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Asefi M, Rezvani N, Saidijam M, Soltanian AR, Khalilian AR, Mahdavinezhad A. Evaluation of epigenetic silencing of the miR-139-5p gene in the pathogenesis of colorectal cancer and its diagnostic biomarker capability in plasma samples. BMC Cancer 2025; 25:877. [PMID: 40375170 PMCID: PMC12079910 DOI: 10.1186/s12885-025-14290-x] [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] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Accepted: 05/08/2025] [Indexed: 05/18/2025] Open
Abstract
BACKGROUND The pathogenesis of CRC requires primary genetic and epigenetic mechanisms including, methylation of CpG islands of the genes. In the current study, micro RNA-139-5p (miR-139-5p) promoter methylated DNA was evaluated in tumor tissue and plasma samples from CRC affected patients. METHODS MiR-139-5p promoter methylation was investigated in 80 samples of tumoral tissue and healthy marginal tissue and the same number of plasma samples, using the MethyLight method. The miR-139-5p expression was assessed using the qPCR method. BT (Bioassay Technology) Elisa kit was applied to measure RAP-1b as a target gene of miR-139-5p. RESULTS Median PMR values of 12.4 (95% CI, 3.23-32.25) and 0.66 (95%CI, 0.51-1.0) were obtained from plasma samples of CRC patients and controls, sequentially. In plasma samples, the sensitivity and specificity of miR-139-5p promoter methylated marker were 75% and 92.5%, in the same order (AUC = 0.958). Lower expression of miR-139-5p in plasma and tumor tissue of patients (P < 0.001) was shown. Also, a significant rise of RAP-1b protein concentration was observed in both mentioned specimens. CONCLUSION Hyper-methylation of miR-139-5p could be suggested as high accuracy diagnostic biomarker for the detection of CRC in plasma samples, pending further validation with large prospective studies.
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Affiliation(s)
- Masoud Asefi
- Research Center for Molecular Medicine, Institute of Cancer, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Nayebali Rezvani
- Department of Clinical Biochemistry, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Massoud Saidijam
- Research Center for Molecular Medicine, Institute of Cancer, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Ali Reza Soltanian
- Modeling of Noncommunicable Diseases Research Center, Institute of Health Sciences and Technologies, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Ali Reza Khalilian
- Department of Internal Medicine, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Ali Mahdavinezhad
- Research Center for Molecular Medicine, Institute of Cancer, Hamadan University of Medical Sciences, Hamadan, Iran.
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Doghish AS, Abdel Mageed SS, Mohammed OA, Abdel-Reheim MA, Zaki MB, Mohamed AH, Rizk NI, Abulsoud AI, Abdelmaksoud NM, El-Dakroury WA, Aly SH. Natural compounds as regulators of miRNAs: exploring a new avenue for treating colorectal cancer. Funct Integr Genomics 2025; 25:42. [PMID: 39982533 DOI: 10.1007/s10142-025-01547-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 01/15/2025] [Accepted: 02/01/2025] [Indexed: 02/22/2025]
Abstract
Colorectal cancer (CRC) ranks as the second leading cause of cancer-related death globally, impacting both genders equally. The increasing global mortality rates from CRC are strongly linked to contemporary dietary habits, characterized by excessive meat consumption, alcohol intake, and insufficient physical activity. Thus, there is an unprecedented need to develop less hazardous and new therapies for CRC. CRC affects a substantial global population. The main treatments for CRC include chemotherapy and surgical intervention. Nonetheless, the advancement of innovative, safer, and more effective pharmaceuticals for CRC therapy is of paramount importance due to the widespread adverse effects and the dynamic nature of drug resistance. A growing amount of research suggests that natural chemicals may effectively battle CRC and, in certain cases, serve as alternatives to chemotherapeutics. Evidence suggests that miRNAs control important cancer features, including the maintenance of proliferative signals. These features also involve evasion of growth inhibition, resistance to cell death, and immortalization of replication. Additionally, miRNAs play a role in angiogenesis, invasion, and metastasis. Numerous compounds, including those exhibiting cytotoxic and apoptogenic properties against different malignancies, such as CRC, are sourced from diverse marine and medicinal plants. These chemicals stimulate several signaling pathways originating from different phytochemical families. This article evaluates the existing understanding of the anti-CRC capabilities of several phytochemical substances. Furthermore, their impact on several signaling pathways associated with cancer is examined. This article also highlights the potential of medicinal plants as a source of promising anti-CRC chemicals through modulating miRNA expression and the role of nanoparticle-based miRNA therapeutics in enhancing CRC treatment by improving tumor targeting and minimizing off-target effects.
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Affiliation(s)
- Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo, 11829, Egypt.
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo, 11231, Egypt.
| | - Sherif S Abdel Mageed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo, 11829, Egypt
| | - Osama A Mohammed
- Department of Pharmacology, College of Medicine, University of Bisha, Bisha, 61922, Saudi Arabia
| | | | - Mohamed Bakr Zaki
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, Menoufia, 32897, Egypt
- Department of Biochemistry, Faculty of Pharmacy, Menoufia National University, km Cairo- Alexandria Agricultural Road, Tukh Tanbisha, Menofia, Egypt
| | - Ashraf Hassan Mohamed
- Faculty of Physical Therapy, Badr University in Cairo (BUC), Badr City, Cairo, 11829, Egypt
| | - Nehal I Rizk
- Department of Biochemistry, Faculty of Pharmacy and Drug Technology, Egyptian Chinese University, Cairo, 11786, Egypt
| | - Ahmed I Abulsoud
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo, 11231, Egypt
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo, 11785, Egypt
| | - Nourhan M Abdelmaksoud
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo, 11785, Egypt
| | - Walaa A El-Dakroury
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo, 11829, Egypt
| | - Shaza H Aly
- Department of Pharmacognosy, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo, 11829, Egypt
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3
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Sampaio Moura N, Schledwitz A, Alizadeh M, Patil SA, Raufman JP. Matrix metalloproteinases as biomarkers and therapeutic targets in colitis-associated cancer. Front Oncol 2024; 13:1325095. [PMID: 38288108 PMCID: PMC10824561 DOI: 10.3389/fonc.2023.1325095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Accepted: 12/26/2023] [Indexed: 01/31/2024] Open
Abstract
Colorectal cancer (CRC) remains a major cause of morbidity and mortality. Therapeutic approaches for advanced CRC are limited and rarely provide long-term benefit. Enzymes comprising the 24-member matrix metalloproteinase (MMP) family of zinc- and calcium-dependent endopeptidases are key players in extracellular matrix degradation, a requirement for colon tumor expansion, invasion, and metastasis; hence, MMPs are an important research focus. Compared to sporadic CRC, less is known regarding the molecular mechanisms and the role of MMPs in the development and progression of colitis-associated cancer (CAC) - CRC on a background of chronic inflammatory bowel disease (IBD) - primarily ulcerative colitis and Crohn's disease. Hence, the potential of MMPs as biomarkers and therapeutic targets for CAC is uncertain. Our goal was to review data regarding the role of MMPs in the development and progression of CAC. We sought to identify promising prognostic and therapeutic opportunities and novel lines of investigation. A key observation is that since MMPs may be more active in early phases of CAC, using MMPs as biomarkers of advancing neoplasia and as potential therapeutic targets for adjuvant therapy in those with advanced stage primary CAC rather than overt metastases may yield more favorable outcomes.
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Affiliation(s)
- Natalia Sampaio Moura
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Alyssa Schledwitz
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Madeline Alizadeh
- The Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Seema A. Patil
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Jean-Pierre Raufman
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD, United States
- Medical Service, Veterans Affairs Maryland Healthcare System, Baltimore, MD, United States
- Marlene and Stewart Greenebaum Cancer Center, University of Maryland Medical Center, Baltimore, MD, United States
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, United States
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4
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Li SQ, Xie LY, Cai ZM, Wei HT, Xie MZ, Hu BL, Ning SF. Systematic analyzing a five- miRNA panel and its diagnostic value of plasma expression in colorectal cancer. Mol Biol Rep 2023; 50:7253-7261. [PMID: 37418078 DOI: 10.1007/s11033-023-08642-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 06/27/2023] [Indexed: 07/08/2023]
Abstract
BACKGROUND Aberrant expression of miRNAs have been implicated in cancers, but the role of miRNAs in colorectal cancer (CRC) remains need to be elucidated. This study aimed to identify miRNAs that related to colorectal cancer (CRC) pathogenesis and determine the diagnostic value. METHODS Three GEO datasets (GSE128449, GSE35602 and GSE49246) with 131 samples were used to screen miRNAs that differential expression between tumor and control tissues. The expression of the identified miRNAs was validated in 50 clinical tissue samples and the GSE35834 dataset. The clinical significance of these miRNAs was analyzed in the TCGA dataset and clinical tissue samples. The expression of miRNAs in tissues and plasma samples were tested by RT-PCR assay in clinical samples, and their diagnostic value was determined. RESULTS The analysis of three GEO datasets revealed that miR-595 and miR-1237 were upregulated, while miR-126, miR-139, and miR-143 were downregulated in CRC tissues compared to control tissues. The differential expression of the five miRNAs in CRC tissues was confirmed using clinical tissue samples and GEO databases. There was no significant correlation between the TNM stage and tumor stage of CRC and any of the five miRNAs. Plasma expression of the miRNAs differed significantly between CRC and non-cancer patients, and each miRNA had moderate diagnostic value for CRC. Combining the five miRNAs provided better diagnostic potential for CRC than a single miRNA. CONCLUSIONS This study demonstrated that five miRNAs were related to the pathogenesis of CRC, but independent of the stage of CRC; Plasma expression of these miRNAs have moderate diagnostic value, and combination of these miRNAs showed better diagnostic ability in CRC.
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Affiliation(s)
- Si-Qi Li
- Department of Research, Guangxi Medical University Cancer Hospital, No. 71 Hedi Road, Nanning, 530021, China
| | - Li-Ye Xie
- Department of Research, Guangxi Medical University Cancer Hospital, No. 71 Hedi Road, Nanning, 530021, China
| | - Zheng-Min Cai
- Department of Research, Guangxi Medical University Cancer Hospital, No. 71 Hedi Road, Nanning, 530021, China
| | - Hao-Tang Wei
- Department of Gastrointestinal Surgery, Third Affiliated Hospital of Guangxi Medical University, Nanning, 530031, China
| | - Ming-Zhi Xie
- Department of Chemotherapy, Guangxi Medical University Cancer Hospital, Nanning, 530031, China
| | - Bang-Li Hu
- Department of Research, Guangxi Medical University Cancer Hospital, No. 71 Hedi Road, Nanning, 530021, China.
| | - Shu-Fang Ning
- Department of Research, Guangxi Medical University Cancer Hospital, No. 71 Hedi Road, Nanning, 530021, China.
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Tariq L, Arafah A, Sehar N, Ali A, Khan A, Rasool I, Rashid SM, Ahmad SB, Beigh S, Dar TUH, Rehman MU. Novel insights on perils and promises of miRNA in understanding colon cancer metastasis and progression. Med Oncol 2023; 40:282. [PMID: 37639075 DOI: 10.1007/s12032-023-02099-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 06/19/2023] [Indexed: 08/29/2023]
Abstract
Colorectal cancer (CRC) is the third highest frequent malignancy and ultimate critical source of cancer-associated mortality around the world. Regardless of latest advances in molecular and surgical targeted medicines that have increased remedial effects in CRC patients, the 5-year mortality rate for CRC patients remains dismally low. Evidence suggests that microRNAs (miRNAs) execute an essential part in the development and spread of CRC. The miRNAs are a type of short non-coding RNA that exhibited to control the appearance of tumor suppressor genes and oncogenes. miRNA expression profiling is already being utilized in clinical practice as analytical and prognostic biomarkers to evaluate cancer patients' tumor genesis, advancement, and counteraction to drugs. By modulating their target genes, dysregulated miRNAs are linked to malignant characteristics (e.g., improved proliferative and invasive capabilities, cell cycle aberration, evasion of apoptosis, and promotion of angiogenesis). This review presents an updated summary of circulatory miRNAs, tumor-suppressive and oncogenic miRNAs, and the potential reasons for dysregulated miRNAs in CRC. Further we will explore the critical role of miRNAs in CRC drug resistance.
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Affiliation(s)
- Lubna Tariq
- Department of Biotechnology, Baba Ghulam Shah Badshah University, Rajouri, Jammu and Kashmir, 183254, India
| | - Azher Arafah
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, 11451, Riyadh, Saudi Arabia
| | - Nouroz Sehar
- Centre for Translational and Clinical Research, School of Chemical & Life Sciences, Jamia Hamdard, New Delhi, 110062, India
| | - Aarif Ali
- Division of Veterinary Biochemistry, Faculty of Veterinary Science and Animal Husbandry, SKUAST-Kashmir, Alusteng, Shuhama, Srinagar, Jammu and Kashmir, 190006, India
| | - Andleeb Khan
- Department of Pharmacology and Toxicology, College of Pharmacy, Jazan University, 45142, Jazan, Saudi Arabia
| | - Iyman Rasool
- Department of Pathology, Government Medical College (GMC-Srinagar), Karanagar, Srinagar, Jammu and Kashmir, 190006, India
| | - Shahzada Mudasir Rashid
- Division of Veterinary Biochemistry, Faculty of Veterinary Science and Animal Husbandry, SKUAST-Kashmir, Alusteng, Shuhama, Srinagar, Jammu and Kashmir, 190006, India
| | - Sheikh Bilal Ahmad
- Division of Veterinary Biochemistry, Faculty of Veterinary Science and Animal Husbandry, SKUAST-Kashmir, Alusteng, Shuhama, Srinagar, Jammu and Kashmir, 190006, India
| | - Saba Beigh
- Department of Public Health, Faculty of Applied Medical Science, Al Baha University, 65431, Al Baha, Saudi Arabia
| | - Tanveer Ul Hassan Dar
- Department of Biotechnology, Baba Ghulam Shah Badshah University, Rajouri, Jammu and Kashmir, 183254, India
| | - Muneeb U Rehman
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, 11451, Riyadh, Saudi Arabia.
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Liu X, Hu Y, Li C, Chen J, Liu X, Shen Y, Xu Y, Chen W, Xu X. Overexpression of YEATS2 Remodels the Extracellular Matrix to Promote Hepatocellular Carcinoma Progression via the PI3K/AKT Pathway. Cancers (Basel) 2023; 15:cancers15061850. [PMID: 36980736 PMCID: PMC10046954 DOI: 10.3390/cancers15061850] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 03/12/2023] [Indexed: 03/30/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers and the fourth leading cause of death in men. YEATS domain containing 2 (YEATS2) gene encodes a scaffolding subunit of the ATAC complex. We found that YEATS2 was upregulated in HCC tissues and was associated with a poor prognosis. However, the role of YEATS2 in HCC remains unclear. The purpose of this study was to investigate the effect of YEATS2 on the progression of HCC and to elucidate its related mechanisms. We found that overexpression of YEATS2 promoted tumor cell proliferation, migration, and invasion through the PI3K/AKT signaling pathway and regulation of extracellular matrix. These findings help to understand the role of YEATS2 in HCC, and YEATS2 may become a new target for HCC therapy.
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Affiliation(s)
- Xin Liu
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Yi Hu
- Department of Oncology, General Hospital of Central Theater Command, Wuhan 430061, China
| | - Cairong Li
- School of Clinical Medicine, Xianning Medical College, Hubei University of Science and Technology, Xianning 437100, China
| | - Jiayu Chen
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Xiaohong Liu
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Yang Shen
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Yangtao Xu
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Wenliang Chen
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Ximing Xu
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060, China
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7
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Bissa M, Kim S, Galli V, Fourati S, Sarkis S, Arakelyan A, de Castro IS, Rahman MA, Fujiwara S, Vaccari M, Tomalka JA, Stamos JD, Schifanella L, Gorini G, Moles R, Gutowska A, Ferrari G, Lobanov A, Montefiori DC, Nelson GW, Cam MC, Chakhtoura M, Haddad EK, Doster MN, McKinnon K, Brown S, Venzon DJ, Choo-Wosoba H, Breed MW, Killoran KE, Kramer J, Margolis L, Sekaly RP, Hager GL, Franchini G. HIV vaccine candidate efficacy in female macaques mediated by cAMP-dependent efferocytosis and V2-specific ADCC. Nat Commun 2023; 14:575. [PMID: 36732510 PMCID: PMC9894672 DOI: 10.1038/s41467-023-36109-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Accepted: 01/15/2023] [Indexed: 02/04/2023] Open
Abstract
The development of an effective vaccine to protect against HIV acquisition will be greatly bolstered by in-depth understanding of the innate and adaptive responses to vaccination. We report here that the efficacy of DNA/ALVAC/gp120/alum vaccines, based on V2-specific antibodies mediating apoptosis of infected cells (V2-ADCC), is complemented by efferocytosis, a cyclic AMP (cAMP)-dependent antiphlogistic engulfment of apoptotic cells by CD14+ monocytes. Central to vaccine efficacy is the engagement of the CCL2/CCR2 axis and tolerogenic dendritic cells producing IL-10 (DC-10). Epigenetic reprogramming in CD14+ cells of the cyclic AMP/CREB pathway and increased systemic levels of miRNA-139-5p, a negative regulator of expression of the cAMP-specific phosphodiesterase PDE4D, correlated with vaccine efficacy. These data posit that efferocytosis, through the prompt and effective removal of apoptotic infected cells, contributes to vaccine efficacy by decreasing inflammation and maintaining tissue homeostasis.
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Affiliation(s)
- Massimiliano Bissa
- Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, MD, USA.
| | - Sohyoung Kim
- Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Veronica Galli
- Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, MD, USA
| | - Slim Fourati
- Department of Pathology, Case Western Reserve University, Cleveland, OH, USA
- Department of Pathology, Emory University, Atlanta, GA, USA
| | - Sarkis Sarkis
- Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, MD, USA
| | - Anush Arakelyan
- Section on Intercellular Interactions, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | | | - Mohammad Arif Rahman
- Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, MD, USA
| | - Saori Fujiwara
- Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Monica Vaccari
- Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, MD, USA
- Tulane National Primate Research Center, Tulane University, Covington, LA, USA
| | - Jeffrey A Tomalka
- Department of Pathology, Case Western Reserve University, Cleveland, OH, USA
- Department of Pathology, Emory University, Atlanta, GA, USA
| | - James D Stamos
- Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, MD, USA
| | - Luca Schifanella
- Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, MD, USA
| | - Giacomo Gorini
- Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, MD, USA
| | - Ramona Moles
- Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, MD, USA
| | - Anna Gutowska
- Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, MD, USA
| | - Guido Ferrari
- Division of Surgical Sciences, Duke University School of Medicine, Durham, NC, USA
| | - Alexei Lobanov
- Collaborative Bioinformatics Resource, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - David C Montefiori
- Division of Surgical Sciences, Duke University School of Medicine, Durham, NC, USA
| | - George W Nelson
- Collaborative Bioinformatics Resource, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Margaret C Cam
- Collaborative Bioinformatics Resource, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Marita Chakhtoura
- Department of Medicine, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Elias K Haddad
- Department of Medicine, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Melvin N Doster
- Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, MD, USA
| | - Katherine McKinnon
- Vaccine Branch Flow Cytometry Core, National Cancer Institute, Bethesda, MD, USA
| | - Sophia Brown
- Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, MD, USA
- Vaccine Branch Flow Cytometry Core, National Cancer Institute, Bethesda, MD, USA
| | - David J Venzon
- Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Hyoyoung Choo-Wosoba
- Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Matthew W Breed
- Laboratory Animal Sciences Program, Leidos Biomedical Research Inc., Frederick National Laboratory, Frederick, MD, USA
| | - Kristin E Killoran
- Laboratory Animal Sciences Program, Leidos Biomedical Research Inc., Frederick National Laboratory, Frederick, MD, USA
| | - Joshua Kramer
- Laboratory Animal Sciences Program, Leidos Biomedical Research Inc., Frederick National Laboratory, Frederick, MD, USA
| | - Leonid Margolis
- Section on Intercellular Interactions, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Rafick P Sekaly
- Department of Pathology, Case Western Reserve University, Cleveland, OH, USA
- Department of Pathology, Emory University, Atlanta, GA, USA
| | - Gordon L Hager
- Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Genoveffa Franchini
- Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, MD, USA.
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8
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Hou F, Li X, Wang Y, Xiao X. MicroRNA-183 accelerates the proliferation of hepatocyte during liver regeneration through targeting programmed cell death protein 6. Genes Genomics 2022; 44:1017-1029. [PMID: 35190998 DOI: 10.1007/s13258-022-01223-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 01/20/2022] [Indexed: 11/25/2022]
Abstract
BACKGROUND Liver regeneration is a highly orchestrated process concerning the modulation of various microRNAs (miRs). miR-183 was recently found to be involved in the process of liver regeneration, that miR-183 was remarkably up-regulated at 2-6 h after partial hepatectomy. OBJECTIVE This study was aimed to explore the mechanism of miR-183 in on liver regeneration. METHODS After partial hepatectomy (PH) or transfection, we measured the changes of miR-183 and programmed cell death protein 6 (PDCD6) levels in rats and the hepatocytes. The histopathology was observed with hematoxylin-eosin staining. The miR-183 mimic and inhibitor plasmids were intravenously injected into rats, and the liver weight/body weight ratio was calculated. The prediction of TargetScan and the validation of luciferase activity assay were employed to confirm the targeting relationship between miR-183 and PDCD6. The viability, apoptosis and cell cycle of transfected rat hepatocyte BRL-3A were determined via MTT and flow cytometry assays. RESULTS MiR-183 expression showed a contrary tendency with that of PDCD6 during liver regeneration. Enhanced miR-183 in rats could notably increase liver/body weight ratio, while its inhibition did conversely. Overexpressed PDCD6, a target of miR-183, repressed the viability and cell cycle in hepatocytes, whereas its silence led to contrary results. Overexpressed miR-183 in BRL-3A cells enhanced cell viability and promoted the cell cycle yet suppressed apoptosis, whereas its inhibition showed contrary results, which were offset by PDCD6. CONCLUSIONS Collectively, miR-183 promoted liver regeneration via targeting PDCD6.
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Affiliation(s)
- Fangxing Hou
- Queen Mary School, Nanchang University, Nanchang, Jiangxi, China
| | - Xing Li
- Oncology Chemotherapy Department, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou, Hainan, China
| | - Yanfeng Wang
- Department of Pathology, Beidahuang Industry Group General Hospital, No. 235, hashuang Road, Nangang District, Harbin, 150000, China.
| | - Xiangzuo Xiao
- Department of Radiology, The First Affiliated Hospital of Nanchang University, No. 17 Yongwaizheng Street, Nanchang, 330006, Jiangxi, China.
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9
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Pezeshkian Z, Nobili S, Peyravian N, Shojaee B, Nazari H, Soleimani H, Asadzadeh-Aghdaei H, Ashrafian Bonab M, Nazemalhosseini-Mojarad E, Mini E. Insights into the Role of Matrix Metalloproteinases in Precancerous Conditions and in Colorectal Cancer. Cancers (Basel) 2021; 13:cancers13246226. [PMID: 34944846 PMCID: PMC8699154 DOI: 10.3390/cancers13246226] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/06/2021] [Accepted: 12/07/2021] [Indexed: 01/06/2023] Open
Abstract
Simple Summary Colorectal cancer (CRC) is one of the most common cancer worldwide. CRC is derived from polyps and many factors, such as Matrix Metalloproteinases (MMPs) can gain the progression of colorectal carcinogenesis. Many investigations have indicated the role of MMPs in CRC development while there is not enough knowledge about the function of MMPs in precancerous conditions. This review summarizes the current information about the role of MMPs in polyps and CRC progression. Abstract Colorectal cancer (CRC) is the third and second cancer for incidence and mortality worldwide, respectively, and is becoming prevalent in developing countries. Most CRCs derive from polyps, especially adenomatous polyps, which can gradually transform into CRC. The family of Matrix Metalloproteinases (MMPs) plays a critical role in the initiation and progression of CRC. Prominent MMPs, including MMP-1, MMP-2, MMP-7, MMP-8, MMP-9, MMP-12, MMP-13, MMP-14, and MMP-21, have been detected in CRC patients, and the expression of most of them correlates with a poor prognosis. Moreover, many studies have explored the inhibition of MMPs and targeted therapy for CRC, but there is not enough information about the role of MMPs in polyp malignancy. In this review, we discuss the role of MMPs in colorectal cancer and its pathogenesis
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Affiliation(s)
- Zahra Pezeshkian
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 19835-178, Iran; (Z.P.); (N.P.); (B.S.); (H.A.-A.)
| | - Stefania Nobili
- Department of Neurosciences, Imaging and Clinical Sciences, “G. D’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy;
- Center for Advanced Studies and Technology (CAST), University “G. D’Annunzio” Chieti-Pescara, 66100 Chieti, Italy
| | - Noshad Peyravian
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 19835-178, Iran; (Z.P.); (N.P.); (B.S.); (H.A.-A.)
| | - Bahador Shojaee
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 19835-178, Iran; (Z.P.); (N.P.); (B.S.); (H.A.-A.)
| | - Haniye Nazari
- Department of Microbiology, Faculty of Advanced Science and Technology, Tehran Medical Science, Islamic Azad University, Tehran 19395-1495, Iran;
| | - Hiva Soleimani
- Department of General Biology, Faculty of Fundamental Science, Islamic Azad University of Shahr-E-Qods, Tehran 37515-374, Iran;
| | - Hamid Asadzadeh-Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 19835-178, Iran; (Z.P.); (N.P.); (B.S.); (H.A.-A.)
| | - Maziar Ashrafian Bonab
- School of Medicine, University of Sunderland, City Campus, Chester Road, Sunderland SR1 3SD, UK;
| | - Ehsan Nazemalhosseini-Mojarad
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 19835-178, Iran
- Correspondence: (E.N.-M.); (E.M.)
| | - Enrico Mini
- Department of Health Sciences, University of Florence, 50139 Florence, Italy
- DENOTHE Excellence Center, University of Florence, 50139 Florence, Italy
- Correspondence: (E.N.-M.); (E.M.)
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10
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Xu J, Huang QY, Ge CJ. Identification of prognostic long intergenic non-coding RNAs as competing endogenous RNAs with KRAS mutations in colorectal cancer. Oncol Lett 2021; 22:717. [PMID: 34429757 PMCID: PMC8371979 DOI: 10.3892/ol.2021.12978] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 05/28/2021] [Indexed: 01/17/2023] Open
Abstract
Colorectal cancer (CRC) is recognized as a common type of human cancer, and KRAS mutations are correlated with poor CRC survival outcomes. The evaluation and prediction of CRC results remain challenging. In the present study, RNA sequencing and clinical data from The Cancer Genome Atlas were used to identify KRAS mutation-related prognostic long intergenic non-coding RNAs (lincRNAs) in CRC. Significantly dysregulated lincRNAs and independent prognostic lincRNAs with KRAS mutations in CRC were identified. Two lincRNAs with KRAS mutations, LINC00265 and AL390719.2, were selected as key prognostic lincRNAs for both 10- and 5-year survival rates. In addition, competing endogenous (ce)RNA models were constructed to comprehensively assess the oncogenic performance of the two key lincRNAs. The ceRNA models suggested that LINC00265 and AL390719.2 are critical for the cell cycle and cancer pathways. Finally, reverse transcription-quantitative PCR was used to validate the ceRNA models in 12 pairs of CRC tissue samples. These prognostic lincRNAs may provide novel biomarkers for the prognostic prediction of CRC. The ceRNA model may also demonstrate the underlying mechanism of these lincRNAs in CRC.
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Affiliation(s)
- Jun Xu
- Department of General Surgery, The First College of Clinical Medical Science, China Three Gorges University, Yichang, Hubei 443000, P.R. China
| | - Qiu-Yun Huang
- Department of General Surgery, The First College of Clinical Medical Science, China Three Gorges University, Yichang, Hubei 443000, P.R. China
| | - Cun-Jin Ge
- Department of Gastroenterology, The First College of Clinical Medical Science, China Three Gorges University, Yichang, Hubei 443000, P.R. China
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11
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Ahn SH, Kim H, Lee I, Lee JH, Cho S, Choi YS. MicroRNA-139-5p Regulates Fibrotic Potentials via Modulation of Collagen Type 1 and Phosphorylated p38 MAPK in Uterine Leiomyoma. Yonsei Med J 2021; 62:726-733. [PMID: 34296550 PMCID: PMC8298864 DOI: 10.3349/ymj.2021.62.8.726] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 05/16/2021] [Accepted: 06/07/2021] [Indexed: 01/26/2023] Open
Abstract
PURPOSE This study aimed to elucidate whether microRNA-139-5p is involved in the pathogenesis of uterine leiomyoma. MATERIALS AND METHODS Human leiomyoma and matched human smooth muscle samples were obtained from 10 women who underwent hysterectomy for uterine leiomyoma. MicroRNA (miRNA) expression was analyzed by quantitative real-time polymerase chain reaction. To assess the effects of miR-139-5p on cultured leiomyoma cells, cell migration, collagen gel contraction, wound healing, and the expression levels of hallmark proteins were evaluated in cells transfected with a miR-139-5p mimic. RESULTS The expression of miR-139-5p was significantly lower in leiomyoma tissues than in matched smooth muscle tissues. Restored miR-139-5p expression in miR-139-5p mimic-transfected human leiomyoma cells resulted in decreased contractility of the ECM and cell migration. In addition, upregulation of miR-139-5p decreased the protein expression of collagen type 1 and phosphorylated p38 MAPK. CONCLUSION Expression of miR-139-5p is downregulated in leiomyoma cells and modulation of miR-139-5p may be involved inthe pathogenesis of leiomyomas through the regulation of collagen type 1 and phosphorylated p38 MAPK. Therefore, miR-139-5p is a potential therapeutic target for leiomyoma.
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Affiliation(s)
- So Hyun Ahn
- Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
- Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Heeyon Kim
- Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea
- Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Inha Lee
- Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
- Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Jae Hoon Lee
- Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea
- Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
| | - SiHyun Cho
- Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea
- Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Young Sik Choi
- Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
- Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea
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12
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Mansoori H, Darbeheshti F, Daraei A, Mokhtari M, Tabei MB, Abdollahzadeh R, Dastsooz H, Bastami M, Nariman-Saleh-Fam Z, Salmani H, Mansoori Y, Tahmasebi S. Expression signature of lncRNA APTR in clinicopathology of breast cancer: Its potential oncogenic function in dysregulation of ErbB signaling pathway. GENE REPORTS 2021. [DOI: 10.1016/j.genrep.2021.101116] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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13
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Feng J, Wei Q, Yang M, Wang X, Liu B, Li J. Development and validation of a novel miRNA classifier as a prognostic signature for stage II/III colorectal cancer. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:747. [PMID: 34268360 PMCID: PMC8246165 DOI: 10.21037/atm-20-1751] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Accepted: 10/19/2020] [Indexed: 12/04/2022]
Abstract
Background The TNM staging remains the gold standard for determining the prognosis of patients with colorectal cancer (CRC), which is inadequate at identifying the subset of high-risk stage II and III patients that have a high potential of developing tumor recurrence and may experience death. Emerging evidence indicates that not only microRNAs (miRNAs) play important functional role in CRC development but may serve as important disease biomarkers. In this study we aimed to develop a miRNA-based classifier as a prognostic signature for improving the clinical outcome of patients with stage II/III CRC. Methods We performed a systematic and comprehensive discovery step to identify differentially expressed miRNAs in CRC. We subsequently determined the prognostic relevance of these miRNAs in stage II/III patients using qRT-PCR and developed a miRNA-based classifier for predicting disease-free survival (DFS) in a clinical cohort (n=186). Results Based upon miRNA expression profiling studies, we identified a panel of 10 miRNAs which are consistently differentially expressed in CRC vs. normal tissues. By using cox proportional hazard models, we then developed 6-miRNA-classifier (miR-183, -20a, -21, -195, -139 and -20a) to predict prognosis in clinical cohort, that had significantly superior predictive performance compared to other clinicopathological factors, and could successfully identify high-risk stage II and III CRC patients with poor prognosis [hazard ratio (HR) =2.16; P=0.0048]. In a multivariate analysis, this miRNA-based classifier emerged as an independent prognostic signature for poor DFS. Conclusions Our miRNA-based classifier is a reliable predictive tool for determining prognosis in patents with stage II/III CRC, and might be able to identify high-risk patients that are candidates for more targeted personalized clinical management and surveillance.
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Affiliation(s)
- Junlan Feng
- Department of General Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Qing Wei
- Department of Pathology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Muqing Yang
- Department of General Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xiaodong Wang
- Department of General Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Bin Liu
- Department of General Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Jiyu Li
- Department of General Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
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14
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Bocchetti M, Ferraro MG, Ricciardiello F, Ottaiano A, Luce A, Cossu AM, Scrima M, Leung WY, Abate M, Stiuso P, Caraglia M, Zappavigna S, Yau TO. The Role of microRNAs in Development of Colitis-Associated Colorectal Cancer. Int J Mol Sci 2021; 22:3967. [PMID: 33921348 PMCID: PMC8068787 DOI: 10.3390/ijms22083967] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 04/01/2021] [Accepted: 04/08/2021] [Indexed: 12/13/2022] Open
Abstract
Colorectal cancer (CRC) is the third most deadly cancer worldwide, and inflammatory bowel disease (IBD) is one of the critical factors in CRC carcinogenesis. IBD is responsible for an unphysiological and sustained chronic inflammation environment favoring the transformation. MicroRNAs (miRNAs) belong to a class of highly conserved short single-stranded segments (18-25 nucleotides) non-coding RNA and have been extensively discussed in both CRC and IBD. However, the role of miRNAs in the development of colitis-associated CRC (CAC) is less clear. The aim of this review is to summarize the major upregulated (miR-18a, miR-19a, miR-21, miR-31, miR-155 and miR-214) and downregulated (miR-124, miR-193a-3p and miR-139-5p) miRNAs in CAC, and their roles in genes' expression modulation in chronic colonic-inflammation-induced carcinogenesis, including programmed cell-death pathways. These miRNAs dysregulation could be applied for early CAC diagnosis, to predict therapy efficacy and for precision treatment.
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Affiliation(s)
- Marco Bocchetti
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy; (M.B.); (A.L.); (A.M.C.); (M.A.); (P.S.); (M.C.)
- Biogem Scarl, Molecular Oncology and Precision Medicine Laboratory, via Camporeale, 83031 Ariano Irpino, Italy;
| | - Maria Grazia Ferraro
- Department of Pharmacy, School of Medicine and Surgery, University of Naples “Federico II”, via D. Montesano 49, 80131 Naples, Italy;
| | | | - Alessandro Ottaiano
- SSD-Innovative Therapies for Abdominal Metastases, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy;
| | - Amalia Luce
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy; (M.B.); (A.L.); (A.M.C.); (M.A.); (P.S.); (M.C.)
- School of Science and Technology, Nottingham Trent University, Nottingham NG11 8NS, UK
| | - Alessia Maria Cossu
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy; (M.B.); (A.L.); (A.M.C.); (M.A.); (P.S.); (M.C.)
- Biogem Scarl, Molecular Oncology and Precision Medicine Laboratory, via Camporeale, 83031 Ariano Irpino, Italy;
| | - Marianna Scrima
- Biogem Scarl, Molecular Oncology and Precision Medicine Laboratory, via Camporeale, 83031 Ariano Irpino, Italy;
| | - Wing-Yan Leung
- Division of Haematology, Department of Medicine, The University of Hong Kong, Hong Kong, China;
| | - Marianna Abate
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy; (M.B.); (A.L.); (A.M.C.); (M.A.); (P.S.); (M.C.)
| | - Paola Stiuso
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy; (M.B.); (A.L.); (A.M.C.); (M.A.); (P.S.); (M.C.)
| | - Michele Caraglia
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy; (M.B.); (A.L.); (A.M.C.); (M.A.); (P.S.); (M.C.)
- Biogem Scarl, Molecular Oncology and Precision Medicine Laboratory, via Camporeale, 83031 Ariano Irpino, Italy;
| | - Silvia Zappavigna
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy; (M.B.); (A.L.); (A.M.C.); (M.A.); (P.S.); (M.C.)
| | - Tung On Yau
- John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham NG11 8NS, UK
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15
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Ianza A, Sirico M, Bernocchi O, Generali D. Role of the IGF-1 Axis in Overcoming Resistance in Breast Cancer. Front Cell Dev Biol 2021; 9:641449. [PMID: 33829018 PMCID: PMC8019779 DOI: 10.3389/fcell.2021.641449] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 03/04/2021] [Indexed: 12/12/2022] Open
Abstract
Over the last two decades, many studies have demonstrated that the insulin-like growth factor-1 (IGF-1) is involved in a number of patho-physiological processes, as well as in the development of different types of solid tumors, including breast cancer (BC). Preclinical and clinical data showed that IGF-1 receptor (R) is overexpressed and hyper-phosphorylated in several subtypes of BCs. The central implications of this pathway in tumor cell proliferation and metastasis make it an important therapeutic target. Moreover, the IGF-1 axis has shown strong interconnection with estrogen regulation and endocrine therapy, suggesting a possible solution to anti-estrogen resistance. IGF-1R might also interfere with other pivotal therapeutic strategies, such as anti HER2 treatments and mTOR inhibitors; several clinical trials are ongoing evaluating the role of IGF-1R inhibition in modulating resistance mechanisms to target therapies. Our aim is to offer an overview of the most recent and significant field of application of IGF-1 inhibitors and relevant therapeutic strategies, weighing their possible future impact on clinical practice.
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Affiliation(s)
- Anna Ianza
- Department of Medical, Surgery and Health Sciences, Azienda Sanitaria Universitaria Giuliano Isontina, Trieste, Italy
| | - Marianna Sirico
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom
- Breast Cancer Unit and Translational Research Unit, ASST Cremona, Cremona, Italy
| | - Ottavia Bernocchi
- Department of Medical, Surgery and Health Sciences, Azienda Sanitaria Universitaria Giuliano Isontina, Trieste, Italy
| | - Daniele Generali
- Department of Medical, Surgery and Health Sciences, Azienda Sanitaria Universitaria Giuliano Isontina, Trieste, Italy
- Breast Cancer Unit and Translational Research Unit, ASST Cremona, Cremona, Italy
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy
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16
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Angius A, Scanu AM, Arru C, Muroni MR, Rallo V, Deiana G, Ninniri MC, Carru C, Porcu A, Pira G, Uva P, Cossu-Rocca P, De Miglio MR. Portrait of Cancer Stem Cells on Colorectal Cancer: Molecular Biomarkers, Signaling Pathways and miRNAome. Int J Mol Sci 2021; 22:1603. [PMID: 33562604 PMCID: PMC7915330 DOI: 10.3390/ijms22041603] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 02/02/2021] [Accepted: 02/02/2021] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer death worldwide, and about 20% is metastatic at diagnosis and untreatable. Increasing evidence suggests that the heterogeneous nature of CRC is related to colorectal cancer stem cells (CCSCs), a small cells population with stemness behaviors and responsible for tumor progression, recurrence, and therapy resistance. Growing knowledge of stem cells (SCs) biology has rapidly improved uncovering the molecular mechanisms and possible crosstalk/feedback loops between signaling pathways that directly influence intestinal homeostasis and tumorigenesis. The generation of CCSCs is probably connected to genetic changes in members of signaling pathways, which control self-renewal and pluripotency in SCs and then establish function and phenotype of CCSCs. Particularly, various deregulated CCSC-related miRNAs have been reported to modulate stemness features, controlling CCSCs functions such as regulation of cell cycle genes expression, epithelial-mesenchymal transition, metastasization, and drug-resistance mechanisms. Primarily, CCSC-related miRNAs work by regulating mainly signal pathways known to be involved in CCSCs biology. This review intends to summarize the epigenetic findings linked to miRNAome in the maintenance and regulation of CCSCs, including their relationships with different signaling pathways, which should help to identify specific diagnostic, prognostic, and predictive biomarkers for CRC, but also develop innovative CCSCs-targeted therapies.
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Affiliation(s)
- Andrea Angius
- Institute of Genetic and Biomedical Research (IRGB), CNR, Cittadella Universitaria di Cagliari, 09042 Monserrato, Italy;
| | - Antonio Mario Scanu
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Via P. Manzella, 4, 07100 Sassari, Italy; (A.M.S.); (M.R.M.); (G.D.); (M.C.N.); (A.P.); (P.C.-R.)
| | - Caterina Arru
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (C.A.); (C.C.); (G.P.)
| | - Maria Rosaria Muroni
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Via P. Manzella, 4, 07100 Sassari, Italy; (A.M.S.); (M.R.M.); (G.D.); (M.C.N.); (A.P.); (P.C.-R.)
| | - Vincenzo Rallo
- Institute of Genetic and Biomedical Research (IRGB), CNR, Cittadella Universitaria di Cagliari, 09042 Monserrato, Italy;
| | - Giulia Deiana
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Via P. Manzella, 4, 07100 Sassari, Italy; (A.M.S.); (M.R.M.); (G.D.); (M.C.N.); (A.P.); (P.C.-R.)
| | - Maria Chiara Ninniri
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Via P. Manzella, 4, 07100 Sassari, Italy; (A.M.S.); (M.R.M.); (G.D.); (M.C.N.); (A.P.); (P.C.-R.)
| | - Ciriaco Carru
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (C.A.); (C.C.); (G.P.)
| | - Alberto Porcu
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Via P. Manzella, 4, 07100 Sassari, Italy; (A.M.S.); (M.R.M.); (G.D.); (M.C.N.); (A.P.); (P.C.-R.)
| | - Giovanna Pira
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (C.A.); (C.C.); (G.P.)
| | - Paolo Uva
- IRCCS G. Gaslini, 16147 Genoa, Italy;
| | - Paolo Cossu-Rocca
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Via P. Manzella, 4, 07100 Sassari, Italy; (A.M.S.); (M.R.M.); (G.D.); (M.C.N.); (A.P.); (P.C.-R.)
- Department of Diagnostic Services, “Giovanni Paolo II” Hospital, ASSL Olbia-ATS Sardegna, 07026 Olbia, Italy
| | - Maria Rosaria De Miglio
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Via P. Manzella, 4, 07100 Sassari, Italy; (A.M.S.); (M.R.M.); (G.D.); (M.C.N.); (A.P.); (P.C.-R.)
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17
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Zhang W, Qu X, Zhu Z, Wang L, Qi Q, Zhou P, Wang X, Li W. Inhibition of miR-139-5p by topical JTXK gel promotes healing of Staphylococcus aureus-infected skin wounds. Cells Dev 2021; 166:203658. [PMID: 33994349 DOI: 10.1016/j.cdev.2021.203658] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 10/21/2020] [Accepted: 01/04/2021] [Indexed: 01/01/2023]
Abstract
BACKGROUND The inflammatory skin wound response is regulated by argonaute 2-bound microRNAs (Ago2-miRNAs) such as miR-139-5p, which inhibit transcription of their target mRNAs. Jiang Tang Xiao Ke (JTXK) is a traditional Chinese medicine that reduces miR-139-5p expression, suggesting that topical application of JTXK may have effects on wound healing. METHODS miR-139-/- mice and wild-type (WT) mice were employed to characterize the in vivo effects of miR-139-5p on sterile wound healing. Neutrophil migration and activation into the wound site were examined by live imaging analysis in lys-EGFP mice and myeloperoxidase/aminophenyl fluorescein assays, respectively. In silico and in vitro studies in differentiated HL60 cells were performed to identify miR-139-5p's downstream mediator(s). miR-139-/- neutrophil transplantation (with or without Eif4g2-knockdown rescue) or a topical JTXK gel preparation (with or without miR-139-5p mimic rescue) were employed to characterize the in vivo effects of miR-139-5p and JTXK, respectively, on Staphylococcus aureus (S. aureus)-infected wound healing. RESULTS miR-139-/- mice display impaired sterile wound healing but improved S. aureus-infected wound healing. Eif4g2, a protein that supports neutrophil proliferation and differentiation, was identified as a key downstream mediator of miR-139-5p. miR-139-/- mice show elevated neutrophilic activation and Eif4g2 upregulation. miR-139-/- neutrophils enhanced S. aureus-infected wound healing in an Eif4g2-dependent manner. Moreover, topical JTXK gel therapy also enhanced S. aureus-infected wound healing in a miR-139-5p-dependent manner. CONCLUSIONS miR-139-5p negatively regulates the neutrophilic response during S. aureus-infected wound healing, suggesting that JTXK or other miR-139-5p suppressants may be effective for treating infected skin wounds.
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Affiliation(s)
- Weitao Zhang
- Department of Dermatology, Affiliated Hospital of Shaanxi University of traditional Chinese Medicine, Xianyang, China.
| | - Xu Qu
- Department of Dermatology, Affiliated Hospital of Shaanxi University of traditional Chinese Medicine, Xianyang, China
| | - Zhang Zhu
- Department of Dermatology, Affiliated Hospital of Shaanxi University of traditional Chinese Medicine, Xianyang, China
| | - Liwen Wang
- Department of Dermatology, Affiliated Hospital of Shaanxi University of traditional Chinese Medicine, Xianyang, China
| | - Qian Qi
- Shaanxi University of Traditional Chinese Medicine, Xianyang, China
| | - Pengjun Zhou
- Department of Dermatology, Affiliated Hospital of Shaanxi University of traditional Chinese Medicine, Xianyang, China
| | - Xiaoli Wang
- Department of Dermatology, Affiliated Hospital of Shaanxi University of traditional Chinese Medicine, Xianyang, China
| | - Wenna Li
- Department of Dermatology, Affiliated Hospital of Shaanxi University of traditional Chinese Medicine, Xianyang, China
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18
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Catellani C, Ravegnini G, Sartori C, Angelini S, Street ME. GH and IGF System: The Regulatory Role of miRNAs and lncRNAs in Cancer. Front Endocrinol (Lausanne) 2021; 12:701246. [PMID: 34484116 PMCID: PMC8415755 DOI: 10.3389/fendo.2021.701246] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 07/13/2021] [Indexed: 12/13/2022] Open
Abstract
Growth hormone (GH) and the insulin-like growth factor (IGF) system are involved in many biological processes and have growth-promoting actions regulating cell proliferation, differentiation, apoptosis and angiogenesis. A recent chapter in epigenetics is represented by microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) which regulate gene expression. Dysregulated miRNAs and lncRNAs have been associated with several diseases including cancer. Herein we report the most recent findings concerning miRNAs and lncRNAs regulating GH and the IGF system in the context of pituitary adenomas, osteosarcoma and colorectal cancer, shedding light on new possible therapeutic targets. Pituitary adenomas are increasingly common intracranial tumors and somatotroph adenomas determine supra-physiological GH secretion and cause acromegaly. Osteosarcoma is the most frequent bone tumor in children and adolescents and was reported in adults who were treated with GH in childhood. Colorectal cancer is the third cancer in the world and has a higher prevalence in acromegalic patients.
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Affiliation(s)
- Cecilia Catellani
- Department of Mother and Child, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
- PhD Program in Clinical and Experimental Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Gloria Ravegnini
- Department of Pharmacy & Biotechnology, University of Bologna, Bologna, Italy
| | - Chiara Sartori
- Department of Mother and Child, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Sabrina Angelini
- Department of Pharmacy & Biotechnology, University of Bologna, Bologna, Italy
| | - Maria E. Street
- Department of Mother and Child, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
- *Correspondence: Maria E. Street,
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Luo YF, Wan XX, Zhao LL, Guo Z, Shen RT, Zeng PY, Wang LH, Yuan JJ, Yang WJ, Yue C, Mo ZH. MicroRNA-139-5p upregulation is associated with diabetic endothelial cell dysfunction by targeting c-jun. Aging (Albany NY) 2020; 13:1186-1211. [PMID: 33293476 PMCID: PMC7835005 DOI: 10.18632/aging.202257] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Accepted: 10/03/2020] [Indexed: 12/28/2022]
Abstract
Dysfunction of endothelial cells (ECs) and their progenitor cells is an important feature of diabetic vascular disease. MicroRNA (miR)-139-5p is involved in inhibiting the metastasis and progression of diverse malignancies. However, the role of miR-139-5p in ECs still remains unclarified. Here we demonstrated that miR-139-5p expression was elevated in endothelial colony-forming cells (ECFCs) isolated from patients with diabetes, ECs derived from the aorta of diabetic rodents, and human umbilical vein endothelial cells (HUVECs) cultured in high glucose media. MiR-139-5p mimics inhibited tube formation, migration, proliferation, and down-regulated expression of c-jun, vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF)-B, in ECFCs and HUVECs, respectively; moreover, miR-139-5p inhibitors reversed the tendency. Further, gain- and-loss function experiments and ChIP assay indicated that miR-139-5p regulate functions of ECFCs by targeting c-jun-VEGF/PDGF-B pathway. In vivo experiments (Matrigel plug assay and hindlimb ischemia model) showed that miR-139-5p downregulation further promoted ECFC-mediated angiogenesis and blood perfusion. In conclusion, diabetes-mediated high miR-139-5p expression inhibits the c-jun-VEGF/PDGF-B pathway, thus decreasing ECFCs migration, tube formation and proliferation, which subsequently reduces ECs survival. Therefore, miR-139-5p might be an important therapeutic target in the treatment of diabetic vasculopathy in the future.
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Affiliation(s)
- Yu-Fang Luo
- Department of Endocrinology, Third Xiangya Hospital of Central South University and Diabetic Foot Research Center of Central South University, Changsha 410013, Hunan Province, China
| | - Xin-Xing Wan
- Department of Endocrinology, Third Xiangya Hospital of Central South University and Diabetic Foot Research Center of Central South University, Changsha 410013, Hunan Province, China
| | - Li-Ling Zhao
- Department of Endocrinology, Third Xiangya Hospital of Central South University and Diabetic Foot Research Center of Central South University, Changsha 410013, Hunan Province, China
| | - Zi Guo
- Department of Endocrinology, Third Xiangya Hospital of Central South University and Diabetic Foot Research Center of Central South University, Changsha 410013, Hunan Province, China
| | - Rui-Ting Shen
- Key Laboratory of Hormones and Development (Ministry of Health), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300070, China
| | - Ping-Yu Zeng
- Center of Experimental Medicine, Third Xiangya Hospital of Central South University, Changsha 410013, Hunan Province, China
| | - Ling-Hao Wang
- Department of Endocrinology, Third Xiangya Hospital of Central South University and Diabetic Foot Research Center of Central South University, Changsha 410013, Hunan Province, China
| | - Jing-Jing Yuan
- Department of Endocrinology, Third Xiangya Hospital of Central South University and Diabetic Foot Research Center of Central South University, Changsha 410013, Hunan Province, China
| | - Wen-Jun Yang
- Department of Endocrinology, Third Xiangya Hospital of Central South University and Diabetic Foot Research Center of Central South University, Changsha 410013, Hunan Province, China
| | - Chun Yue
- Department of Endocrinology, Third Xiangya Hospital of Central South University and Diabetic Foot Research Center of Central South University, Changsha 410013, Hunan Province, China
| | - Zhao-Hui Mo
- Department of Endocrinology, Third Xiangya Hospital of Central South University and Diabetic Foot Research Center of Central South University, Changsha 410013, Hunan Province, China
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20
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Schaalan M, Mohamed W, Fathy S. MiRNA-200c, MiRNA-139 and ln RNA H19; new predictors of treatment response in H-pylori- induced gastric ulcer or progression to gastric cancer. Microb Pathog 2020; 149:104442. [PMID: 32795593 DOI: 10.1016/j.micpath.2020.104442] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 08/03/2020] [Accepted: 08/05/2020] [Indexed: 02/07/2023]
Abstract
Recent evidence indicates that the pathogenesis of gastric ulcer and progression to gastric cancer could be attributed to altered inflammatory/immunological response and associated differential non-coding RNAs expression signatures. However, co-expression profiling of lncRNA-miRNAs in GU/GC patients are scarcely focused on. Therefore, in the present study the expression of H19 and related miRNAs including miR-139, and miR-200 were assayed in the plasma samples of treatment responsive GU vs nonresponsive GC patients. This study is a case-control study carried out on 130 subjects recruited from the Gastrointestinal Endoscopy Unit in Al-Kasr Al-Aini Hospital, in Egypt. All recruited patients were diagnosed with H-pylori infection, 50 of them were gastric cancer patients (GC), with previous H-pylori induced gastric ulcer but were treatment non-respondent. Real-time PCR was performed to evaluate the expression level of serum non-coding RNA; miRNA-200c, miR-139, Ln RNA H19 in patients with peptic ulcer treatment non-respondent, who progressed to GC vs non-progressed gastric ulcer patients (GU) (n = 50), and compared to early diagnosed H-pylori-gastric ulcer patients (n = 30). The association between these miRNAs and the FGF-18/FGF-R signaling indicators of H-pylori-GC pathogenesis were then investigated. RESULTS: showed that the H19 level was significantly elevated while miR-139 and miR-200c expression were significantly down-regulated in GC patients, compared to GU participants (P < 0.01). The herein investigated ncRNAs are correlated to the disease duration with Ln H19 being significantly correlated with all inflammatory markers; TNF-α, INF-γ, TAC, MMP-9, and FGF18/FGFR2. A significant correlation was also observed between miRNA 200c and each of miRNA 139 and FGFR2. Moreover, ROC analysis revealed that miRNA 200c showed the highest AUC (0.906) and 81.2% sensitivity and 100% specificity. Moreover, the combined analysis of miRNA 200c/miRNA 139 revealed superior AUC (0.96) and 93% sensitivity and 100% specificity, than each separately. As for discriminative accuracy between stages III to IV of gastric cancer, LncRNA H19 showed the highest diagnostic accuracy (95.5%), specificity (100%), and sensitivity (90.9%). The current study demonstrated that the combination of serum miRNA 200c/miRNA 139 expression levels (down-regulation) could provide a new potential prognostic panel for GU predictive response and potential sequelae. In conclusion, LncRNA H19 and related miRNAs, miRNA 200c/miRNA 139, could serve as a potential diagnostic biomarker for early gastric cancer diagnosis.
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Affiliation(s)
- Mona Schaalan
- Department of Clinical Pharmacy, Clinical and Translational Research Unit, Faculty of Pharmacy, Misr International University, Cairo, Egypt.
| | - Waleed Mohamed
- Department of Internal Medicine, Kasr El Aini Teaching Hospitals, Cairo University, Cairo, Egypt.
| | - Shimaa Fathy
- Department of Clinical Pharmacy, Clinical and Translational Research Unit, Faculty of Pharmacy, Misr International University, Cairo, Egypt.
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21
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Both endogenous and exogenous miR-139-5p inhibit Fusobacterium nucleatum-related colorectal cancer development. Eur J Pharmacol 2020; 888:173459. [PMID: 32768506 DOI: 10.1016/j.ejphar.2020.173459] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 07/28/2020] [Accepted: 07/31/2020] [Indexed: 12/15/2022]
Abstract
Colorectal cancer (CRC) is one of the most common cancers worldwide. Colorectal carcinogenesis represents a heterogeneous process which influenced by diet, environmental and microbial exposures. Microbes in the gut might take up microRNAs (miRNAs) and these miRNAs might affect microbes in turn. Our previous work identified miR-139-5p as a tumor suppressor gene down-regulated in CRC. At present, the regulatory role and mechanism of miR-139-5p between Fusobacterium nucleatum and CRC are unclear. In this study, after co-incubating Fusobacterium nucleatum with CRC cells, MTT assay, colony formation assay and wound-healing assay showed that Fusobacterium nucleatum could stimulate cell proliferation and migration. After knocking down the expression of c-met in cells, western blot assay proved that knocking down c-met could weaken this stimulation. C-met is one of the target genes of miR-139-5p. Experimented with miR-139-5p overexpressed CRC cell lines, we found the same results as knocking down c-met, which means that endogenous miR-139-5p can reduce the stimulation. Next, by co-incubating the exogenous miR-139-5p mimics with Fusobacterium nucleatum, we proved that exogenous miR-139-5p could inhibit the proliferation of Fusobacterium nucleatum. After treating CRC cells with Fusobacterium nucleatum, which incubated with miR-139-5p mimics in advance, MTT assay indicated that the stimulation of Fusobacterium nucleatum was weakened. Besides, we speculated the binding site between miR-139-5p and Fusobacterium nucleatum. In sum, our study suggests a new prospect for the treatment of CRC, and the combination of Fusobacterium nucleatum and miR-139-5p could be used as a more valuable comprehensive biomarker for CRC prognosis.
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22
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Mehrgou A, Ebadollahi S, Seidi K, Ayoubi-Joshaghani MH, Ahmadieh Yazdi A, Zare P, Jaymand M, Jahanban-Esfahlan R. Roles of miRNAs in Colorectal Cancer: Therapeutic Implications and Clinical Opportunities. Adv Pharm Bull 2020; 11:233-247. [PMID: 33880345 PMCID: PMC8046386 DOI: 10.34172/apb.2021.029] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 05/03/2020] [Accepted: 07/26/2020] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most disseminated diseases across the globe engaging the digestive system. Various therapeutic methods from traditional to the state-of-the-art ones have been applied in CRC patients, however, the attempts have been unfortunate to lead to a definite cure. MiRNAs are a smart group of non-coding RNAs having the capabilities of regulating and controlling coding genes. By utilizing this stock-in-trade biomolecules, not only disease’s symptoms can be eliminated, there may also be a good chance for the complete cure of the disease in the near future. Herein, we provide a comprehensive review delineating the therapeutic relationship between miRNAs and CRC. To this, various clinical aspects of miRNAs which act as a tumor suppressor and/or an oncogene, their underlying cellular processes and clinical outcomes, and, in particular, their effects and expression level changes in patients treated with chemo- and radiotherapy are discussed. Finally, based on the results deducted from scientific research studies, therapeutic opportunities based on targeting/utilizing miRNAs in the preclinical as well as clinical settings are highlighted.
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Affiliation(s)
- Amir Mehrgou
- Department of Medical Genetics and Molecular Biology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Shima Ebadollahi
- Department of Biochemistry and Biophysics, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Khaled Seidi
- Biotechnology Research Center, Tabriz University of Medical Sciences, 9841 Tabriz, Iran
| | - Mohammad Hosein Ayoubi-Joshaghani
- Drug Applied Research Center, Tabriz University of Medical Sciences, 9841 Tabriz, Iran.,Student Research Committees, Tabriz University of Medical Sciences, 9841 Tabriz, Iran
| | | | - Peyman Zare
- Dioscuri Center of Chromatin Biology and Epigenomics, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.,Faculty of Medicine, Cardinal Stefan Wyszyński University in Warsaw, 01-938 Warsaw, Poland
| | - Mehdi Jaymand
- Nano Drug Delivery Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Rana Jahanban-Esfahlan
- Stem Cell Research Center, Tabriz University of Medical Sciences, 9841 Tabriz, Iran.,Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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23
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Zhu JH, De Mello RA, Yan QL, Wang JW, Chen Y, Ye QH, Wang ZJ, Tang HJ, Huang T. MiR-139-5p/SLC7A11 inhibits the proliferation, invasion and metastasis of pancreatic carcinoma via PI3K/Akt signaling pathway. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165747. [PMID: 32109492 DOI: 10.1016/j.bbadis.2020.165747] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Revised: 02/14/2020] [Accepted: 02/23/2020] [Indexed: 01/04/2023]
Abstract
OBJECTIVE Pancreatic carcinoma (PANC) is one of the important aggressive cancers, with deficiency in effective therapeutics. The study aimed to investigate the effects and molecular mechanism of miR-139-5p/SLC7A11 on the proliferation and metastasis of PANC. METHODS Bioinformatics was used to analyze the differentially expressed genes in the TCGA database. PANC cell lines with overexpressed miR-139-5p and Solute Carrier Family 7, Member 11 (SLC7A11) was established, and have been used to detect cell proliferation, invasion and metastasis of PANC Subsequently, bioinformatic analysis and dual luciferase reporter assay were performed to confirm that SLC7A11 was a target gene of miR-139-5p. Xenograft mice model was used to explore the functions of miR-139-5p in PANC tumorigenicity. RESULTS MiR-139-5p could regulate and affect the protein expression of P13K and Akt associated with phosphatidylinositol signaling pathway by inhibiting SLC7A11. MiR-139-5p was found to be lowly expressed in PANC tissues, while SLC7A11 was highly expressed. Low expression of miR-139-5p and high expression of SLC7A11 were positively associated with poor clinical outcomes. PANC cell proliferation, invasion and metastasis could be inhibited by miR-139-5p overexpression and be promoted by SLC7A11 overexpression. MiR-139-5p overexpression could suppress PANC tumor growth and the expressions of SLC7A11, p-PI3K, p-Akt in tumor tissues. Therefore, the inhibitory of miR-139-5p to PANC cell proliferation, invasion and metastasis was partly due to its inhibiting effect on SLC7A11 expression. CONCLUSION Our study proves that miR-139-5p/SLC7A11 has important functions on PANC, suggesting that miR-139-5p can be used as a biomarker for PANC patients.
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Affiliation(s)
- Jin-Hui Zhu
- Department of General Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
| | | | - Qiu-Liang Yan
- Department of General Surgery, Jinhua People's Hospital, Jinhua 321000, China
| | - Jian-Wei Wang
- Department of Surgical Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Yan Chen
- Department of General Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Qing-Huang Ye
- Department of General Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Zhi-Jiang Wang
- Department of General Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Hai-Jun Tang
- Department of General Surgery, Shaoxing People's Hospital, Shaoxing 312000, China.
| | - Tao Huang
- Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
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24
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Xiao F, Chen W, Yu C, Zhao G. MicroRNA-663b enhances migration and invasion by targeting adenomatous polyposis coli 2 in colorectal carcinoma cells. Oncol Lett 2020; 19:3701-3710. [PMID: 32382323 PMCID: PMC7202279 DOI: 10.3892/ol.2020.11482] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Accepted: 12/12/2019] [Indexed: 12/16/2022] Open
Abstract
Colorectal carcinoma (CRC) is one of the leading causes of cancer-associated mortality worldwide. Dysregulation of microRNA (miR)-663b has been reported in a variety of diseases. However, the specific biological function of miR-663b in CRC requires further investigation. The aim of the present study was to elucidate the role and underlying molecular mechanism of action of miR-663b in CRC. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis and western blot analysis were employed to measure the expression of miR-663b at the RNA and protein level, respectively. Flow cytometry was used to detect cell apoptosis. Cell proliferation, migration and invasion were evaluated by the Cell Counting Kit-8, wound healing and Transwell assays, respectively. A dual-luciferase reporter assay was used to validate the potential target gene of miR-663b. The expression of miR-663b was identified to be markedly upregulated in CRC cells. Ectopic miR-663b expression promoted CRC cell proliferation, migration and invasion, and inhibited apoptosis. The dual-luciferase reporter assay identified adenomatous polyposis coli 2 (APC2) as a direct target of miR-663b in CRC cells. Further investigation indicated that miR-663b was involved in CRC cell invasion through the Wnt/β-catenin pathway. Therefore, overexpression of miR-663b was able to promote CRC cell proliferation, migration and invasion by regulating the Wnt/β-catenin pathway through targeting APC2, suggesting that miR-663b may be a useful target for the diagnosis and treatment of CRC.
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Affiliation(s)
- Fenqiang Xiao
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Wangbin Chen
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Chao Yu
- Department of Medical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Gang Zhao
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
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25
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Soleimani A, Rahmani F, Saeedi N, Ghaffarian R, Khazaei M, Ferns GA, Avan A, Hassanian SM. The potential role of regulatory microRNAs of RAS/MAPK signaling pathway in the pathogenesis of colorectal cancer. J Cell Biochem 2019; 120:19245-19253. [PMID: 31512778 DOI: 10.1002/jcb.29268] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Accepted: 06/11/2019] [Indexed: 12/17/2022]
Abstract
Colorectal cancer (CRC) is the leading cause of cancer death worldwide. Dysregulation of RAS/MAPK signaling axis is frequently found in CRC patients. The RAS/MAPK axis regulates cancer cell proliferation, apoptosis, inflammation, migration, and metastasis. Oncogenic or tumor-suppressor microRNAs (miRNAs) for RAS/MAPK signaling play a key role in the pathogenesis of CRC and are considered as novel potential biomarkers for diagnosis and prognosis of human malignancies. This review summarizes the current knowledge of mechanisms of action of RAS/MAPK miRNAs in the development and progression of CRC for a better understanding and hence a better management of this disease.
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Affiliation(s)
- Atena Soleimani
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Farzad Rahmani
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Nikoo Saeedi
- Student Research Committee, Mashhad Branch, Islamic Azad University, Mashhad, Iran
| | - Rana Ghaffarian
- Student Research Committee, Mashhad Branch, Islamic Azad University, Mashhad, Iran
| | - Majid Khazaei
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medical Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Division of Medical Education, Brighton & Sussex Medical School, Brighton, Sussex, UK
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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26
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Zhu M, Zhang W, Ma J, Dai Y, Zhang Q, Liu Q, Yang B, Li G. MicroRNA-139-5p regulates chronic inflammation by suppressing nuclear factor-κB activity to inhibit cell proliferation and invasion in colorectal cancer. Exp Ther Med 2019; 18:4049-4057. [PMID: 31616518 PMCID: PMC6781828 DOI: 10.3892/etm.2019.8032] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Accepted: 08/22/2019] [Indexed: 12/12/2022] Open
Abstract
The inflammatory microenvironment, which mediates the initiation and malignant development of tumors, has been reported to be associated with microRNA (miRNA) dysregulation. In the present study, the expression of miR-139-5p was analyzed in colorectal cancer (CRC) cell lines SW480, HT29, HCT-8, LoVo and HCT116, aiming to investigate the function and mechanism of miR-139-5p in the regulation of the malignant phenotypes of CRC. miR-139-5p expression was found to be considerably downregulated in CRC cell lines compared with the human normal colon mucosal epithelial cell line NCM460. Subsequently, it was demonstrated that overexpression of miR-139-5p in colon cancer cell lines significantly suppressed the cell proliferation in vitro and in vivo. In addition, overexpression of miR-139-5p further inhibited the invasion ability of colon cancer cells in vitro, concomitantly with downregulation of key invasion-associated proteins, including matrix metalloproteinase 9 (MMP9) and MMP7. Furthermore, it was demonstrated that overexpression of miR-139-5p decreased the expression levels of inflammatory cytokines, including interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α), by suppressing nuclear factor (NF)-κB activity. Therefore, these findings collectively indicated that miR-139-5p regulated chronic inflammation by suppressing NF-κB activity in order to inhibit cell proliferation and invasion in CRC, thereby indicating a novel molecular mechanism in CRC therapy.
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Affiliation(s)
- Mingming Zhu
- Department of Abdominal Tumor Surgery, Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650118, P.R. China
| | - Wen Zhang
- Department of Abdominal Tumor Surgery, Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650118, P.R. China
| | - Jun Ma
- Department of Abdominal Tumor Surgery, Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650118, P.R. China
| | - Youguo Dai
- Department of Abdominal Tumor Surgery, Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650118, P.R. China
| | - Qi Zhang
- Department of Abdominal Tumor Surgery, Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650118, P.R. China
| | - Qin Liu
- Department of Abdominal Tumor Surgery, Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650118, P.R. China
| | - Burong Yang
- Department of Abdominal Tumor Surgery, Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650118, P.R. China
| | - Gang Li
- Department of Abdominal Tumor Surgery, Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650118, P.R. China
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Improving the anticancer effect of afatinib and microRNA by using lipid polymeric nanoparticles conjugated with dual pH-responsive and targeting peptides. J Nanobiotechnology 2019; 17:89. [PMID: 31426807 PMCID: PMC6699136 DOI: 10.1186/s12951-019-0519-6] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Accepted: 07/30/2019] [Indexed: 02/06/2023] Open
Abstract
Background The emergence of resistance to chemotherapy or target therapy, tumor metastasis, and systemic toxicity caused by available anticancer drugs hamper the successful colorectal cancer (CRC) treatment. The rise in epidermal growth factor receptor (EGFR; human epidermal growth factor receptor 1; HER1) expression and enhanced phosphorylation of HER2 and HER3 are associated with tumor resistance, metastasis and invasion, thus resulting in poor outcome of anti-CRC therapy. The use of afatinib, a pan-HER inhibitor, is a potential therapeutic approach for resistant CRC. Additionally, miR-139 has been reported to be negatively correlated with chemoresistance, metastasis, and epithelial–mesenchymal transition (EMT) of CRC. Hence, we develop a nanoparticle formulation consisting of a polymer core to carry afatinib or miR-139, which is surrounded by lipids modified with a targeting ligand and a pH-sensitive penetrating peptide to improve the anticancer effect of cargos against CRC cells. Results Our findings show that this formulation displays a spherical shape with core/shell structure, homogeneous particle size distribution and negative zeta potential. The prepared formulations demonstrate a pH-sensitive release profile and an enhanced uptake of cargos into human colorectal adenocarcinoma Caco-2 cells in response to the acidic pH. This nanoparticle formulation incorporating afatinib and miR-139 exhibits low toxicity to normal cells but shows a better inhibitory effect on Caco-2 cells than other formulations. Moreover, the encapsulation of afatinib and miR-139 in peptide-modified nanoparticles remarkably induces apoptosis and inhibits migration and resistance of Caco-2 cells via suppression of pan-HER tyrosine kinase/multidrug resistance/metastasis pathways. Conclusion This study proposes a multifunctional nanoparticle formulation for targeted modulation of apoptosis/EGFR/HER/EMT/resistance/progression pathways to increase the sensitivity of colon cancer cells to afatinib. Electronic supplementary material The online version of this article (10.1186/s12951-019-0519-6) contains supplementary material, which is available to authorized users.
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28
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Min L, Zhu S, Chen L, Liu X, Wei R, Zhao L, Yang Y, Zhang Z, Kong G, Li P, Zhang S. Evaluation of circulating small extracellular vesicles derived miRNAs as biomarkers of early colon cancer: a comparison with plasma total miRNAs. J Extracell Vesicles 2019; 8:1643670. [PMID: 31448068 PMCID: PMC6691764 DOI: 10.1080/20013078.2019.1643670] [Citation(s) in RCA: 172] [Impact Index Per Article: 28.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 07/10/2019] [Accepted: 07/11/2019] [Indexed: 02/06/2023] Open
Abstract
Early diagnosis of colon cancer (CC) is clinically important, as it can significantly improve patients’ survival rate and quality of life. Although the potential role for small extracellular vesicles (sEVs) in early detection of many diseases has been repeatedly mentioned, systematic screening of plasma sEVs derived early CC specific biomarkers has not yet been reported. In this work, plasma sEVs enriched fractions were derived from 15 early-stage (TisN0M0) CC patients and 10 normal controls (NC). RNA sequencing identified a total number of 95 sEVs enriched fraction derived miRNAs with differential expression between CC and NC, most of which (60/95) was in well accordance with tissue results in the Cancer Genome Atlas (TCGA) dataset. Among those miRNAs, we selected let-7b-3p, miR-139-3p, miR-145-3p, and miR-150-3p for further validation in an independent cohort consisting of 134 participants (58 CC and 76 NC). In the validation cohort, the AUC of 4 individual miRNAs ranged from 0.680 to 0.792. A logistic model combining two miRNAs (i.e. let-7b-3p and miR-145-3p) achieved an AUC of 0.901. Adding the 3rd miRNA into this model can further increase the AUC to 0.927. Side by side comparison revealed that sEVs miRNA profile outperformed cell-free plasma miRNA in the diagnosis of early CC. In conclusion, we suggested that circulating sEVs enriched fractions have a distinct miRNA profile in CC patients, and sEVs derived miRNA could be used as a promising biomarker to detect CC at an early stage.
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Affiliation(s)
- Li Min
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, P. R. China
| | - Shengtao Zhu
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, P. R. China
| | - Lei Chen
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, P. R. China
| | - Xiang Liu
- Department of R&D, Echo Biotech Co., Ltd, Beijing, P. R. China
| | - Rui Wei
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, P. R. China
| | - Libo Zhao
- Department of R&D, Echo Biotech Co., Ltd, Beijing, P. R. China
| | - Yuqing Yang
- Department of R&D, Echo Biotech Co., Ltd, Beijing, P. R. China
| | - Zheng Zhang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, P. R. China
| | - Guanyi Kong
- Department of R&D, Echo Biotech Co., Ltd, Beijing, P. R. China
| | - Peng Li
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, P. R. China
| | - Shutian Zhang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, P. R. China
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29
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Su C, Huang DP, Liu JW, Liu WY, Cao YO. miR-27a-3p regulates proliferation and apoptosis of colon cancer cells by potentially targeting BTG1. Oncol Lett 2019; 18:2825-2834. [PMID: 31452761 PMCID: PMC6676402 DOI: 10.3892/ol.2019.10629] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Accepted: 05/13/2019] [Indexed: 01/16/2023] Open
Abstract
microRNA (miR/miRNA)-27a-3p has been reported to be abnormally expressed in various types of cancer, including colorectal cancer (CRC). B-cell translocation gene 1 (BTG1) has also been implicated with CRC. However, the association between miR-27a-3p and BTG1 in CRC, to the best of our knowledge, has not been investigated. In order to assess whether miR-27a-3p is associated with CRC, reverse transcription-quantitative PCR was performed on 20 paired CRC and paracancerous tissues for miRNA analysis. For the screening and validation of miR-27a-3p expression in colon cancer, several colon cancer cell lines (HCT-116, HCT8, SW480, HT29, LOVO and Caco2) and the normal colorectal epithelial cell line NCM460 were examined. The highest expression levels of miR-27a-3p were detected in the HCT-116, which was selected for further experimentation. The HCT-116 cells were divided into control, miR-27a-3p mimic and inhibitor groups, and cell proliferation was tested using an MTT assay. Additionally, miR-27a-3p inhibitor/mimic or BTG1 plasmid were transfected into the HCT-116 cells, and flow cytometry was performed to analyze cell cycle distributions. TUNEL analysis was performed to detect apoptosis. Protein levels of factors in the downstream signaling pathway mediated by miR-27a-3p [ERK/mitogen-activated extracellular signal-regulated kinase (MEK)] were detected. miR-27a-3p was revealed to be overexpressed in human CRC tissues and colon cancer cell lines. Knockdown of miR-27a-3p suppressed proliferation of HCT-116 cells and apoptosis was increased. It further markedly upregulated expression levels of BTG1 and inhibited activation of proteins of the ERK/MEK signaling pathway. In addition, overexpression of BTG1 in HCT-116 cells triggered G1/S phase cell cycle arrest and increased apoptosis via the ERK/MEK signaling pathway. In conclusion, the present study demonstrated that the effects of miR-27a-3p on colon cancer cell proliferation and apoptosis were similar to those of the tumor suppressor gene BTG1. The miR-27a-3p/BTG1 axis may have potential implications for diagnostic and therapeutic approaches in CRC.
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Affiliation(s)
- Chang Su
- Department of Surgery, Minhang Branch, Zhongshan Hospital, Fudan University, Shanghai 201199, P.R. China
| | - Dong-Ping Huang
- Department of Surgery, People's Hospital of Putuo District, Shanghai 200060, P.R. China
| | - Jian-Wen Liu
- Department of Molecular and Cellular Pharmacology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, P.R. China
| | - Wei-Yan Liu
- Department of Surgery, Minhang Branch, Zhongshan Hospital, Fudan University, Shanghai 201199, P.R. China
| | - Yi-Ou Cao
- Department of Surgery, Minhang Branch, Zhongshan Hospital, Fudan University, Shanghai 201199, P.R. China
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30
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Hu X, Zheng W, Luo Y, Ou X, Song L, Zhang S, He T, Guo Z, Zhu J, Shi H, Huang W, Yu R. Arca subcrenata Polypeptides Inhibit Human Colorectal Cancer HT-29 Cells Growth via Suppression of IGF-1R/Akt/mTOR Signaling and ATP Production. Nutr Cancer 2019; 72:260-272. [PMID: 31295033 DOI: 10.1080/01635581.2019.1625935] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Arca subcrenata Lischke, widely scattering offshore at neritic regions, is very popular on dining table due to its edible and medical functional meatball. This study aims to investigate the suppression of a polypeptide fraction from A. subcrenata (PAS) on human colorectal cancer HT-29 cells, and its underlying mechanism. The results showed that PAS inhibited the growth of HT-29 cells with an IC50 value of 117 μg/ml after 48 h treatment, and significantly suppressed the tumor growth in nude mice bearing-xenografted HT-29 cells at the dosage of 63 mg/kg, with little influence on normal colon cells and normal colonic mucosa. PAS was then inspiringly found to induce apoptosis and G2/M phase arrest in HT-29 cells. The effect mechanism was involved in the inhibition of IGF-1/IGF-1R signaling activation, which was responsible for inactivating downstream Akt/mTOR pathway. Immunofluorescence assay also showed that PAS could reduce phosphorylation of IGF-1R (Tyr1165/1166). IGF-1, an IGF-1R activator, could reverse the suppression of PAS on IGF-1R phosphorylation. Furthermore, PAS significantly inhibited ATP production of HT-29 cells both in vitro and in vivo. Our results provide positive evidence that A. subcrenata has the potential to be a candidate for the treatment of colorectal cancer.
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Affiliation(s)
- Xianjing Hu
- Biotechnological Institute of Chinese Materia Medical, Jinan University, Guangzhou, China.,Department of Pharmacology, College of Pharmacy, Jinan University, Guangzhou, China
| | - Weiming Zheng
- Department of Pharmacology, College of Pharmacy, Jinan University, Guangzhou, China
| | - Yuanyuan Luo
- Department of Pharmacology, College of Pharmacy, Jinan University, Guangzhou, China
| | - Xiaozheng Ou
- Department of Pharmacology, College of Pharmacy, Jinan University, Guangzhou, China
| | - Liyan Song
- Department of Pharmacology, College of Pharmacy, Jinan University, Guangzhou, China
| | - Sirui Zhang
- Department of Pharmacology, College of Pharmacy, Jinan University, Guangzhou, China
| | - Tingsha He
- Department of Pharmacology, College of Pharmacy, Jinan University, Guangzhou, China
| | - Zhongyi Guo
- Department of Pharmacology, College of Pharmacy, Jinan University, Guangzhou, China
| | - Jianhua Zhu
- Biotechnological Institute of Chinese Materia Medical, Jinan University, Guangzhou, China
| | - Hui Shi
- Biotechnological Institute of Chinese Materia Medical, Jinan University, Guangzhou, China
| | - Weijuan Huang
- Department of Pharmacology, College of Pharmacy, Jinan University, Guangzhou, China
| | - Rongmin Yu
- Biotechnological Institute of Chinese Materia Medical, Jinan University, Guangzhou, China.,Department of Pharmacology, College of Pharmacy, Jinan University, Guangzhou, China
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31
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Wu G, Ju X, Wang Y, Li Z, Gan X. Up-regulation of SNHG6 activates SERPINH1 expression by competitive binding to miR-139-5p to promote hepatocellular carcinoma progression. Cell Cycle 2019; 18:1849-1867. [PMID: 31258024 DOI: 10.1080/15384101.2019.1629772] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
We aimed to assess the roles of small nucleolar RNA host gene 6 (SNHG6) in hepatocellular carcinoma (HCC) progression, and establish the lncRNA-miRNA-mRNA regulation mechanism for HCC therapy. SNHG6 is one of the host genes in small nucleolar RNAs (snoRNAs), which make a difference in the development of human cancers. SERPINH1 is a gene encoding a member of the serpin superfamily of serine proteinase inhibitors with miRNA predicted by TargetScan and DIANA Tools. SNHG6, serpin family H member 1 (SERPINH1) and miR-139-5p expression levels in HCC tissues and cells were determined by quantitative real-time PCR (qRT-PCR). Migration and invasion of HCC cells were measured by transwell assay. Cell cycle analysis was determined by using flow cytometry. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay and colony formation assay were performed for cell viability analysis. The expression of SERPINH1 was detected by qRT-PCR and western blot. Dual-luciferase reporter gene assay was conducted to identify the targeted relationship between miR-139-5p and SNHG6, as well as SERPINH1 and miR-139-5p. The positive regulation between SNHG6 and SERPINH1 was demonstrated in this study. In contrast, miR-139-5p was significantly down-regulated in HCC cells, the inhibition of miR-139-5p promotes the proliferation of HCC cells, and accelerated the cell cycle of HCC cells. Our study demonstrated the co-expression of SNHG6 and SERPINH1 in HCC cells for the first time, which revealed that SNHG6 could serve as a novel oncogene for the HCC therapy by its regulation.
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Affiliation(s)
- Gang Wu
- a Department of Hepatobiliary Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China , Chengdu , Sichuan , China
| | - Xueming Ju
- b Department of Ultrasound, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China , Chengdu , Sichuan , China
| | - Youyu Wang
- c Department of Thoracic Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China , Chengdu , Sichuan , China
| | - Zhixi Li
- d Department of Pediatric Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China , Chengdu , Sichuan , China
| | - Xianfeng Gan
- a Department of Hepatobiliary Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China , Chengdu , Sichuan , China
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32
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Ma X, Liu J, Li J, Li Y, Le VM, Li S, Liang X, Liu L, Liu J. miR-139-5p reverses stemness maintenance and metastasis of colon cancer stem-like cells by targeting E2-2. J Cell Physiol 2019; 234:22703-22718. [PMID: 31120140 DOI: 10.1002/jcp.28836] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 04/30/2019] [Accepted: 05/01/2019] [Indexed: 12/20/2022]
Abstract
Colon cancer stem cells (CCSCs) stand for a critical subpopulation of colon cancer cells that possess self-renewal and multilineage differentiation potentials and drive tumorigenicity. Due to their impact on treatment tolerance, CCSCs have been a hot research topic in the past few years. We have previously reported that miR-139-5p is a vital tumor repressive noncoding RNA whose level decreases in the clinical colon cancer samples with the increase of tumor malignancy. This research discovered that miR-139-5p targets the Wnt/β-catenin/TCF7L2 downstream effector E2-2 in CCSCs. E2-2 is a pivot molecule in the negative feedback loop of miR-139-5p/Wnt/β-catenin/TCF7L2. Its small interfering RNA reverses the stemness maintenance and epithelial-mesenchymal transition of colon cancer CSCs. This study provides a theoretical foundation for the clinical diagnosis and medical treatment of recurrent or metastatic colon cancer with miR-139-5p and its target E2-2.
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Affiliation(s)
- Xiaoying Ma
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, People's Republic of China
| | - Jiajun Liu
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, People's Republic of China
| | - Jiyu Li
- Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Yueqi Li
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, People's Republic of China
| | - Van Minh Le
- Research Center of Ginseng and Medicinal Materials, National Institute of Medicinal Materials, Ho Chi Minh City, Vietnam
| | - Shaoyu Li
- Department of Clinical Laboratory, The Third Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People's Republic of China
| | - Xin Liang
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, People's Republic of China
| | - Lingshuang Liu
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China
| | - Jianwen Liu
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, People's Republic of China
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33
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Fan L, Wu Y, Wang J, He J, Han X. Sevoflurane inhibits the migration and invasion of colorectal cancer cells through regulating ERK/MMP-9 pathway by up-regulating miR-203. Eur J Pharmacol 2019; 850:43-52. [PMID: 30685432 DOI: 10.1016/j.ejphar.2019.01.025] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 01/18/2019] [Accepted: 01/23/2019] [Indexed: 02/08/2023]
Abstract
Surgery resection is the primary treatment for colorectal cancer (CRC) patients with the risk of cancer dissemination and metastasis. Sevoflurane is one inhalational anesthesia which regulates migration and invasion in varying cancers. However, the effect of sevoflurane on CRC cells and its mechanism remain poorly understood. In this study, SW620 and HCT116 cells were treated with different concentrations of sevoflurane for 6 h in vitro. We measured the effect of sevoflurane on cell survival, migration and invasion by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide or trans-well assays. Moreover, we explored the interaction between sevoflurane and miR-203 and Roundabout1 (Robo1) as well as the extracellular signal-regulated kinase (ERK) and matrix metalloproteinase-9 (MMP-9) pathway. Results showed that sevoflurane inhibited cell migration and invasion in SW620 and HCT116 cells in a concentration dependent manner. Moreover, different concentrations of sevoflurane suppressed the phosphorylation of ERK. miR-203 expression was impaired while sevoflurane reversed the expression of miR-203 in CRC cells. In addition, inhibition of miR-203 attenuated the inhibitory effect of sevoflurane on cell migration, invasion and phosphorylated ERK level. Notably, MMP-9, as a downstream of ERK, was involved in sevoflurane-mediated processes in CRC cells. Besides, Robo1 was indicated as a target of miR-203 and inhibited by sevoflurane treatment. These results indicated that sevoflurane suppressed cell migration and invasion through regulating ERK/MMP-9 pathway via miR-203/Robo1 in CRC cells, indicating important clinical implications for anesthetic agents to prevent metastasis in CRC.
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Affiliation(s)
- Lihua Fan
- Department of Anesthesiology, Wenzhou Medical University, The Sixth Affiliated Hospital, Lishui, Zhejiang 323000, China.
| | - Yini Wu
- Department of Anesthesiology, Wenzhou Medical University, The Sixth Affiliated Hospital, Lishui, Zhejiang 323000, China
| | - Jianping Wang
- Department of Anorectal Surgery, Wenzhou Medical University, The Fifth Affiliated Hospital, Lishui, Zhejiang 323000, China.
| | - Jiaqun He
- Department of Anesthesiology, Wenzhou Medical University, The Sixth Affiliated Hospital, Lishui, Zhejiang 323000, China
| | - Xin Han
- Department of Anesthesiology, Wenzhou Medical University, The Sixth Affiliated Hospital, Lishui, Zhejiang 323000, China
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34
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Yan M, Wang J, Ren Y, Li L, He W, Zhang Y, Liu T, Li Z. Over-expression of FSIP1 promotes breast cancer progression and confers resistance to docetaxel via MRP1 stabilization. Cell Death Dis 2019; 10:204. [PMID: 30814489 PMCID: PMC6393503 DOI: 10.1038/s41419-018-1248-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Revised: 10/24/2018] [Accepted: 10/25/2018] [Indexed: 12/19/2022]
Abstract
Fibrous sheath-interacting protein 1 (FSIP1) functions centrally in breast carcinogenesis and progression, although its exact role remains to be clarified. Therefore, we sought to establish a correlation between the clinico-pathological features of breast cancer and FSIP1 expression in breast cancer tissues, as well as to validate its role in tumor progression and chemo-resistance. We analyzed FSIP1 expression in the breast cancer and para-tumor tissues by immunohistochemistry. We performed MTT, Caspase-Glo 3/7 Assay, Annexin V staining, wound healing and trans-well assays to evaluate cellular apoptosis, proliferation, migration and invasion in FSIP1 knockout and wild-type breast cancer cell lines. Additionally, we examined the effects of FSIP1 on docetaxel sensitivity in a nude mice model transplanted with control or FSIP1 knockout breast cancer cells, and also evaluate its role in tumor metastasis. FSIP1 and MRP1 interaction was determined by co-immunoprecipitation and mass spectrometry. We found that breast cancer cells and tissues consistently demonstrated elevated FSIP1 expressions, which correlated with poor overall survival. Notably, patients with high FSIP1 expression in their tumors undergoing docetaxel neoadjuvant chemotherapy had shorter disease-free survival. FSIP1 knockout in breast cancer cells significantly increased their sensitivity to docetaxel both in vitro and in vivo. Mechanistically, FSIP1 bound to the multidrug resistance protein 1 (MRP1) and stabilized it, and knocking out FSIP1 decreased MRP1 expression and increased cellular docetaxel accumulation. In sum, FSIP1 promotes breast carcinogenesis and mediates docetaxel resistance, and may serve as a novel target in the development of breast cancer therapies.
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Affiliation(s)
- Meisi Yan
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150000, China.,Department of Pathology, Harbin Medical University, Harbin, 150081, China.,Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, TX, 77030, Anderson, USA
| | - Jinsong Wang
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150000, China
| | - Yanlv Ren
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150000, China
| | - Lin Li
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150000, China
| | - Weidan He
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150000, China
| | - Ying Zhang
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150000, China
| | - Tong Liu
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150000, China. .,Department of Pathology, The University of Texas MD Anderson Cancer Center, TX, 77030, Anderson, USA.
| | - Zhigao Li
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150000, China.
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35
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Circular RNA circBACH2 plays a role in papillary thyroid carcinoma by sponging miR-139-5p and regulating LMO4 expression. Cell Death Dis 2019; 10:184. [PMID: 30796202 PMCID: PMC6385235 DOI: 10.1038/s41419-019-1439-y] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 01/19/2019] [Accepted: 02/04/2019] [Indexed: 12/16/2022]
Abstract
Circular RNAs (circRNAs) are a class of non-coding RNAs that are broadly expressed in various biological cells and function in regulating gene expression. They are structurally stable and tissue-specific. However, the function of human circRNAs and the role of circRNAs in papillary thyroid carcinoma (PTC) remain to be determined. Herein, the function of circRNA circBACH2 was investigated in human PTC cells. First, we detected the expression of circBACH2 in PTC tissues and PTC cell lines by RT-PCR. FISH was used to confirm the subcellular localization of circBACH2. A luciferase reporter assay and AGO2-RIP was used to confirm the relationship between circBACH2 and miR-139-5p. PTC cells were stably transfected with siRNA against circBACH2 and cell proliferation, migration and invasion were detected to evaluate the effect of circBACH2 in PTC, while tumorigenesis was assayed in nude mice. We found that circBACH2 was highly expressed in PTC tissues and PTC cell lines. Mechanistically, we confirmed that circBACH2 could directly bind to miR-139-5p and relieve suppression of the target LMO4. Functionally, we found that inhibiting circBACH2 expression decreased cell proliferation, migration, and invasion. Finally, down-regulating circBACH2 suppressed the growth of PTC xenografts in nude mice. Our findings indicate that circBACH2 acts as a novel oncogenic RNA that sponges miR-139-5p and can be used as a tumor biomarker of PTC. What's more, these results revealed that the circBACH2/miR-139-5p/LMO4 axis could be targeted as a potential treatment strategy for PTC.
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36
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Li Y, Chen Y, Qiu C, Ma X, Lei K, Cai G, Liang X, Liu J. 17-allylamino-17-demethoxygeldanamycin impeded chemotherapy through antioxidant activation via reducing reactive oxygen species-induced cell death. J Cell Biochem 2019; 120:1560-1576. [PMID: 30378153 DOI: 10.1002/jcb.27397] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Accepted: 07/11/2018] [Indexed: 01/24/2023]
Abstract
Hyperthermia enhances the anticancer effects of thymidylate synthase (TYMS) inhibitors (raltitrexed, RTX) and improves the precise biochemical mechanisms partially through enhancement of intracellular drug absorption. Recent research focuses on the potential anticancer drug target Heat Shock Protein 90 (HSP90), which could increase the sensitivity of cancer cells to TYMS inhibitors; however, with different HSP90 inhibitors, several research studies finally showed a poor efficacy in preclinical or clinical research. Here, we showed that 17-allylamino-17-demethoxygeldanamycin (17-AAG, HSP90 inhibitor) affects the efficacy of chemotherapy through antioxidant activation-induced resistance. In this study, we found that RTX, alone or in combination with hyperthermia, triggers reactive oxygen species (ROS) exposure and thus induces cell death. Also, the addition of hyperthermia showed more ROS exposure and function. The pharmacologic inhibition of HSP90 reversed the effects of chemotherapeutical treatments, while the overexpression of HSP90 showed no relation with these effects, which demonstrated that dysregulation of HSP90 might have a significant impact on chemotherapeutic treatments. The addition of 17-AAG increased the activation of antioxidant with increased antioxidant enzymes, thus affecting the RTX efficacy.
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Affiliation(s)
- Yueqi Li
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
| | - Yiyang Chen
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
| | - Cen Qiu
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
| | - Xiaoying Ma
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
| | - Kecheng Lei
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
| | - Guoxiang Cai
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xin Liang
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
| | - Jianwen Liu
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
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37
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Zhang P, Yin J, Yuan L, Wang Q, Du X, Dong R, Wang C, Bai Q, Ji L, Zhang G, Lu J. MicroRNA-139 suppresses hepatocellular carcinoma cell proliferation and migration by directly targeting Topoisomerase I. Oncol Lett 2019; 17:1903-1913. [PMID: 30675254 DOI: 10.3892/ol.2018.9746] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 02/01/2018] [Indexed: 12/21/2022] Open
Abstract
microRNAs (miRNAs) have been determined to be associated with cancer progression and metastasis. Mir-139 is located on 11q13.4 and exhibits anti-oncogenic and anti-metastatic activity in human cancers. It is downregulated in various malignant tumor types. In the present study, the potential functions and targets of miR-139 in hepatocellular carcinoma (HCC) were explored. Using a combinational analysis of four miRNA target prediction tools and biological experiments, it was determined that Topoisomerase I (TOP1) is a direct target of miR-139 in HCC. Several traditional topoisomerase inhibitors have demonstrated anticancer activity, but their side effects outnumbered their anticancer potential. The present study determined that overexpression of miR-139 significantly inhibits HCC cell proliferation (P<0.05) and migration (P<0.05), which is largely due to TOP1 downregulation. The present study indicated that miR-139 exerts a tumor-suppressive effect during hepatocarcinogenesis via the suppression of expression of TOP1; therefore, miR-139 is a promising target for the treatment of HCC.
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Affiliation(s)
- Pengfei Zhang
- Department of General Surgery, Tangdu Hospital of The Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China
| | - Jikai Yin
- Department of General Surgery, Tangdu Hospital of The Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China
| | - Lijuan Yuan
- Department of General Surgery, Tangdu Hospital of The Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China
| | - Qing Wang
- Department of General Surgery, Tangdu Hospital of The Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China
| | - Xilin Du
- Department of General Surgery, Tangdu Hospital of The Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China
| | - Rui Dong
- Department of General Surgery, Tangdu Hospital of The Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China
| | - Chengguo Wang
- Department of General Surgery, Tangdu Hospital of The Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China
| | - Qiangshan Bai
- Department of General Surgery, Tangdu Hospital of The Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China
| | - Ling Ji
- Department of Orthopedics, Tangdu Hospital of The Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China
| | - Guizhi Zhang
- Department of Liver Disease, The Third People's Hospital, Linfen, Shanxi 041000, P.R. China
| | - Jianguo Lu
- Department of General Surgery, Tangdu Hospital of The Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China
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38
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MiR-139 in digestive system tumor diagnosis and detection: Bioinformatics and meta-analysis. Clin Chim Acta 2018; 485:33-41. [DOI: 10.1016/j.cca.2018.06.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Revised: 06/02/2018] [Accepted: 06/04/2018] [Indexed: 12/18/2022]
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39
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Noruzi S, Azizian M, Mohammadi R, Hosseini SA, Rashidi B, Mohamadi Y, Nesaei A, Seiri P, Sahebkar A, Salarinia R, Aghdam AM, Mirzaei H. Micro-RNAs as critical regulators of matrix metalloproteinases in cancer. J Cell Biochem 2018; 119:8694-8712. [PMID: 30132957 DOI: 10.1002/jcb.27182] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2018] [Accepted: 05/24/2018] [Indexed: 12/25/2022]
Abstract
Metastasis is known to be one of the important factors associated with cancer-related deaths worldwide. Several cellular and molecular targets are involved in the metastasis process. Among these targets, matrix metalloproteinases (MMPs) play central roles in promoting cancer metastasis. MMPs could contribute toward tumor growth, angiogenesis, migration, and invasion via degradation of the extracellular matrix and activation of pre-pro-growth factors. Therefore, identification of various cellular and molecular pathways that affect MMPs could contribute toward a better understanding of the metastatic pathways involved in various tumors. Micro-RNAs are important targets that could affect MMPs. Multiple lines of evidence have indicated that deregulation of various micro-RNAs, including miR-9, Let-7, miR-10b, and miR-15b, affects metastasis of tumor cells via targeting MMPs.
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Affiliation(s)
- Somaye Noruzi
- Department of Medical Biotechnology and Molecular Sciences, School of Medicine, North Khorasan University of Medical Sciences, Bojnourd, Iran
| | - Mitra Azizian
- Department of Clinical Biochemistry, Ftabaculty of Medicine, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Rezvan Mohammadi
- Department of Medical Biotechnology and Molecular Sciences, School of Medicine, North Khorasan University of Medical Sciences, Bojnourd, Iran
| | - Seyede Atefe Hosseini
- Department of Medical Biotechnology and Molecular Sciences, School of Medicine, North Khorasan University of Medical Sciences, Bojnourd, Iran
| | - Bahman Rashidi
- Department of Anatomical Sciences, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Yousef Mohamadi
- Department of Anatomy, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Department of Anatomy, Faculty of medicine, Qom University of Medical Sciences, Qom, Iran
| | - Abolfazl Nesaei
- Department of Basic Sciences, Faculty of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Parvaneh Seiri
- Department of Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.,Biotechnology Research Center, Institute of Pharmaceutical Technology, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Reza Salarinia
- Department of Medical Biotechnology and Molecular Sciences, School of Medicine, North Khorasan University of Medical Sciences, Bojnourd, Iran
| | - Arad Mobasher Aghdam
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamed Mirzaei
- Department of Biomaterials, Tissue Engineering and Nanotechnology, School of Advanced Technologies in Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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40
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Li Z, Pan W, Shen Y, Chen Z, Zhang L, Zhang Y, Luo Q, Ying X. IGF1/IGF1R and microRNA let-7e down-regulate each other and modulate proliferation and migration of colorectal cancer cells. Cell Cycle 2018; 17:1212-1219. [PMID: 29886785 DOI: 10.1080/15384101.2018.1469873] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
MicroRNA let-7 has been reported to be down-regulated in several human cancers and is now characterized as a tumor suppressor. IGF1R is over-expressed in many cancers and IGF1/IGF1R pathway is attractive target for anticancer therapy. However, the crosstalk between let-7 and IGF1/IGF1R are largely unknown. The present study showed IGF1R were significantly over-expressed in colorectal cancer tissues compared with adjacent normal tissues through immunohistochemical analysis. qRT-PCR results showed that let-7a, let-7b and let-7e were down-regulated in colorectal cancer tissues. Bioinformatics analysis revealed that both IGF1 and IGF1R mRNA are potential targets for let-7 miRNA family. Ectopic transfection of let-7e led to a significant reduction in IGF1R at protein level and their downstream Akt inhibition, as well as a reduction in cell proliferation, migration and invasion in colorectal cancer cells, while inhibition of let-7e enhanced the expression of IGF1R. On the other hand, IGF1 stimulation can significantly down-regulate the expression of let-7e in colorectal cancer cells. Taken together, our findings identify a negative feedback regulation between let-7e and IGF1/IGF1R, and suggest that let-7e could be used in IGF1R-targeted therapeutics in anticancer therapy. ABBREVIATIONS IGF1: insulin-like growth factor 1; IGF1R: IGF1 receptor; miRNA: microRNA; CRC: colorectal cancer; EGFR: epidermal growth factor receptor; HRP: horseradish peroxidase; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide; p-Akt: phospho-Akt; PI3K: phosphoinositide 3-kinase; qRT-PCR: quantitative reverse transcription-PCR; IHC: immunohistochemical; siRNA: small interfering RNA; 3'-UTR: 3'-untranslated region.
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Affiliation(s)
- Zhenjun Li
- a Department of Colorectal Surgery , Shaoxing People's Hospital , Shaoxing , China
| | - Weihuo Pan
- a Department of Colorectal Surgery , Shaoxing People's Hospital , Shaoxing , China
| | - Yi Shen
- a Department of Colorectal Surgery , Shaoxing People's Hospital , Shaoxing , China
| | - Zhiliang Chen
- a Department of Colorectal Surgery , Shaoxing People's Hospital , Shaoxing , China
| | - Lihua Zhang
- a Department of Colorectal Surgery , Shaoxing People's Hospital , Shaoxing , China
| | - Yuping Zhang
- a Department of Colorectal Surgery , Shaoxing People's Hospital , Shaoxing , China
| | - Quan Luo
- b Digestive Endoscopy Center , Shaoxing People's Hospital , Shaoxing , China
| | - Xiaojiang Ying
- a Department of Colorectal Surgery , Shaoxing People's Hospital , Shaoxing , China
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41
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Bai F, Zhou H, Ma M, Guan C, Lyu J, Meng QH. A novel RNA sequencing-based miRNA signature predicts with recurrence and outcome of hepatocellular carcinoma. Mol Oncol 2018; 12:1125-1137. [PMID: 29719937 PMCID: PMC6026871 DOI: 10.1002/1878-0261.12315] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Accepted: 04/18/2018] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common type of cancer and the second leading cause of cancer-related deaths worldwide. Given that the rate of HCC recurrence 5 years after liver resection is as high as 70%, patient with HCC typically has a poor outcome. A biomarker or set of biomarkers that could predict disease recurrence would have a substantial clinical impact, allowing earlier detection of recurrence and more effective treatment. With the aim of identifying a new microRNA (miRNA) signature associated with HCC recurrence, we analyzed data on 306 patients with HCC for whom both miRNA expression profiles and complete clinical information were available from The Cancer Genome Atlas database. Through this analysis, we identified a six-miRNA signature that could effectively predict patients' recurrence risk; the high-risk and low-risk groups had significantly different recurrence-free survival rates. Time-dependent receiver operating characteristic analysis indicated that this signature had a good predictive performance. Multivariable Cox regression and stratified analyses demonstrated that the six-miRNA signature was independent of other clinical features. Functional enrichment analysis of the gene targets of the six prognostic miRNA indicated enrichment mainly in cancer-related pathways and important cell biological processes. Our results support use of this six-miRNA signature as an independent factor for predicting recurrence and outcome of patients with HCC.
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Affiliation(s)
- Fumao Bai
- Key Laboratory of Laboratory Medicine, Ministry of Education of China, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, China
| | - Huaibin Zhou
- Key Laboratory of Laboratory Medicine, Ministry of Education of China, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, China
| | - Mengni Ma
- Key Laboratory of Laboratory Medicine, Ministry of Education of China, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, China
| | - Chen Guan
- Key Laboratory of Laboratory Medicine, Ministry of Education of China, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, China
| | - Jianxin Lyu
- Key Laboratory of Laboratory Medicine, Ministry of Education of China, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, China
| | - Qing H Meng
- Department of Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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42
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Jeon SH, Yoo JK, Kim CM, Lim ES, Lee SJ, Lee JM, Oh SH, Kim JK. The novel hsa-miR-12528 regulates tumourigenesis and metastasis through hypo-phosphorylation of AKT cascade by targeting IGF-1R in human lung cancer. Cell Death Dis 2018; 9:493. [PMID: 29712908 PMCID: PMC5928042 DOI: 10.1038/s41419-018-0535-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Revised: 01/31/2018] [Accepted: 02/19/2018] [Indexed: 01/01/2023]
Abstract
Lung cancer cases are increasing yearly; however, few novel therapeutic strategies for treating this disease have been developed. Here the dysregulation between microRNAs and oncogenes or tumour-suppressor genes forms a close connection-loop to the development or progression in human lung carcinogenesis. That is, the relationship between microRNAs and carcinogenic mechanism may find the critical clue to improve the treatment efficacy. Accordingly, we identified and characterised a novel microRNA, hsa-miR-12528, in A549 cells. The miR-12528 expression was aberrantly downregulated in cancer cell lines and in the patient tissues derived from human non-small cell lung cancer. In addition, we found that miR-12528 post-transcriptionally controls the translation of the insulin-like growth factor 1 receptor (IGF-1R) gene by directly targeting the 3′-untranslated region of IGF-1R mRNA. Notably, the IGF-1R gene is elevated in the majority of cancers and may be an attractive therapeutic target for anticancer therapy because elevated IGF-1R mediates the signalling amplification of a major oncogenic pathway in neoplasia. In A549 cells, miR-12528 overexpression epigenetically altered the downstream phosphorylation of the primary IGF-1R networks, negatively regulated proliferation, apoptosis and migratory activity, and consequently inhibited tumourigenesis and metastasis in vivo. Therefore, our discovery of hsa-miR-12528 may be able to be applied to the development of molecular-target therapeutic strategies and diagnosis-specific biomarkers for human lung cancer.
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Affiliation(s)
- Seong Ho Jeon
- Department of Pharmacy, College of Pharmacy, CHA University, 689 Sampyeong-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400, Republic of Korea
| | - Jung Ki Yoo
- Department of Pharmacy, College of Pharmacy, CHA University, 689 Sampyeong-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400, Republic of Korea
| | - Chang Min Kim
- Department of Pharmacy, College of Pharmacy, CHA University, 689 Sampyeong-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400, Republic of Korea
| | - Eun Su Lim
- Department of Pharmacy, College of Pharmacy, CHA University, 689 Sampyeong-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400, Republic of Korea
| | - So Jeong Lee
- Department of Pharmacy, College of Pharmacy, CHA University, 689 Sampyeong-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400, Republic of Korea
| | - Ji Min Lee
- Department of Pharmacy, College of Pharmacy, CHA University, 689 Sampyeong-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400, Republic of Korea.,Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam-si, Gyeonggi-do, 463-954, Republic of Korea
| | - Seung-Hun Oh
- Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam-si, Gyeonggi-do, 463-954, Republic of Korea
| | - Jin Kyeoung Kim
- Department of Pharmacy, College of Pharmacy, CHA University, 689 Sampyeong-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400, Republic of Korea.
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43
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Ni H, Dai X, Leng X, Deng M, Qin Y, Ji Q, Xu C, Li J, Liu Y. Higher variety and quantity of microRNA-139-5p isoforms confer suppressive role in hepatocellular carcinoma. J Cell Biochem 2018; 119:6806-6813. [PMID: 29693285 DOI: 10.1002/jcb.26874] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2017] [Accepted: 03/21/2018] [Indexed: 01/14/2023]
Abstract
MiRNA isoforms (isomiRs) were defined as an addition or deletion of one or more nucleotides at the 5' or 3' ends or both. Different isomiRs of the same miRNA can target different genes, which have extended the regulatory scale medicated by miRNA. In this study, we systematically analyzed miRNA isoforms in hepatocellular carcinoma (HCC) based on The Cancer Genome Atlas (TCGA) data and further explore their role by in silico and in vitro studies. We found that higher variety and quantity of miR-139-5p isoforms negatively correlated with the malignancy of HCC. And patients with higher variety and quantity of iso-miR-139-5p exhibited favorable survival, independent of tumor stage. Interestingly, miR-139-5p -1|-1 showed increased complementary effect of its target IGF1R than the archetype of miR-139-5p, and could further inhibit cellular movement more vigorously than its archetype. In conclusion, not only miR-139-5p itself, but its isoforms' variety and quantity confer suppressive role in HCC.
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Affiliation(s)
- Hengli Ni
- Department of Pathology, Medical College of Soochow University, Suzhou, China
| | - Xiaoxiao Dai
- Department of Pathology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Xueqin Leng
- Department of Bioinformatics, Medical College of Soochow University, Soochow University, Suzhou, China
| | - Min Deng
- Department of Pathology, Medical College of Soochow University, Suzhou, China
| | - Yan Qin
- Department of Pathology, Medical College of Soochow University, Suzhou, China.,Department of Pathology, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Qinghua Ji
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Chunfang Xu
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jianming Li
- Department of Pathology, Medical College of Soochow University, Suzhou, China
| | - Yao Liu
- Department of Pathology, Medical College of Soochow University, Suzhou, China.,Department of Pathology, The Second Affiliated Hospital of Soochow University, Suzhou, China
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44
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Wang ZS, Zhong M, Bian YH, Mu YF, Qin SL, Yu MH, Qin J. MicroRNA-187 inhibits tumor growth and invasion by directly targeting CD276 in colorectal cancer. Oncotarget 2018; 7:44266-44276. [PMID: 27329595 PMCID: PMC5190094 DOI: 10.18632/oncotarget.10023] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2015] [Accepted: 05/11/2016] [Indexed: 01/05/2023] Open
Abstract
Aberrantly expressed microRNAs contribute to the initiation and progression of human cancers. However, the underlying functions of microRNA-187 (miR-187) in colorectal cancer (CRC) remain largely unexplored. Here, we demonstrated that miR-187 was significantly down-regulated in CRC tissues and cell lines compared to their normal counterparts. By Kaplan-Meier analysis, we revealed that decreased miR-187 expression was closely associated with shorter overall survival and relapse-free survival of patients with CRC. By gain- and loss-of-function studies, we showed that miR-187 remarkably suppressed CRC cell proliferation, migration, invasion, and promoted cell apoptosis. Furthermore, bioinformatics analysis and luciferase reporter assay identified that CD276 was the direct functional target of miR-187 in CRC. Genetic silencing of CD276 recapitulated similar phenotype as observed in over-expression of miR-187, and restoration of CD276 completely rescued the inhibitory effect of miR-187 in CRC cells. Taken together, our study implied the essential roles of miR-187 in suppressing CRC progression, and a novel link between miR-187 and CD276 in CRC.
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Affiliation(s)
- Zheng-Shi Wang
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China
| | - Ming Zhong
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China
| | - Yu-Hai Bian
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China
| | - Yi-Fei Mu
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China
| | - Shao-Lan Qin
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China
| | - Min-Hao Yu
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China
| | - Jun Qin
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China
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45
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Xu K, Shen K, Liang X, Li Y, Nagao N, Li J, Liu J, Yin P. MiR-139-5p reverses CD44+/CD133+-associated multidrug resistance by downregulating NOTCH1 in colorectal carcinoma cells. Oncotarget 2018; 7:75118-75129. [PMID: 27738333 PMCID: PMC5342727 DOI: 10.18632/oncotarget.12611] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Accepted: 09/25/2016] [Indexed: 12/27/2022] Open
Abstract
MiRNAs may promote or inhibit tumor recurrence and drug resistance. MiR-139-5p is reportedly downregulated in colorectal cancer patient samples, but it is unknown whether and how miR-139-5p regulates drug resistance. Cancer stem cells (CSCs) are postulated to be important promoters of multiple drug resistance (MDR). In this study, we established a MDR cell model which strongly expressed the CSC-associated biomarkers CD44 and CD133. MiR-139-5p expression was reduced in MDR cell lines, while overexpression of miR-139-5p reversed CD44+/CD133+-associated MDR. We also identified NOTCH1, an important protein for stem cell maintenance and function, as a direct target of miR-139-5p, both in vitro and in a knockout mouse model. Notch1 expression was upregulated in tumor samples and inversely correlated with expression of miR-139-5p. Silencing NOTCH1 exerted an effect similar to overexpression of miR-139-5p by inhibiting the CD44+ and CD133+ population and reversing the drug-resistant phenotype. In conclusion, miR-139-5p downregulated NOTCH1 signaling to reverse CD44+/CD133+-associated MDR in colorectal cancer cells. Given this insight into the miRNA regulation of MDR, miR-139-5p could be a promising therapeutic target for colorectal cancer therapy.
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Affiliation(s)
- Ke Xu
- Central Laboratory, Putuo Hospital and Interventional Cancer Institute of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, PR China
| | - Ke Shen
- State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, PR China
| | - Xin Liang
- State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, PR China
| | - Yueqi Li
- State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, PR China
| | - Norio Nagao
- Department of Life and Environmental Sciences, Prefectural University of Hiroshima, Shobara, 727-0023, Japan
| | - Jiyu Li
- Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, PR China
| | - Jianwen Liu
- State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, PR China
| | - Peihao Yin
- Central Laboratory, Putuo Hospital and Interventional Cancer Institute of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, PR China
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46
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Yu X, Ma C, Fu L, Dong J, Ying J. MicroRNA-139 inhibits the proliferation, migration and invasion of gastric cancer cells by directly targeting ρ-associated protein kinase 1. Oncol Lett 2018; 15:5977-5982. [PMID: 29552227 DOI: 10.3892/ol.2018.8038] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Accepted: 10/24/2017] [Indexed: 12/18/2022] Open
Abstract
The expression, function and underlying mechanisms of microRNA-139 (miR-139) in gastric cancer were investigated in the present study. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to detect miR-139 expression in gastric cancer tissues and cell lines. The effects of miR-139 overexpression on gastric cancer cell proliferation, migration and invasion were evaluated. ρ-associated protein kinase 1 (ROCK1) was predicted as a downstream target of miR-139 and its role in gastric cancer was assessed by bioinformatics analysis, luciferase reporter assay, RT-qPCR and western blot analysis. ROCK1 overexpression was established to investigate if the effects of miR-139 on gastric cancer cells may be attenuated. The results indicated that miR-139 was aberrantly downregulated in gastric cancer tissues and cell lines. Increased miR-139 expression reduced gastric cancer cell proliferation, migration and invasion. ROCK1 was demonstrated to be a direct target of miR-139 in gastric cancer and ROCK1 overexpression reversed the suppressive effects on gastric cancer cell proliferation, migration and invasion induced by miR-139 overexpression. The present study provides clear evidence demonstrating the anti-oncogenic activity of miR-139 in human gastric cancer, as mediated by the targeted downregulation of ROCK1.
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Affiliation(s)
- Xuechun Yu
- Department of Gastroenterology, People's Hospital of Xuyi, Huai'an, Jiangsu 211700, P.R. China
| | - Chaojian Ma
- Department of Gastroenterology, People's Hospital of Xuyi, Huai'an, Jiangsu 211700, P.R. China
| | - Ling Fu
- Department of Gastroenterology, People's Hospital of Xuyi, Huai'an, Jiangsu 211700, P.R. China
| | - Jingwu Dong
- Department of Gastroenterology, People's Hospital of Xuyi, Huai'an, Jiangsu 211700, P.R. China
| | - Jie Ying
- Department of Infectious Diseases, People's Hospital of Xuyi, Huai'an, Jiangsu 211700, P.R. China
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47
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Zhang T, Cai X, Li Q, Xue P, Chen Z, Dong X, Xue Y. Hsa-miR-875-5p exerts tumor suppressor function through down-regulation of EGFR in colorectal carcinoma (CRC). Oncotarget 2018; 7:42225-42240. [PMID: 27302926 PMCID: PMC5173130 DOI: 10.18632/oncotarget.9944] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Accepted: 04/09/2016] [Indexed: 12/29/2022] Open
Abstract
Hsa-miRNA-875-5p (miR-875-5p) has recently been discovered to have anticancer efficacy in different organs. However, the role of miR-875-5p on colorectal carcinoma (CRC) is still ambiguous. In this study, we investigated the role of miR-875-5p on the development of CRC. The results indicated that miR-875-5p was significantly down-regulated in primary tumor tissues and very low levels were found in CRC cell lines. Ectopic expression of miR-875-5p in CRC cell lines significantly suppressed cell growth as evidenced by cell viability assay, colony formation assay and BrdU staining, through inhibition of cyclin D1, cyclin D2, CDK4 and up-regulation of p57(Kip2) and p21(Waf1/Cip1). In addition, miR-875-5p induced apoptosis, as indicated by concomitantly with up-regulation of key apoptosis protein cleaved caspase-3, and down-regulation of anti-apoptosis protein Bcl2. Moreover, miR-875-5p inhibited cellular migration and invasiveness through inhibition of matrix metalloproteinases (MMP)-7 and MMP-9. Further, oncogene EGFR was revealed to be a putative target of miR-875-5p, which was inversely correlated with miR-875-5p expression in CRC. Taken together, our results demonstrated that miR-875-5p played a pivotal role on CRC through inhibiting cell proliferation, migration, invasion, and promoting apoptosis by targeting oncogenic EGFR.
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Affiliation(s)
- Tiening Zhang
- Oncology Center, Shanghai General Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200080, P. R. China
| | - Xun Cai
- Oncology Center, Shanghai General Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200080, P. R. China
| | - Qi Li
- Oncology Center, Shanghai General Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200080, P. R. China
| | - Peng Xue
- Oncology Center, Shanghai General Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200080, P. R. China
| | - Zhixiao Chen
- Oncology Center, Shanghai General Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200080, P. R. China
| | - Xiao Dong
- Oncology Center, Shanghai General Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200080, P. R. China
| | - Ying Xue
- Oncology Center, Shanghai General Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200080, P. R. China
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48
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Zhou L, Liang X, Zhang L, Yang L, Nagao N, Wu H, Liu C, Lin S, Cai G, Liu J. MiR-27a-3p functions as an oncogene in gastric cancer by targeting BTG2. Oncotarget 2018; 7:51943-51954. [PMID: 27409164 PMCID: PMC5239526 DOI: 10.18632/oncotarget.10460] [Citation(s) in RCA: 112] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Accepted: 06/17/2016] [Indexed: 12/12/2022] Open
Abstract
microRNA-27a (miR-27a) is frequently dysregulated in human carcinoma, including gastric cancer. The B-cell translocation gene 2 (BTG2) has been implicated in gastric carcinogenesis. However, till now, the link between miR-27a and BTG2 in gastric cancer has not been reported. Here, we found that two isoforms of mature miR-27a, miR-27a-5p and miR-27-3p, were both frequently overexpressed in gastric cancer tissues and cell lines, whereas the expression level of miR-27-3p in gastric cancer was significantly higher than that of miR-27a-5p. And overexpression of miR-27a-3p, but not miR-27a-5p, markedly promoted gastric cancer cell proliferation in vitro as well as tumor growth in vivo. Further experiments revealed that BTG2 was a direct and functional target of miR-27a-3p in gastric cancer and miR-27a-3p inhibition obviously up-regulated the expression of BTG2. In turn, overexpression of BTG2 triggered G1/S cell cycle arrest, induced subsequent apoptosis, and inhibited C-myc activation following Ras/MEK/ERK signaling pathway, which involved in the biological effects of miR-27a-3p/BTG2 axis on gastric carcinogenesis and cancer progression. Overall, these results suggested that the miR-27a-3p/BTG2 axis might represent a promising diagnostic biomarker for gastric cancer patients and could be a potential therapeutic target in the management of gastric cancer.
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Affiliation(s)
- Lin Zhou
- Department of Laboratory Medicine, Changzhen Hospital, Second Military Medical University, Shanghai 200003, China
| | - Xin Liang
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
| | - Lingling Zhang
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
| | - Liyan Yang
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
| | - Norio Nagao
- Department of Life and Environmental Sciences, Prefectural University of Hiroshima, Shobara, 727-0023 Japan
| | - Hongkun Wu
- Department of Laboratory Medicine, Changzhen Hospital, Second Military Medical University, Shanghai 200003, China
| | - Chang Liu
- Department of Laboratory Medicine, Changzhen Hospital, Second Military Medical University, Shanghai 200003, China
| | - Shengchao Lin
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
| | - Guoxiang Cai
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032,China
| | - Jianwen Liu
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
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49
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Jung CK, Jung SH, Yim SH, Jung JH, Choi HJ, Kang WK, Park SW, Oh ST, Kim JG, Lee SH, Chung YJ. Predictive microRNAs for lymph node metastasis in endoscopically resectable submucosal colorectal cancer. Oncotarget 2017; 7:32902-15. [PMID: 27096956 PMCID: PMC5078061 DOI: 10.18632/oncotarget.8766] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Accepted: 03/28/2016] [Indexed: 12/19/2022] Open
Abstract
Accurate prediction of regional lymph node metastasis (LNM) in endoscopically resected T1-stage colorectal cancers (CRCs) can reduce unnecessary surgeries. To identify miRNA markers that can predict LNM in T1-stage CRCs, the study was conducted in two phases; (I) miRNA classifier construction by miRNA-array and quantitative reverse transcription PCR (qRT-PCR) using 36 T1-stage CRC samples; (II) miRNA classifier validation in an independent set of 20 T1-stage CRC samples. The expression of potential downstream target genes of miRNAs was assessed by immunohistochemistry. In the discovery analysis by miRNA microarray, expression of 66 miRNAs were significantly different between LNM-positive and negative CRCs. After qRT-PCR validation, 11 miRNAs were consistently significant in the combined classifier construction set. Among them, miR-342-3p was the most significant one (P=4.3×10-4). Through logistic regression analysis, we developed a three-miRNA classifier (miR-342-3p, miR-361-3p, and miR-3621) for predicting LNM in T1-stage CRCs, yielding the area under the curve of 0.947 (94% sensitivity, 85% specificity and 89% accuracy). The discriminative ability of this system was consistently reliable in the independent validation set (83% sensitivity, 64% specificity and 70% of accuracy). Of the potential downstream targets of the three-miRNAs, expressions of E2F1, RAP2B, and AKT1 were significantly associated with LNM. In conclusion, this classifier can predict LNM more accurately than conventional pathologic criteria and our study results may be helpful to avoid unnecessary bowel surgery after endoscopic resection in early CRC.
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Affiliation(s)
- Chan Kwon Jung
- Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Seung-Hyun Jung
- Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.,Integrated Research Center for Genome Polymorphism, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.,Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Seon-Hee Yim
- Integrated Research Center for Genome Polymorphism, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Ji-Han Jung
- Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Hyun Joo Choi
- Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Won-Kyung Kang
- Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Sung-Won Park
- Integrated Research Center for Genome Polymorphism, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.,Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Seong-Taek Oh
- Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Jun-Gi Kim
- Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Sug Hyung Lee
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.,Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Yeun-Jun Chung
- Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.,Integrated Research Center for Genome Polymorphism, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
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Bian Z, Zhang J, Li M, Feng Y, Yao S, Song M, Qi X, Fei B, Yin Y, Hua D, Huang Z. Long non-coding RNA LINC00152 promotes cell proliferation, metastasis, and confers 5-FU resistance in colorectal cancer by inhibiting miR-139-5p. Oncogenesis 2017; 6:395. [PMID: 29180678 PMCID: PMC5868057 DOI: 10.1038/s41389-017-0008-4] [Citation(s) in RCA: 88] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Revised: 08/18/2017] [Accepted: 09/21/2017] [Indexed: 01/15/2023] Open
Abstract
Long intergenic non-coding RNA 152 (LINC00152) is a recently identified tumor-promoting long non-coding RNA. However, the biological functions of LINC00152 in colorectal cancer (CRC) remain unclear and require further research. The aim of the present study is to explore the roles of LINC00152 in cellular function and its possible molecular mechanism. In this study, we discovered that LINC00152 was overexpressed in CRC tissues and negatively related to the survival time of CRC patients. Functional analyses revealed that LINC00152 could promote cell proliferation. Furthermore, LINC00152 could increase the resistance of CRC cells to 5-fluorouracil (5-FU) by suppressing apoptosis. We also discovered that LINC00152 could enhance cell migration and invasion. Mechanistic studies demonstrated that LINC00152 could regulate the expression of NOTCH1 through sponging miR-139-5p and inhibiting its activity from promoting CRC progression and development. Altogether, our work points out a novel LINC00152/miR-139-5p/NOTCH1 regulatory axis in CRC progression and development.
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Affiliation(s)
- Zehua Bian
- Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214062, China
| | - Jiwei Zhang
- Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214062, China
| | - Min Li
- Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214062, China
| | - Yuyang Feng
- Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214062, China
| | - Surui Yao
- Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214062, China
| | - Mingxun Song
- Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214062, China
| | - Xiaowei Qi
- Department of Pathology, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214062, China
| | - Bojian Fei
- Department of Surgical Oncology, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214062, China
| | - Yuan Yin
- Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214062, China
| | - Dong Hua
- Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214062, China
- Department of Medical Oncology, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214062, China
| | - Zhaohui Huang
- Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214062, China.
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