, Tianjin Key Laboratory of Film Electronic & Communication Devices, Tianjin University of Technology, Tianjin 300384, China
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12
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Wang J, Wen T, Li Z, Che X, Gong L, Yang X, Zhang J, Tang H, He L, Qu X, Liu Y. MicroRNA-1224 Inhibits Tumor Metastasis in Intestinal-Type Gastric Cancer by Directly Targeting FAK. Front Oncol 2019; 9:222. [PMID: 31019895 PMCID: PMC6458237 DOI: 10.3389/fonc.2019.00222] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 03/13/2019] [Indexed: 12/20/2022] Open
Abstract
Intestinal-type gastric cancer (GC) of the Lauren classification system has specific epidemiological characteristics and carcinogenesis patterns. MicroRNAs (miRNAs) have prognostic significance, and some can be used as prognostic biomarkers in GC. In this study, we identified miR-1224 as a potential survival-related miRNA in intestinal-type GC patients by The Cancer Genome Atlas (TCGA) analysis. Using quantitative real-time PCR (qRT-PCR), we showed that the relative expression of miR-1224 was significantly decreased in intestinal-type GC tissues compared to matched adjacent normal mucosa tissues (p < 0.01). We found that high miR-1224 expression was associated with no lymph-node metastasis (p < 0.05) and good prognosis (p = 0.028) in 90 intestinal-type GC tissues. Transfection of intestinal-type GC cells with miR-1224 mimics showed that miR-1224 suppressed cell migration in vitro (wound healing assay and Transwell migration assay), whereas the transfection of cells with miR-1224 inhibitor promoted cell migration in vitro. miR-1224 also suppressed intestinal-type GC cell metastasis in a xenograft mouse model. Furthermore, bioinformatics, luciferase reporter, Western blotting, and immunohistochemistry (IHC) studies demonstrated that miR-1224 directly bound to the focal adhesion kinase (FAK) gene, and downregulated its expression, which decreased STAT3 and NF-κB signaling and subsequent the epithelial-to-mesenchymal transition (EMT). Repression of FAK is required for the miR-1224-mediated inhibition of cell migration in intestinal-type GC. The present study demonstrated that miR-1224 is downregulated in intestinal-type GC. miR-1224 inhibits the metastasis of intestinal-type GC by suppressing FAK-mediated activation of the STAT3 and NF-κB pathways, and subsequent EMT. miR-1224 could represent an important prognostic factor in intestinal-type GC.
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Affiliation(s)
- Jin Wang
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Ti Wen
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Zhi Li
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Xiaofang Che
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Libao Gong
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Xianghong Yang
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jingdong Zhang
- Department of Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China
| | - Huali Tang
- Department of Medical Oncology, The Central Hospital of Zhuanghe, Zhuanghe, China
| | - Lingzi He
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Xiujuan Qu
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Yunpeng Liu
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
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Jiang X, Hou D, Wei Z, Zheng S, Zhang Y, Li J. Extracellular and intracellular microRNAs in pancreatic cancer: from early diagnosis to reducing chemoresistance. ACTA ACUST UNITED AC 2019. [DOI: 10.1186/s41544-019-0014-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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Tiwari P, Gupta S, Kumar A, Sharma M, Sundararajan VS, Kothari SL, Mathur SK, Medicherla KM, Suravajhala P, Malik B. Characterizing and Functional Assignment of Noncoding RNAs. ENCYCLOPEDIA OF BIOINFORMATICS AND COMPUTATIONAL BIOLOGY 2019:47-59. [DOI: 10.1016/b978-0-12-809633-8.20077-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Liu XL, Cao HX, Fan JG. MicroRNAs as biomarkers and regulators of nonalcoholic fatty liver disease. J Dig Dis 2016; 17:708-715. [PMID: 27628945 DOI: 10.1111/1751-2980.12408] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Revised: 08/29/2016] [Accepted: 09/11/2016] [Indexed: 12/11/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a complicated disease affected by the interaction of environmental and genetic factors; however, the precise pathogenesis of the disease has not been fully determined. There is a need to better understand the pathogenesis of NAFLD and to identify non-invasive diagnostic modalities. Recent advances in systematic biology and epigenetics have improved our understanding of the genotype-phenotype relationships in NAFLD. MicroRNAs (miRNAs) are important regulators of a wide range of biological processes. MiRNAs are extremely stable and protect from RNAase-mediated degradation in body fluids, making them attractive candidate biomarkers for the early detection of the disease and the monitoring of disease progression. In this review, we summarized the current knowledge on miRNAs as potential biomarkers of NAFLD at different stages and for the prognosis of advanced diseases. Furthermore, we discussed the implications of miRNAs that functioning in lipid metabolism and hepatic steatosis as well as in hepatic inflammation and fibrosis with regard to the pathogenesis of NAFLD.
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Affiliation(s)
- Xiao Lin Liu
- Department of Gastroenterology and Center for Fatty Liver, XinHua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Hai Xia Cao
- Department of Gastroenterology and Center for Fatty Liver, XinHua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jian Gao Fan
- Department of Gastroenterology and Center for Fatty Liver, XinHua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
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Expression of miRNA-122 Induced by Liver Toxicants in Zebrafish. BIOMED RESEARCH INTERNATIONAL 2016; 2016:1473578. [PMID: 27563662 PMCID: PMC4987457 DOI: 10.1155/2016/1473578] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Revised: 06/20/2016] [Accepted: 07/04/2016] [Indexed: 11/17/2022]
Abstract
MicroRNA-122 (miRNA-122), also known as liver-specific miRNA, has recently been shown to be a potent biomarker in response to liver injury in mammals. The objective of this study was to examine its expression in response to toxicant treatment and acute liver damage, using the zebrafish system as an alternative model organism. For the hepatotoxicity assay, larval zebrafish were arrayed in 24-well plates. Adult zebrafish were also tested and arrayed in 200 mL cages. Animals were exposed to liver toxicants (tamoxifen or acetaminophen) at various doses, and miRNA-122 expression levels were analyzed using qRT-PCR in dissected liver, brain, heart, and intestine, separately. Our results showed no significant changes in miRNA-122 expression level in tamoxifen-treated larvae; however, miRNA-122 expression was highly induced in tamoxifen-treated adults in a tissue-specific manner. In addition, we observed a histological change in adult liver (0.5 μM) and cell death in larval liver (5 μM) at different doses of tamoxifen. These results indicated that miRNA-122 may be utilized as a liver-specific biomarker for acute liver toxicity in zebrafish.
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17
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Yang IP, Tsai HL, Miao ZF, Huang CW, Kuo CH, Wu JY, Wang WM, Juo SHH, Wang JY. Development of a deregulating microRNA panel for the detection of early relapse in postoperative colorectal cancer patients. J Transl Med 2016; 14:108. [PMID: 27126129 PMCID: PMC4850676 DOI: 10.1186/s12967-016-0856-2] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2015] [Accepted: 04/06/2016] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is the third leading cause of cancer mortality worldwide and is associated with high recurrence and mortality, despite recent advancements in therapeutic strategies. MicroRNA (miR) deregulation is associated with CRC development and recurrence; therefore, miRs may be reliable biomarkers for detecting early relapse postoperatively. METHODS In this study ten candidates were identified using miR arrays: miR-7, miR-31, miR-93, miR-141, miR-195, miR-375, miR-429, miR-494, miR-650, and let-7b. Substantial differences were observed in their expression levels between early relapsed (recurrences within 12 months after surgery) and non-early relapsed CRC patients. The validation study, including 50 early relapsed and 54 non-early relapsed patients, confirmed miR expression alterations in cancer tissue samples. RESULTS Using a miR real-time quantitative polymerase chain reaction (RT-qPCR), we observed that expression levels of miR-93, miR-195, and let-7b were significantly decreased, whereas those of miR-7, miR-141 and miR-494 showed increases that were more significant in the CRC tissue samples from the early relapsed patients than in those from the non-early relapsed patients. Disease-free survival and overall survival were significantly worse in the high miR-7, miR-141, and miR-494 expression subgroups and the low miR-93 and miR-195 expression subgroups (all P < 0.05). A panel of 6 miRs (miR-7, miR-93, miR-195, miR-141, miR-494, and let-7b), at a cut-off value of 2 deregulated miRs, distinguished early relapsed CRC from non-early relapsed CRC, with a sensitivity of 76.6 % and a specificity of 71.4 %. By combining this 6-miRs panel with 6 clinicopathologic factors, at a cut-off value of 4, distinguished early relapsed CRC from non-early relapsed CRC, with a sensitivity of 89.4 % and a specificity of 88.9 %. CONCLUSIONS This study showed that the developed miR panel has the potential to improve predicting early relapse in CRC patients.
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Affiliation(s)
- I-Ping Yang
- />Department of Genomic Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- />Department of Nursing, Shu-Zen College of Medicine and Management, Kaohsiung, Taiwan
| | - Hsiang-Lin Tsai
- />Division of General Surgery Medicine, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- />Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- />Division of Gastroenterology and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- />Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Zhi-Feng Miao
- />Division of Gastroenterology and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- />Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, No. 100 Tzyou First Road, Kaohsiung, 807 Taiwan
| | - Ching-Wen Huang
- />Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- />Division of Gastroenterology and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- />Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, No. 100 Tzyou First Road, Kaohsiung, 807 Taiwan
| | - Chao-Hung Kuo
- />Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- />Department of Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jeng-Yih Wu
- />Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- />Department of Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wen-Ming Wang
- />Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- />Department of Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Suh-Hang Hank Juo
- />Department of Genomic Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- />Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, Kaohsiung, Taiwan
- />Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- />Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jaw-Yuan Wang
- />Department of Genomic Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- />Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- />Division of Gastroenterology and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- />Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- />Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, No. 100 Tzyou First Road, Kaohsiung, 807 Taiwan
- />Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, Kaohsiung, Taiwan
- />Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- />Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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Yang IP, Tsai HL, Huang CW, Lu CY, Miao ZF, Chang SF, Juo SHH, Wang JY. High blood sugar levels significantly impact the prognosis of colorectal cancer patients through down-regulation of microRNA-16 by targeting Myb and VEGFR2. Oncotarget 2016; 7:18837-18850. [PMID: 26934556 PMCID: PMC4951333 DOI: 10.18632/oncotarget.7719] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2015] [Accepted: 01/19/2016] [Indexed: 01/05/2023] Open
Abstract
The high prevalence of type 2 diabetes mellitus in colorectal cancer patients is a crucial public health issue worldwide. The deregulation of microRNAs has been shown to be associated with the progression of CRC; however, the effects of high blood sugar levels on miR deregulation and, in turn, CRC remain unexplored. In this study, 520 CRC patients were classified into two groups according to their blood sugar levels (≧110 or <110 mg/dL). Clinicopathologic features, clinical outcomes, and serum miR-16 levels of the two groups were then analyzed, while cell cycles, cell proliferation, migration, and cellular miR-16 expression were investigated via D-(+)-glucose administration. Additionally, the target genes of miR-16 were identified. Through multivariate analysis, both the disease-free survival and overall survival of the CRC patients were found to be associated with the UICC stage, perineural invasion, and blood glucose levels (P < 0.05). Serum miR-16 levels were significantly lower in the high blood glucose patients than in the normal blood glucose patients (P = 0.0329). With D-(+)-glucose administration, the proliferation and migration of CRC cells in vitro increased remarkably (P < 0.05), while their accumulation in the G1 phase decreased significantly. Cellular miR-16 expression was suppressed by D-(+)-glucose administration. The expression levels of two target genes, Myb and VEGFR2, were affected significantly by miR-16, while glucose administration inhibited miR-16 expression and enhanced tumor cell proliferation and migration. Hyperglycemia can impact the clinical outcomes of CRC patients, likely by inhibiting miR-16 expression and the expression of its downstream genes Myb and VEGFR2.
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Affiliation(s)
- I-Ping Yang
- Department of Genomic Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Nursing, Shu-Zen College of Medicine and Management, Kaohsiung, Taiwan
| | - Hsiang-Lin Tsai
- Department of Surgery, Division of General Surgery Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Surgery, Division of Gastroenterology and General Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ching-Wen Huang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Surgery, Division of Gastroenterology and General Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chien-Yu Lu
- Department of Internal Medicine, Division of Gastroenterology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Zhi-Feng Miao
- Department of Surgery, Division of Gastroenterology and General Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Se-Fen Chang
- Department of Nursing, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Suh-Hang Hank Juo
- Department of Genomic Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jaw-Yuan Wang
- Department of Genomic Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Surgery, Division of Gastroenterology and General Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, Kaohsiung, Taiwan
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The Role of miRNAs in the Regulation of Pancreatic Cancer Stem Cells. Stem Cells Int 2016; 2016:8352684. [PMID: 27006664 PMCID: PMC4783541 DOI: 10.1155/2016/8352684] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Revised: 12/24/2015] [Accepted: 01/27/2016] [Indexed: 12/17/2022] Open
Abstract
Pancreatic ductal adenocarcinoma is currently one of the deadliest cancers with low overall survival rate. This disease leads to an aggressive local invasion and early metastases and is poorly responsive to treatment with chemotherapy or chemoradiotherapy. Several studies have shown that pancreatic cancer stem cells (PCSCs) play different roles in the regulation of drug resistance and recurrence in pancreatic cancer. MicroRNA (miRNA), a class of newly emerging small noncoding RNAs, is involved in the modulation of several biological activities ranging from invasion to metastases development, as well as drug resistance of pancreatic cancer. In this review, we synthesize the latest findings on the role of miRNAs in regulating different biological properties of pancreatic cancer stem cells.
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20
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Alemar B, Gregório C, Ashton-Prolla P. miRNAs As Diagnostic and Prognostic Biomarkers in Pancreatic Ductal Adenocarcinoma and Its Precursor Lesions: A Review. Biomark Insights 2015; 10:113-24. [PMID: 26688661 PMCID: PMC4677802 DOI: 10.4137/bmi.s27679] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Revised: 08/30/2015] [Accepted: 09/06/2015] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC), a rare but lethal tumor, is difficult to diagnose without performing an invasive procedure. miRNAs are known to be deregulated in PDAC patients, and recent studies have shown that they can be used as diagnostic and prognostic of the disease. The detection of miRNAs in samples acquired through minimally or noninvasive procedures, such as serum, plasma, and saliva, can have a positive impact on the clinical management of these patients. This article is a comprehensive review of the major studies that have evaluated the expression of miRNAs as biomarkers in pancreatic cancer and its premalignant lesions.
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Affiliation(s)
- Bárbara Alemar
- Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
- Laboratório de Medicina Genômica, Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
| | - Cleandra Gregório
- Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
- Laboratório de Medicina Genômica, Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
| | - Patricia Ashton-Prolla
- Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
- Laboratório de Medicina Genômica, Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
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Affiliation(s)
- Monica Neagu
- Immunology Laboratory, “Victor Babes” National Institute of Pathology, 99-101 Splaiul Independentei, 050096, Bucharest, Romania
| | - Radu Albulescu
- Biochemistry-Proteomics Laboratory, “Victor Babes” National Institute of Pathology & National Institute for Chemical Pharmaceutical R&D Bucharest
| | - Cristiana Tanase
- Biochemistry-Proteomics Laboratory, “Victor Babes” National Institute of Pathology & “Titu Maiorescu” University, Faculty of Medicine
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Tanase CP, Neagu AI, Necula LG, Mambet C, Enciu AM, Calenic B, Cruceru ML, Albulescu R. Cancer stem cells: involvement in pancreatic cancer pathogenesis and perspectives on cancer therapeutics. World J Gastroenterol 2014; 20:10790-10801. [PMID: 25152582 PMCID: PMC4138459 DOI: 10.3748/wjg.v20.i31.10790] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 02/07/2014] [Accepted: 04/05/2014] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is one of the most aggressive and lethal malignancies. Despite remarkable progress in understanding pancreatic carcinogenesis at the molecular level, as well as progress in new therapeutic approaches, pancreatic cancer remains a disease with a dismal prognosis. Among the mechanisms responsible for drug resistance, the most relevant are changes in individual genes or signaling pathways and the presence of highly resistant cancer stem cells (CSCs). In pancreatic cancer, CSCs represent 0.2%-0.8% of pancreatic cancer cells and are considered to be responsible for tumor growth, invasion, metastasis and recurrence. CSCs have been extensively studied as of late to identify specific surface markers to ensure reliable sorting and for signaling pathways identified to play a pivotal role in CSC self-renewal. Involvement of CSCs in pancreatic cancer pathogenesis has also highlighted these cells as the preferential targets for therapy. The present review is an update of the results in two main fields of research in pancreatic cancer, pathogenesis and therapy, focused on the narrow perspective of CSCs.
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Aberrant MicroRNAs in Pancreatic Cancer: Researches and Clinical Implications. Gastroenterol Res Pract 2014; 2014:386561. [PMID: 24899890 PMCID: PMC4034662 DOI: 10.1155/2014/386561] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2013] [Revised: 03/11/2014] [Accepted: 03/24/2014] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a high rate of mortality and poor prognosis. Numerous studies have proved that microRNA (miRNA) may play a vital role in a wide range of malignancies, including PDAC, and dysregulated miRNAs, including circulating miRNAs, are associated with PDAC proliferation, invasion, chemosensitivity, and radiosensitivity, as well as prognosis. Greater understanding of the roles of miRNAs in PDAC could provide insights into this disease and identify potential diagnostic markers and therapeutic targets. The current review focuses on recent advances with respect to the roles of miRNAs in PDAC and their practical value.
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Jiping Z, Ming F, Lixiang W, Xiuming L, Yuqun S, Han Y, Zhifang L, Yundong S, Shili L, Chunyan C, Jihui J. MicroRNA-212 inhibits proliferation of gastric cancer by directly repressing retinoblastoma binding protein 2. J Cell Biochem 2014; 114:2666-72. [PMID: 23794145 DOI: 10.1002/jcb.24613] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2013] [Accepted: 06/11/2013] [Indexed: 01/02/2023]
Abstract
Retinoblastoma binding protein 2 (RBP2), a newly found histone demethylase, is overexpressed in gastric cancer. We examined the upstream regulatory mechanism of RBP2 at the microRNA (miRNA) level and the role in gastric carcinogenesis. We used bioinformatics to predict that microRNA-212 (miR-212) might be a direct upstream regulator of RBP2 and verified the regulation in gastric epithelial-derived cell lines. Overexpression of miR-212 significantly inhibited the expression levels of RBP2, whereas knockdown of miR-212 promoted RBP2 expression. Furthermore, we identified the putative miR-212 targeting sequence in the RBP2 3' UTR by luciferase assay. MiR-212 inhibited the colony formation ability of cells by repressing RBP2 expression and increasing that of P21(CIP1) and P27(kip1), both critical in cell cycle arrest. In addition, the expression of RBP2 and miR-212 in tumor tissue and matched normal tissue from 18 patients further supported the results in vivo. MiR-212 directly regulates the expression of RBP2 and inhibits cell growth in gastric cancer, which may provide new clues to treatment.
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Affiliation(s)
- Zeng Jiping
- Department of Microbiology/Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, Shandong University School of Medicine, Jinan, China; Department of Biochemistry, Shandong University School of Medicine, Jinan, China
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25
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Yamamoto H, Watanabe Y, Maehata T, Morita R, Yoshida Y, Oikawa R, Ishigooka S, Ozawa SI, Matsuo Y, Hosoya K, Yamashita M, Taniguchi H, Nosho K, Suzuki H, Yasuda H, Shinomura Y, Itoh F. An updated review of gastric cancer in the next-generation sequencing era: Insights from bench to bedside and vice versa. World J Gastroenterol 2014; 20:3927-3937. [PMID: 24744582 PMCID: PMC3983448 DOI: 10.3748/wjg.v20.i14.3927] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 01/15/2014] [Accepted: 03/10/2014] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is one of the most common malignancies and remains the second leading cause of cancer-related death worldwide. There is an increasing understanding of the roles that genetic and epigenetic alterations play in GCs. Recent studies using next-generation sequencing (NGS) have revealed a number of potential cancer-driving genes in GC. Whole-exome sequencing of GC has identified recurrent somatic mutations in the chromatin remodeling gene ARID1A and alterations in the cell adhesion gene FAT4, a member of the cadherin gene family. Mutations in chromatin remodeling genes (ARID1A, MLL3 and MLL) have been found in 47% of GCs. Whole-genome sequencing and whole-transcriptome sequencing analyses have also discovered novel alterations in GC. Recent studies of cancer epigenetics have revealed widespread alterations in genes involved in the epigenetic machinery, such as DNA methylation, histone modifications, nucleosome positioning, noncoding RNAs and microRNAs. Recent advances in molecular research on GC have resulted in the introduction of new diagnostic and therapeutic strategies into clinical settings. The anti-human epidermal growth receptor 2 (HER2) antibody trastuzumab has led to an era of personalized therapy in GC. In addition, ramucirumab, a monoclonal antibody targeting vascular endothelial growth factor receptor (VEGFR)-2, is the first biological treatment that showed survival benefits as a single-agent therapy in patients with advanced GC who progressed after first-line chemotherapy. Using NGS to systematically identify gene alterations in GC is a promising approach with remarkable potential for investigating the pathogenesis of GC and identifying novel therapeutic targets, as well as useful biomarkers. In this review, we will summarize the recent advances in the understanding of the molecular pathogenesis of GC, focusing on the potential use of these genetic and epigenetic alterations as diagnostic biomarkers and novel therapeutic targets.
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Tong F, Cao P, Yin Y, Xia S, Lai R, Liu S. MicroRNAs in gastric cancer: from benchtop to bedside. Dig Dis Sci 2014; 59:24-30. [PMID: 24114043 DOI: 10.1007/s10620-013-2887-3] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2013] [Accepted: 09/11/2013] [Indexed: 12/11/2022]
Abstract
Gastric carcinogenesis represents a stepwise progression from chronic inflammation to invasive adenocarcinomas and distant metastasis. It has been widely accepted that these pathologic changes are contributed by aberrant activation or inactivation of protein-coding proto-oncogenes and tumor suppressor genes. However, recent discoveries in microRNA research have reshaped our understanding of the role of non-protein-coding genes in carcinogenesis. MicroRNAs (miRNAs) are a family of 18-25-nucleotide small RNAs that negatively regulate gene expression at the post-transcriptional level during various crucial cell processes such as apoptosis, differentiation and development. Changes in miRNA expression profiles have been observed in a variety of human tumors, including gastric cancer. Further studies demonstrated that miRNAs may function as tumor suppressors and oncogenes. These findings have shown great potential of miRNAs as a novel class of therapeutic targets. In addition, it was found that some miRNAs were directly involved in patients with gastric cancer, including prognosis prediction, treatment selection, and in the search for unknown primary sites. MiRNAs have also been proved to be detectable in serum and plasma. In this review, we summarize the function of miRNAs in gastric cancer. Furthermore, we describe the pathophysiological roles of these miRNAs and their clinical potential as diagnostic biomarkers and therapeutic targets.
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Affiliation(s)
- Fuyi Tong
- First Clinical Medical School, Nanjing University of Chinese Medicine, Nanjing, 210029, People's Republic of China
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27
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Dumitrascu GR, Bucur O. Critical physiological and pathological functions of Forkhead Box O tumor suppressors. Discoveries (Craiova) 2013; 1:e5. [PMID: 32309538 PMCID: PMC6941590 DOI: 10.15190/d.2013.5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The Forkhead box, subclass O (FOXO) proteins are critical transcription factors, ubiquitously expressed in the human body. These proteins are characterized by a remarkable functional diversity, being involved in cell cycle arrest, apoptosis, oxidative detoxification, DNA damage repair, stem cell maintenance, cell differentiation, cell metabolism, angiogenesis, cardiac development, aging and others. In addition, FOXO have critical implications in both normal and cancer stem cell biology. New strategies to modulate FOXO expression and activity may now be developed since the discovery of novel FOXO regulators and non-coding RNAs (such as microRNAs) targeting FOXO transcription factors. This review focuses on physiological and pathological functions of FOXO proteins and on their action as fine regulators of cell fate and context-dependent cell decisions. A better understanding of the structure and critical functions of FOXO transcription factors and tumor suppressors may contribute to the development of novel therapies for cancer and other diseases.
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Affiliation(s)
- Georgiana R Dumitrascu
- "Victor Babes" National Institute of Pathology and Biomedical Sciences, Bucharest, Romania
| | - Octavian Bucur
- Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA
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28
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Munoz‐Garrido P, Marzioni M, Hijona E, Bujanda L, Banales JM. MicroRNAs in Liver Diseases. MICRORNAS IN MEDICINE 2013:509-522. [DOI: 10.1002/9781118300312.ch31] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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29
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Wang F, Sun GP, Zou YF, Zhong F, Ma T, Li XQ, Wu D. Helicobacter pylori infection predicts favorable outcome in patients with gastric cancer. ACTA ACUST UNITED AC 2013; 20:e388-95. [PMID: 24155636 DOI: 10.3747/co.20.1417] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Recent studies have suggested a controversial role of Helicobacter pylori infection in gastric cancer prognosis. The aim of the present study was to investigate the potential impact of H. pylori status on the prognosis of patients with gastric cancer in a Chinese prospective cohort. METHODS Between 2007 and 2009, 261 patients with curatively resected gastric cancer were enrolled in the study. H. pylori status was defined by means of immunohistochemical staining in tumour and non-neoplastic tissues. Treatment prognosis was measured in terms of cancer-specific survival and disease-free survival (dfs). Univariate and multivariate Cox regression models were used to assess the association between H. pylori status and patient prognosis. RESULTS Positivity for H. pylori infection was observed in 188 of the 261 patients (72.0%). In patients positive for H. pylori, mean cancer-specific survival was 55.2 months [95% confidence interval (ci): 53.4 to 56.9 months] and mean dfs was 53.9 months (95% ci: 51.8 to 56.0 months); the same survivals were, respectively, 45.1 months (95% ci: 42.2 to 47.9 months) and 43.7 months (95% ci: 40.4 to 47.0 months) in patients negative for H. pylori. In univariate analysis, positive H. pylori status was associated with better cancer-specific survival [hazard ratio (hr): 0.486; 95% ci: 0.271 to 0.870; p = 0.015] and dfs (hr: 0.540; 95% ci: 0.307 to 0.950; p = 0.033). In multivariate analysis, H. pylori was an independent prognostic factor for cancer-specific survival (hr: 0.485; 95% ci: 0.265 to 0.889; p = 0.019). CONCLUSIONS Our study demonstrates that positive H. pylori status is a beneficial prognostic indicator in patients with gastric cancer and might suggest possible therapeutic approaches for gastric cancer. Further research is required to better understand inflammation mechanisms and cancer progression.
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Affiliation(s)
- F Wang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, PR China
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30
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Zhang GJ, Zhou H, Xiao HX, Li Y, Zhou T. Up-regulation of miR-224 promotes cancer cell proliferation and invasion and predicts relapse of colorectal cancer. Cancer Cell Int 2013; 13:104. [PMID: 24152489 PMCID: PMC3832249 DOI: 10.1186/1475-2867-13-104] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2013] [Accepted: 10/20/2013] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND MicroRNAs (miRNAs) are small, non-coding RNAs that can function as oncogenes or tumor suppressors in human cancer. Abnormally expressed miR-224 was found to play a fundamental role in several types of cancer. The aim of this study was to investigate the prognostic and biological values of miR-224 in colorectal cancer (CRC). METHODS Quantitative RT-PCR (qRT-PCR) was used to evaluate expression levels of miR-224. The postoperative survival rate was analyzed with Kaplan-Meier method. The roles of miR-224 in cell proliferation, migration and invasion were analyzed with pre-miR-224 transfected cells. In addition, the regulation of SMAD4 by miR-224 was evaluated by qRT-PCR, Western blotting and luciferase reporter assays. RESULTS In the present study, we demonstrated that miR-224 was significantly up-regulated in CRC tissue samples and associated with disease relapse and a relative poorer disease-free survival rate. Moreover, ectopic expression of miR-224 potently promoted tumor cell proliferation, migration and invasion in vitro. Furthermore, the over-expression of miR-224 in CRC cell lines decreased SMAD4 expression at the translational level and decreased SMAD4-driven luciferase-reporter activity. CONCLUSIONS Our data suggest that miR-224 could play an oncogenic role in the cellular processes of CRC and represent a novel biomarker for tumor relapse of CRC patients.
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Affiliation(s)
- Guang-Jun Zhang
- The First Department of General Surgery, The Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, People's Republic of China.,Institute of Hepatobiliary, Pancreas and Intestinal Disease, North Sichuan Medical College, Nanchong, Sichuan, People's Republic of China
| | - He Zhou
- The First Department of General Surgery, The Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, People's Republic of China.,Institute of Hepatobiliary, Pancreas and Intestinal Disease, North Sichuan Medical College, Nanchong, Sichuan, People's Republic of China
| | - Hua-Xu Xiao
- Department of Pathology, The North Sichuan Medical College, Nanchong, Sichuan, People's Republic of China
| | - Yu Li
- Department of Microbiology and Parasitology, North Sichuan Medical College, Nanchong, Sichuan, People's Republic of China
| | - Tong Zhou
- The First Department of General Surgery, The Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, People's Republic of China.,Institute of Hepatobiliary, Pancreas and Intestinal Disease, North Sichuan Medical College, Nanchong, Sichuan, People's Republic of China
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31
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Yang X, Mattes WB, Shi Q, Weng Z, Salminen WF. Cell‐free microRNAs as Biomarkers in Human Diseases. MICRORNAS IN TOXICOLOGY AND MEDICINE 2013:363-387. [DOI: 10.1002/9781118695999.ch22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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32
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Neagu M, Tanase C. miRNA interactions as a novel molecular panel for clinical outcome of glioblastoma. Biomark Med 2013; 7:201. [PMID: 23547814 DOI: 10.2217/bmm.13.7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Affiliation(s)
- Monica Neagu
- Victor Babes National Institute of Pathology, 99-101 Splaiul Independentei, Bucharest 050096, Romania.
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33
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Shah N, Nelson JE, Kowdley KV. MicroRNAs in Liver Disease: Bench to Bedside. J Clin Exp Hepatol 2013; 3:231-42. [PMID: 25755505 PMCID: PMC3940370 DOI: 10.1016/j.jceh.2013.09.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2013] [Accepted: 09/04/2013] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miRs) are small non-coding RNAs that negatively regulate gene expression by pairing with partially complementary target sequences in the 3'UTRs of mRNAs to promote degradation and/or block translation. Aberrant miR expression is associated with development of multiple diseases including hepatic diseases. The role of miRs in the regulation of gene expression and rapid progress in the field of microRNA research are resulting in momentum toward development of diagnostic markers and novel therapeutic strategies for human liver diseases. Recent studies provide clear evidence that miRs are abundant in the liver and modulate a diverse spectrum of biological functions, thereby supporting an association between alterations of miR homeostasis and pathological liver diseases. Here we review the role of miRs in liver as their physiological and pathological importance has been demonstrated in metabolism, immunity, viral hepatitis, oncogenesis, fatty liver diseases (alcoholic and non-alcoholic), drug-induced liver injury, fibrosis as well as acute liver failure.
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Key Words
- ALD, alcoholic liver disease
- ALF, acute liver failure
- DILI, drug-induced liver injury
- HBV, hepatitis B virus
- HCC, hepatocellular carcinoma
- HCV, hepatitis C virus
- HSC, hepatic stellate cell
- IFN, interferon
- NAFLD, non-alcoholic fatty liver disease
- NASH, non-alcoholic steatohepatitis
- PPAR γ, peroxisome proliferator-activated receptor γ
- TGF, transforming growth factor
- TNF, tumor necrosis factor
- UTR, untranslated region
- down-regulation
- liver
- miR-122
- miRs/miRNA, microRNA
- microRNA
- up-regulation
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Affiliation(s)
- Nihar Shah
- Liver Center of Excellence, Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA, United States
| | - James E. Nelson
- Benaroya Research Institute, Virginia Mason Medical Center, Seattle, WA, United States
| | - Kris V. Kowdley
- Liver Center of Excellence, Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA, United States,Benaroya Research Institute, Virginia Mason Medical Center, Seattle, WA, United States,Address for correspondence: Kris V. Kowdley, MD, 1201 9th Ave., Seattle, WA 98101, United States. Tel.: +1 (206) 287 1083; fax: +1 (206) 341 1934.
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34
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Du Y, Liu M, Gao J, Li Z. Aberrant MicroRNAs Expression Patterns in Pancreatic Cancer and Their Clinical Translation. Cancer Biother Radiopharm 2013; 28:361-9. [PMID: 23621126 DOI: 10.1089/cbr.2012.1389] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Affiliation(s)
- Yiqi Du
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China
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35
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Huang X, Jia Z. Construction of HCC-targeting artificial miRNAs using natural miRNA precursors. Exp Ther Med 2013; 6:209-215. [PMID: 23935748 PMCID: PMC3735510 DOI: 10.3892/etm.2013.1111] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2013] [Accepted: 04/16/2013] [Indexed: 12/31/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, particularly in developing countries. Despite the achievements in clinical therapeutics, the HCC mortality rate remains high. A number of artificial microRNA (amiRNA)-based HCC gene therapy studies have demonstrated significant inhibition of invasion and induction of apoptosis of HCC cancer cells, indicating that this type of therapy may be a promising alternative to current therapeutics. Since the structure of the amiRNA precursor in the specific intracellular environment is critical for the processing to mature amiRNA, a precursor structure that may be efficiently processed is desired. In this study, we constructed amiRNAs targeting firefly luciferase with the precursor structures of six HCC-abundant microRNAs: miR-18a, miR-21, miR-192, miR-221, miR-222 and miR-224, and evaluated the processing efficiency of these amiRNAs in the HCC cell lines Hep3B and HepG2 using a luciferase reporter system. The results demonstrated that these amiRNA precursors are capable of being expressed in HCC cells, with the miR-221 precursor-based amiRNA exhibiting the most efficient inhibition on firefly luciferase at the levels of mRNA and protein activity. This finding provides a basis for constructing HCC-targeting amiRNAs with potent processing efficiency using the precursor structure of miR-221.
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Affiliation(s)
- Xiaoming Huang
- Institute of Hygiene, Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang 310013, P.R. China
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36
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Zhang Y, Yan G, Zhai L, Xu S, Shen H, Yao J, Wu F, Xie L, Tang H, Yu H, Liu M, Yang P, Xu P, Zhang C, Li L, Chang C, Li N, Wu S, Zhu Y, Wang Q, Wen B, Lin L, Wang Y, Zheng G, Zhou L, Lu H, Liu S, He F, Zhong F. Proteome atlas of human chromosome 8 and its multiple 8p deficiencies in tumorigenesis of the stomach, colon, and liver. J Proteome Res 2013; 12:81-88. [PMID: 23256868 DOI: 10.1021/pr300834r] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Chromosome 8, a medium-length euchromatic unit in humans that has an extraordinarily high mutation rate, can be detected not only in evolution but also in multiple mutant diseases, such as tumorigenesis, and further invasion/metastasis. The Chromosome-Centric Human Proteome Project of China systematically profiles the proteomes of three digestive organs (i.e., stomach, colon, and liver) and their corresponding carcinoma tissues/cell lines according to a chromosome organizational roadmap. By rigorous standards, we have identified 271 (38.7%), 330 (47.1%), and 325 (46.4%) of 701 chromosome 8-coded proteins from stomach, colon, and liver samples, respectively, in Swiss-Prot and observed a total coverage rate of up to 58.9% by 413 identified proteins. Using large-scale label-free proteome quantitation, we also found some 8p deficiencies, such as the presence of 8p21-p23 in tumorigenesis of the above-described digestive organs, which is in good agreement with previous reports. To our best knowledge, this is the first study to have verified these 8p deficiencies at the proteome level, complementing genome and transcriptome data.
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Affiliation(s)
- Yang Zhang
- Institutes of Biomedical Sciences and Department of Chemistry, Fudan University, Shanghai 200032, China
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37
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Hwang CK, Wagley Y, Law PY, Wei LN, Loh HH. MicroRNAs in opioid pharmacology. J Neuroimmune Pharmacol 2012; 7:808-19. [PMID: 22068836 PMCID: PMC3295898 DOI: 10.1007/s11481-011-9323-2] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2011] [Accepted: 10/24/2011] [Indexed: 01/20/2023]
Abstract
MicroRNAs (miRNA), a class of ~22-nucleotide RNA molecules, are important gene regulators that bind to the target sites of mRNAs to inhibit the gene expressions either through translational inhibition or mRNA destabilization. There are growing evidences that miRNAs have played several regulatory roles in opioid pharmacology. Like other research fields such as cancer biology, the area where numerous miRNAs are found to be involved in gene regulation, we assume that in opioid studies including research fields of drug additions and opioid receptor regulation, there may be more miRNAs waiting to be discovered. This review will summarize our current knowledge of miRNA functions on opioids biology and briefly describe future research directions of miRNAs related to opioids.
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Affiliation(s)
- Cheol Kyu Hwang
- Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
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38
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Kaur S, Baine MJ, Jain M, Sasson AR, Batra SK. Early diagnosis of pancreatic cancer: challenges and new developments. Biomark Med 2012; 6:597-612. [PMID: 23075238 PMCID: PMC3546485 DOI: 10.2217/bmm.12.69] [Citation(s) in RCA: 162] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Pancreatic cancer is a lethal malignancy with its incidence almost equivalent to mortality. The complex pathophysiology, absence of early diagnostic and prognostic markers and unresponsiveness to radiation and chemotherapies are major barriers against successful therapy. Poor performance of therapeutic agents, even in the initial stage of invasive cases, emphasizes the importance of early detection for improved survival. The present review discusses the challenges and advances in biomarkers including serological signatures, circulating tumor cells, autoantibodies, epigenetic markers and miRNAs that are being explored to detect this cancer at early stages. Considering the long time gap between the development of malignant lesions and full-blown primary and metastatic pancreatic cancer, unique opportunities are being contemplated for the development of potential diagnostic and prognostic markers.
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Affiliation(s)
- Sukhwinder Kaur
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Michael J Baine
- Eppley Institute for Research in Cancer & Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
| | - Maneesh Jain
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Aaron R Sasson
- Department of Surgery, University of Nebraska Medical Center, Omaha, NE, USA
| | - Surinder K Batra
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
- Eppley Institute for Research in Cancer & Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
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39
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Yang IP, Tsai HL, Hou MF, Chen KC, Tsai PC, Huang SW, Chou WW, Wang JY, Juo SHH. MicroRNA-93 inhibits tumor growth and early relapse of human colorectal cancer by affecting genes involved in the cell cycle. Carcinogenesis 2012; 33:1522-1530. [PMID: 22581829 DOI: 10.1093/carcin/bgs166] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
PURPOSE Colorectal cancer (CRC) is associated with high recurrence and mortality. Because deregulation of microRNAs is associated with CRC development and recurrence, the expression levels of microRNAs can be a simple and reliable biomarker to detect postoperative early relapse, thereby helping physicians to treat high-risk patients more efficiently. EXPERIMENTAL DESIGN We used microRNA arrays and observed that microRNA-93 had substantially different expression levels in early (recurrence within 12 months after surgery) and non-early relapse CRC patients. The replication study, which included 35 early relapse and 42 non-early relapse subjects, further confirmed overexpression of microRNA-93 in non-early relapse samples. The in vitro and in vivo effects of microRNA-93 were investigated by examining cell proliferation, migration and invasion, as well as cell cycles, target-gene expression and xenograft in null mice. RESULTS Cellular studies showed that the overexpression of microRNA-93 inhibited colon cancer cell proliferation and migration but not invasion. The cell cycle studies also revealed that microRNA-93 caused an accumulation of the G2 population. However, microRNA-93 could not induce cell apoptosis or necrosis. Functional studies showed that microRNA-93 could suppress CCNB1 protein expression leading to cell cycle arrest in the G2 phase. Moreover, microRNA-93 repressed expression of ERBB2, p21 and VEGF, all of which are involved in cell proliferation. MicroRNA-93 also suppressed tumor growth in null mice. CONCLUSIONS This study showed that microRNA-93 can inhibit tumorigenesis and reduce the recurrence of CRC; these findings may have potential clinical applications for predicting the recurrence of CRC.
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Affiliation(s)
- I-Ping Yang
- Department of Medical Genetics College of Medicine, Kaohsiung Medical University Kaohsiung, Taiwan
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40
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Hsu CM, Lin PM, Wang YM, Chen ZJ, Lin SF, Yang MY. Circulating miRNA is a novel marker for head and neck squamous cell carcinoma. Tumour Biol 2012; 33:1933-42. [PMID: 22811001 DOI: 10.1007/s13277-012-0454-8] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2012] [Accepted: 06/28/2012] [Indexed: 12/18/2022] Open
Abstract
The aim of the study is to investigate the alteration of plasma miRNA in head and neck squamous cell carcinoma (HNSCC). Altered microRNAs (miRNAs) expression has been found in many cancers, including lung cancer, breast cancer, prostate cancer, bladder cancer and colorectal cancer. Many recent studies have demonstrated that aberrant plasma miRNAs were also found in various types of cancers. However the alteration of plasma expression in HNSCC remains unclear. In this present study, the expression profiles of ten miRNAs, let-7a, miR-21, miR26b, miR-34c, miR-99a, miR-133a, miR-137, miR-184, miR-194a, and miR-375, in plasma from 50 patients and 36 healthy subjects were evaluated using real-time quantitative polymerase chain reaction (PCR). Our results demonstrated that the expression level of miR-21 was significantly up-regulated in plasma samples obtained from HNSCC patients (p < 0.01) than those from healthy subjects, which were in consistent with our finding in HNSCC tissues. A 7.7-fold increase of miR-21 in cancerous parts when compared to their non-cancerous counterparts (p < 0.0001) was observed in HNSCC tissues. In addition, the expression levels of miR-21 and miR-26b were both reduced in post-operative HNSCC patients with good prognosis. In contrast, the concentration of plasma miR-21 and miR-26b stayed high after tumor removal in the expired cases. Our study suggests that detecting circulating miR-21 and miR-26b pre- and post-operatively might provide a novel tumor marker for HNSCC.
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Affiliation(s)
- Cheng-Ming Hsu
- Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
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41
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WANG XINWEI, HEEGAARD NIELSHH, ØRUM HENRIK. MicroRNAs in liver disease. Gastroenterology 2012; 142:1431-43. [PMID: 22504185 PMCID: PMC6311104 DOI: 10.1053/j.gastro.2012.04.007] [Citation(s) in RCA: 219] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2011] [Revised: 04/04/2012] [Accepted: 04/09/2012] [Indexed: 02/06/2023]
Abstract
MicroRNAs are small noncoding RNA molecules that regulate gene expression posttranscriptionally through complementary base pairing with thousands of messenger RNAs. They regulate diverse physiological, developmental, and pathophysiological processes. Recent studies have uncovered the contribution of microRNAs to the pathogenesis of many human diseases, including liver diseases. Moreover, microRNAs have been identified as biomarkers that can often be detected in the systemic circulation. We review the role of microRNAs in liver physiology and pathophysiology, focusing on viral hepatitis, liver fibrosis, and cancer. We also discuss microRNAs as diagnostic and prognostic markers and microRNA-based therapeutic approaches for liver disease.
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Affiliation(s)
- XIN WEI WANG
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer institute, National Institutes of Health, Bethesda, Maryland
| | - NIELS H. H. HEEGAARD
- Department of Clinical Biochemistry and Immunology Statens Serum Institut, Copenhagen, Denmark
| | - HENRIK ØRUM
- Santaris Pharma, Kogle Allé 6, Hørsholm, Denmark
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42
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MicroRNA-10a targets CHL1 and promotes cell growth, migration and invasion in human cervical cancer cells. Cancer Lett 2012; 324:186-96. [PMID: 22634495 DOI: 10.1016/j.canlet.2012.05.022] [Citation(s) in RCA: 118] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2012] [Revised: 05/14/2012] [Accepted: 05/16/2012] [Indexed: 01/01/2023]
Abstract
MicroRNAs (miRNAs) play an important role in cancer initiation, progression and metastasis by regulating their target genes. Here, we found microRNA-10a (miR-10a) is upregulated in human cervical cancer and promotes the colony formation activity, migration and invasion of HeLa and C33A cells. Subsequently, CHL1 is confirmed as a target of miR-10a and is negatively regulated by miR-10a at mRNA and protein levels. Furthermore, knockdown of CHL1 expression results in increased colony formation activity, migration and invasion. Finally, overexpression of CHL1 lacked the 3'UTR abolished the effects of miR-10a. Our results may provide a strategy for blocking tumor metastasis.
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Fassan M, Croce CM, Rugge M. miRNAs in precancerous lesions of the gastrointestinal tract. World J Gastroenterol 2011; 17:5231-5239. [PMID: 22219591 PMCID: PMC3247686 DOI: 10.3748/wjg.v17.i48.5231] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2011] [Revised: 09/13/2011] [Accepted: 10/14/2011] [Indexed: 02/06/2023] Open
Abstract
In spite of the well-established understanding of the phenotypic lesions occurring in the shift from native epithelia to invasive (adeno) carcinoma, the molecular typing of the precancerous changes in the gastrointestinal tract remains unreliable. In recent years, no biomarkers have aroused as much interest as the miRNAs, a class of non-coding RNA molecules that function as endogenous silencers of numerous target genes. Aberrant miRNA expression is a hallmark of human disease, including cancer. Unlike most mRNAs, miRNAs are both long-living in vivo and very stable in vitro. Such characteristics allow their testing in paraffin-embedded tissue samples, which is essential in the biological profiling of small (phenotypically characterized) preneoplastic lesions of the gastrointestinal tract (as well as in other fields of human pathology). The upcoming challenge lies in the reliable identification of disease-specific targets of dysregulated miRNAs, to enable miRNA testing in the clinical management of the secondary prevention of gastrointestinal cancer.
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Kresty LA, Clarke J, Ezell K, Exum A, Howell AB, Guettouche T. MicroRNA alterations in Barrett's esophagus, esophageal adenocarcinoma, and esophageal adenocarcinoma cell lines following cranberry extract treatment: Insights for chemoprevention. J Carcinog 2011; 10:34. [PMID: 22279419 PMCID: PMC3263009 DOI: 10.4103/1477-3163.91110] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2011] [Accepted: 10/05/2011] [Indexed: 12/23/2022] Open
Abstract
Background: Aberrant expression of small noncoding endogenous RNA molecules known as microRNAs (miRNAs) is documented to occur in multiple cancer types including esophageal adencarcinoma (EAC) and its only known precursor, Barrett's esophagus (BE). Recent studies have linked dysregulation of specific miRNAs to histological grade, neoplastic progression and metastatic potential. Materials and Methods: Herein, we present a summary of previously reported dysregulated miRNAs in BE and EAC tissues as well as EAC cell lines and evaluate a cranberry proanthocyanidin rich extract's (C-PAC) ability to modulate miRNA expression patterns of three human EAC cell lines (JHEso-Ad-1, OE33 and OE19). Results: A review of 13 published studies revealed dysregulation of 87 miRNAs in BE and EAC tissues, whereas 52 miRNAs have been reported to be altered in BE or EAC cell lines, with 48% overlap with miRNA changes reported in tissues. We report for the first time C-PAC–induced modulation of five miRNAs in three EAC cell lines resulting in 26 validated gene targets and identification of key signaling pathways including p53, angiogenesis, T-cell activation and apoptosis. Additionally, mutiple cancer related networks were ideintified as modulated by C-PAC utilizing Kyoto Encyclopedia of Genes and Genomes (KEGG), Protein Analysis Through Evolutionary Relationships (PANTHER), and MetaCore analysis tools. Conclusions: Study results support the cancer inhibitory potential of C-PAC is in part attributable to C-PAC's ability to modify miRNA profiles within EAC cells. A number of C-PAC–modulated miRNAs have been been identified as dysregulated in BE and EAC. Further insights into miRNA dysregulation and modulation by select cancer preventive agents will support improved targeted interventions in high-risk cohorts.
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Affiliation(s)
- Laura A Kresty
- Department of Epidemiology and Public Health, University of Miami Miller School of Medicine and Sylvester Cancer Center, Miami, FL, USA
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