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Niu Z, Zhang Y, Wang Y, Liu D, Wang J, Shi T, Xu X, Li L. MTFR2 promotes endometrial carcinoma cell proliferation and growth via the miR-132-3p/PI3K/Akt signaling pathway. Front Med (Lausanne) 2025; 11:1505071. [PMID: 40129972 PMCID: PMC11931630 DOI: 10.3389/fmed.2024.1505071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Accepted: 11/25/2024] [Indexed: 03/26/2025] Open
Abstract
Objective Understanding the mechanisms underlying endometrial cancer progression is crucial for the development of effective targeted therapies. In this study, we investigated the role of MTFR2 in endometrial cancer cell. Methods The expression of MTFR2 in endometrial cancer was analyzed using The Cancer Genome Atlas (TCGA) dataset and detected in endometrial cancer tissues and cells, respectively. Gain-of-function and loss-of-function approaches were utilized to investigate the impact of MTFR2 on endometrial cancer cell proliferation and tumorigenesis in both in vitro and in vivo settings. Computational tools were employed to predict microRNAs (miRNAs) that potentially regulate MTFR2, and these predictions were experimentally validated. Results The expression of MTFR2 is enhanced in endometrial carcinoma, and it is positively correlated with the poor prognosis of patients. Functional studies show that MTFR2 promoted the proliferation, migration and invasion of endometrial cancer cells. Bioinformatics analysis and luciferase assays identified that MTFR2 is a potential target of miR-132-3p, and transfection with miR-132-3p mimics attenuated the MTFR2-induced activation of the PI3K/Akt pathway. Conclusion Our findings highlight the critical role of MTFR2 in promoting endometrial cancer cell proliferation and growth through the miR-132-3p/PI3K/Akt signaling pathway. Targeting this signaling axis may offer potential therapeutic strategies for endometrial cancer treatment.
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Affiliation(s)
| | | | | | | | | | | | | | - Lei Li
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Tian YF, Huang CJ, Liu CY, Yang SH, Hung CS, Lin KY, Lai CL, Chang CC. MicroRNA‑24 alleviates colorectal cancer progression via a rs28382740 single nucleotide polymorphism in the long noncoding region of X‑linked inhibitor of apoptosis protein. Oncol Lett 2024; 28:591. [PMID: 39417038 PMCID: PMC11481099 DOI: 10.3892/ol.2024.14724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Accepted: 07/24/2024] [Indexed: 10/19/2024] Open
Abstract
Colorectal cancer (CRC) is one of the most prevalent malignant diseases worldwide. Recurrence is associated with the poor survival of patients with CRC. Targeted therapy and precision medicine for recurrent CRC may improve the clinical outcome. Therefore, finding biomarkers that can detect CRC early, assess its prognosis and survival, and predict its treatment response is key to improving the clinical prognosis. The aim of this study was to assess CRC recurrence by analyzing molecular differences using postoperative specimens. Whole-exome sequencing was first used to evaluate the molecular differences in CRC tissues from patients with recurrent disease, and the results were then verified with tissue array methods. The regulation of single nucleotide polymorphisms (SNPs) in long noncoding regions of interest was analyzed in the presence of target microRNAs (miRs) using luciferase assays. The results demonstrated that in patients with recurrent CRC, the G allele was mainly detected at the rs28382740 SNP in the 3'-untranslated region of the X-linked inhibitor of apoptosis (XIAP)-encoding gene. From the tissue arrays, 60% (3/5) of patients with the G allele of the rs28382740 SNP were diagnosed with CRC recurrence, whilst only 10% (1/10) of patients without the G allele had recurrent CRC (P=0.077). Furthermore, XIAP levels were high in non-CRC (50%; 2/4) and CRC (75%; 3/4) tissues of patients with recurrent disease and CRC (54.5%; 6/11) tissues of patients without recurrent disease. However, but only 9.1% (1/11) of non-CRC tissues of nonrecurrent patients had significantly high XIAP expression levels (P=0.022). Using a luciferase assay, it was demonstrated that miR-24s (miR-24-1-5p and miR-24-2-5p) targeting the rs28382740 SNP reduced XIAP levels in CRC cells with rs28382740 SNP genotype G. These results indicate that apoptosis-related proteins, such as XIAP, may be therapeutic targets or biomarkers for tumor development. The data from the present study support an inhibitory effect of miR-24s on XIAP expression. However, this inhibitory potency depends on the rs28382740 SNP genotype and may alleviate CRC progression by regulating the expression of XIAP.
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Affiliation(s)
- Yu-Feng Tian
- Department of Surgery, Chi Mei Medical Center, Tainan 710402, Taiwan, R.O.C
| | - Chi-Jung Huang
- Department of Biochemistry, National Defense Medical Center, Taipei 114201, Taiwan, R.O.C
- Department of Medical Research, Cathay General Hospital, Taipei 106438, Taiwan, R.O.C
| | - Chih-Yi Liu
- Department of Pathology, Sijhih Cathay General Hospital, New Taipei 221037, Taiwan, R.O.C
- School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei 242062, Taiwan, R.O.C
| | - Shung-Haur Yang
- Department of Colorectal Surgery, National Yang-Ming Chiao Tung University Hospital, Yilan 260006, Taiwan, R.O.C
- School of Medicine, Yang-Ming Chiao Tung University, Taipei 112304, Taiwan, R.O.C
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei 112201, Taiwan, R.O.C
| | - Chih-Sheng Hung
- School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei 242062, Taiwan, R.O.C
- Department of Internal Medicine, Division of Gastroenterology, Cathay General Hospital, Taipei 106438, Taiwan, R.O.C
| | - Kai-Yuan Lin
- Department of Medical Research, Chi Mei Medical Center, Tainan 710402, Taiwan, R.O.C
| | - Ching-Long Lai
- Division of Basic Medical Sciences, Department of Nursing, Chang Gung University of Science and Technology, Taoyuan City 333324, Taiwan, R.O.C
- Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Taoyuan City 333324, Taiwan, R.O.C
| | - Chun-Chao Chang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei 110301, Taiwan, R.O.C
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110301, Taiwan, R.O.C
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Shao Z, Chen X, Qiu H, Xu M, Wen X, Chen Z, Liu Z, Ding X, Zhang L. CircNEK6 promotes the progression of pancreatic ductal adenocarcinoma through targeting miR-503/CCND1 axis. Transl Oncol 2024; 39:101810. [PMID: 37871516 PMCID: PMC10622713 DOI: 10.1016/j.tranon.2023.101810] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 09/16/2023] [Accepted: 10/16/2023] [Indexed: 10/25/2023] Open
Abstract
PURPOSE The present study aimed to reveal the function and underlying molecular mechanism of circRNA NIMA related kinase 6 (circNEK6) in promoting the progression of pancreatic ductal adenocarcinoma (PDAC). METHODS The differentially expressed circRNAs in three paired PDAC tissues and adjacent tissues were identified by RNA sequencing. CircNEK6 was screened out to further explore its relationship with the prognosis of PDAC patients. The target microRNAs and mRNAs of circNEK6 were analyzed through online databases and detected by quantitative real-time polymerase chain reaction. Cell counting kit-8 assay, clone formation assay, transwell assay, flow cytometry and western blot were used to explore the function of circNEK6 on the biological behaviors of PDAC cells. The in vivo antitumor effect of circNEK6 silencing on PDAC was investigated by nude mouse xenograft models. RESULTS 203 differentially expressed circRNAs including circNEK6 were identified between paired PDAC tissues and adjacent tissues, and the expression level of circNEK6 was negatively correlated with the prognosis of PDAC patients. The results of in vitro experiments showed that knockdown of circNEK6 repressed the proliferation, migration and invasion, but induced the apoptosis of PDAC cells. Moreover, circNEK6 silencing inhibited tumor growth and prolonged the survival time of PDAC-bearing mice. Mechanistically, miR-503/cyclin D1 (CCND1) axis was predicted and confirmed as the target of circNEK6. CONCLUSIONS CircNEK6 serves as a competing endogenous RNA of CCND1 by absorbing miR-503, which might be treated as a novel and potential target for PDAC treatment.
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Affiliation(s)
- Zhiying Shao
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221000, China
| | - Xueting Chen
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221000, China
| | - Hui Qiu
- Department of Radiation Oncology, Affiliated Hospital of Xuzhou Medical University, No. 9 Kunpeng North Road, Xuzhou, Jiangsu 221000, China
| | - Muchen Xu
- Department of Radiation Oncology, Dushu Lake Hospital Affilated to Soochow University, Medical Center of Soochow University, Suzhou, Jiangsu 215000, China
| | - Xin Wen
- Department of Radiation Oncology, Affiliated Hospital of Xuzhou Medical University, No. 9 Kunpeng North Road, Xuzhou, Jiangsu 221000, China
| | - Ziqin Chen
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221000, China
| | - Zhengyang Liu
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221000, China
| | - Xin Ding
- Department of Radiation Oncology, Affiliated Hospital of Xuzhou Medical University, No. 9 Kunpeng North Road, Xuzhou, Jiangsu 221000, China.
| | - Longzhen Zhang
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221000, China; Department of Radiation Oncology, Affiliated Hospital of Xuzhou Medical University, No. 9 Kunpeng North Road, Xuzhou, Jiangsu 221000, China.
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Hu P, Wang T, Yan H, Huang Y, Zhao Y, Gao Y. Crucial role of hsa-mir-503, hsa-mir-1247, and their validation in prostate cancer. Aging (Albany NY) 2023; 15:12966-12981. [PMID: 37980162 DOI: 10.18632/aging.205213] [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: 03/04/2023] [Accepted: 10/17/2023] [Indexed: 11/20/2023]
Abstract
BACKGROUND Prostate cancer (PC) is a common urinary system malignancy, and advanced PC patients had a poor prognosis due to recurrence or distant metastasis. Therefore, it's imperative to reveal more details in tumorigenesis and prognosis of PC patients. METHODS The miRNA and mRNA expression profile data of 485 PC patients were obtained from The Cancer Genome Atlas database. The univariate Cox regression was applied to screen miRNAs relating to prognosis of PC. Then miRTarBase was used to predict target mRNAs of miRNAs. The hsa-mir-503/hsa-mir-1247 knockdown in 22RV1 cells was established to evaluate the effect of these two miRNAs on tumor cell migration and invasion ability. Flow cytometry was used to detect the effect of hsa-mir-503/hsa-mir-1247 knockdown on 22RV1 apoptosis rate. RESULTS Univariate Cox regression analysis identified hsa-mir-503 as a poor and hsa-mir-1247 as a favorable prognostic marker. Totally 649 target mRNAs were screened, among which DUSP19, FGF2, and SLC2A5 had a negative correlation with hsa-mir-503, while FGF2 and VSTM4 had a positive correlation with hsa-mir-1247. In 22RV1 cells, hsa-mir-503 was up-regulated, and hsa-mir-1247 was down-regulated. hsa-mir-503 knockdown attenuated the migration and invasion of 22RV1 cells, while hsa-mir-1247 knockdown exhibited the opposite effect. In addition, hsa-mir-503 knockdown promoted 22RV1 cell apoptosis. hsa-mir-1247 overexpression significantly inhibited the tumor growth of PC in vivo. CONCLUSIONS Herein, we demonstrated that hsa-mir-503 and hsa-mir-1247 could serve as new prognostic markers of PC, and hsa-mir-1247 had great potential to inhibit PC progression by suppressing the migration and invasion ability in vitro and in vivo.
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Affiliation(s)
- Ping Hu
- The First Department of Medical Oncology, General Hospital of Ningxia Medical University, Yinchuan 750004, Ningxia, P.R. China
| | - Tao Wang
- The Second Department of Surgical Oncology, General Hospital of Ningxia Medical University, Yinchuan 750004, Ningxia, P.R. China
| | - Hui Yan
- The Second Department of Medicine Oncology, General Hospital of Ningxia Medical University, Yinchuan 750004, Ningxia, P.R. China
| | - Ying Huang
- The Third Department of Medicine Oncology, General Hospital of Ningxia Medical University, Yinchuan 750004, Ningxia, P.R. China
| | - Yanjiao Zhao
- The Third Department of Medicine Oncology, General Hospital of Ningxia Medical University, Yinchuan 750004, Ningxia, P.R. China
| | - Yuanyuan Gao
- The Third Department of Medicine Oncology, General Hospital of Ningxia Medical University, Yinchuan 750004, Ningxia, P.R. China
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Roles of anoikis in colorectal cancer therapy and the assessment of anoikis-regulatory molecules as therapeutic targets. Pathol Res Pract 2023; 241:154256. [PMID: 36455367 DOI: 10.1016/j.prp.2022.154256] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 11/21/2022] [Accepted: 11/25/2022] [Indexed: 11/29/2022]
Abstract
Colorectal cancer (CRC) is a deadly malignancy and therapeutic approaches for CRC are evolving every day. Anoikis is a key mechanism for programmed cell death of cancer cells that undergo anchorage-independent growth at a different matrix than the one which is expected. Yet, anoikis is a less studied mechanism of cell death in comparison to other mechanisms such as apoptosis. Relating to this, resistance to anoikis among cancer cells remains critical for improved metastasis and survival in a new environment evading anoikis. Since CRC cells have the ability to metastasize from proximal sites to secondary organs such as liver and promote cancer in those distant sites, a clear knowledge of the mechanisms essential for anchorage-independent growth and subsequent metastasis is necessary to counteract CRC progression and spread. Therefore, the identification of novel drug candidates and studying the roles of anoikis in assisting CRC therapy using such drugs can prevent anchorage-independent cancer cell growth. Additionally, the identification of novel biomarkers or therapeutic targets seems essential for implementing superior therapy, impeding relapse among malignant cells and improving the survival rate of clinical patients. As there are no reviews published on this topic till date, anoikis as a mechanism of cell death and its therapeutic roles in CRC are discussed in this review. In addition, several molecules were identified as therapeutic targets for CRC.
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Tang SJ, Fan KH, You GR, Huang SF, Kang CJ, Huang YF, Huang YC, Chang JTC, Cheng AJ. Tumor Suppressor miRNA-503 Inhibits Cell Invasion in Head and Neck Cancer through the Wnt Signaling Pathway via the WNT3A/MMP Molecular Axis. Int J Mol Sci 2022; 23:15900. [PMID: 36555553 PMCID: PMC9786678 DOI: 10.3390/ijms232415900] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 12/05/2022] [Accepted: 12/09/2022] [Indexed: 12/23/2022] Open
Abstract
Head and neck cancer (HNC) is the fifth most common cancer worldwide, and its incidence and death rates have been consistently high throughout the past decades. MicroRNAs (miRNAs) have recently gained significant attention because of their role in the regulation of a variety of biological processes via post-transcriptional silencing mechanisms. Previously, we determined a specific profile of miRNAs associated with HNC using a miRNA microarray analysis. Of the 23 miRNAs with highly altered expression in HNC cells, miR-503 was the most significantly downregulated miRNA. In this study, we confirmed that miR-503 acts as a tumor suppressor, as our results showed decreased levels of miR-503 in cancer cells and patients with HNC. We further characterized the role of miR-503 in the malignant functions of HNC. Although there was a minimal effect on cell growth, miR-503 was found to inhibit cellular invasion significantly. Algorithm-based studies identified multiple potential target genes and pathways associated with oncogenic mechanisms. The candidate target gene, WNT3A, was confirmed to be downregulated by miR-503 at both the mRNA and protein levels and validated by a reporter assay. Furthermore, miR-503 modulated multiple invasion-associated genes, including matrix metalloproteinases (MMPs), through the Wnt downstream signaling pathway. Overall, this study demonstrates that miR-503 suppresses HNC malignancy by inhibiting cell invasion through the Wnt signaling pathway via the WNT3A/MMP molecular axis. The modulation of miR-503 may be a novel therapeutic approach to intervene in cancer invasion.
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Affiliation(s)
- Shang-Ju Tang
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Kang-Hsing Fan
- Department of Radiation Oncology, New Taipei Municipal TuCheng Hospital, New Taipei City 236017, Taiwan
| | - Guo-Rung You
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Shiang-Fu Huang
- Department of Otorhinolaryngology—Head and Neck Surgery, Linkou Chang Gung Memorial Hospital, Taoyuan 33302, Taiwan
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Chung-Jan Kang
- Department of Otorhinolaryngology—Head and Neck Surgery, Linkou Chang Gung Memorial Hospital, Taoyuan 33302, Taiwan
| | - Yi-Fang Huang
- Department of General Dentistry, Linkou Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Yu-Chen Huang
- Department of General Dentistry, Linkou Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Joseph Tung-Chieh Chang
- Department of Radiation Oncology and Proton Therapy Center, Linkou Chang Gung Memorial Hospital, Taoyuan 33302, Taiwan
- School of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Ann-Joy Cheng
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Radiation Oncology and Proton Therapy Center, Linkou Chang Gung Memorial Hospital, Taoyuan 33302, Taiwan
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Ferris WF. The Role and Interactions of Programmed Cell Death 4 and its Regulation by microRNA in Transformed Cells of the Gastrointestinal Tract. Front Oncol 2022; 12:903374. [PMID: 35847932 PMCID: PMC9277020 DOI: 10.3389/fonc.2022.903374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 05/30/2022] [Indexed: 11/26/2022] Open
Abstract
Data from GLOBOCAN 2020 estimates that there were 19.3 million new cases of cancer and 10.0 million cancer-related deaths in 2020 and that this is predicted to increase by 47% in 2040. The combined burden of cancers of the gastrointestinal (GI) tract, including oesophageal-, gastric- and colorectal cancers, resulted in 22.6% of the cancer-related deaths in 2020 and 18.7% of new diagnosed cases. Understanding the aetiology of GI tract cancers should have a major impact on future therapies and lessen this substantial burden of disease. Many cancers of the GI tract have suppression of the tumour suppressor Programmed Cell Death 4 (PDCD4) and this has been linked to the expression of microRNAs which bind to the untranslated region of PDCD4 mRNA and either inhibit translation or target the mRNA for degradation. This review highlights the properties of PDCD4 and documents the evidence for the regulation of PDCD4 expression by microRNAs in cancers of the GI tract.
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Abstract
Cancer is an uncontrolled growth of normal cells due to unchecked regulatory mechanisms working inside the rapidly dividing cells. In this complex cancer disease treatment, various strategies are utilized to get rid of cancer cells effectively. The different methods combine approaches used to treat cancer, such as radiotherapy, surgery, and chemotherapy. Chemotherapy is among the most effective ways, along with radiotherapy and surgical removal of cancer tissue. Effective chemotherapy based on modification of conventional drugs along with various molecular therapeutic targets, which involve different inhibitors that work in a specific manner in inhibiting particular events activated in cancer cells-the understanding of molecular signaling pathways holds key in the development of targeted therapeutics. After the fundamental signaling pathway studies, a single signaling pathway targeting approach or multiple targeting could display remarkable results in cancer therapeutics. The signal approach includes the signal pathway target. However, a double targeted pathway could effectively aid in inhibiting cell growth or metastasis either due to triggering natural suicidal mechanism (apoptosis) activation. The particular environment of cells regulates cell growth and differentiation. Various proteins in the extracellular matrix (ECM) regulate the process of cancer initiation or progression. The ECM collagens, elastins proteins, fibronectins, and laminins might reduce the effectiveness of treatment therapy, reflecting them as an essential target. Any dysregulation in the composition of ECM reflects the regulatory ineffectiveness in a particular area. These have an association with poor prognosis, cell propagation, and metastasis, along drug resistance.Regulation in physiological processes associated with developmental process and maintaining the homeostasis. The pathogenesis of cancer might be connected to dysregulation in cell death programs, including autophagy, necrosis, and the most desirable cell death mechanism called apoptosis: programmed cell death, the highly regulatory mechanism of natural cell death involved in tissue development. The apoptosis involves characteristic feather of cell death which includes specific morphological change along with biochemical alteration. It includes tightly regulated irreversible events, i.e., phosphatidylserine externalization and DNA fragmentation, mainly via the intrinsic and extrinsic pathways. Targeting apoptosis in the development of therapeutics could be the ultimate process in treating cancer via chemotherapy. During apoptosis, cell death occurs without causing much damage or inflammation in neighboring cells. Various pro-apoptosis and anti-apoptosis proteins involved in the regulation of apoptosis could act as a remarkable target. The apoptosis inactivation is the critical dysregulatory process in the majority of cancer types. There is an increase in research development regarding apoptosis-targeted therapeutics. A understanding of apoptotic signaling pathways, a fundamental knowledge, aids in developing particular inhibitors for anti-apoptotic and activator of pro-apoptotic proteins.In both apoptosis pathways (extrinsic and intrinsic), pro-apoptotic and anti-apoptotic proteins act as potential regulators in cell division and growth. The pro-apoptotic proteins Bax trigger the activation of the intrinsic pathway, an excellent target for developing therapeutics, and are currently in clinical trials. Similarly, the inhibitor of the anti-apoptotic proteins is also on track in the drug development process. The considerable importance of apoptosis-based anticancer drugs is also due to improving the drug sensitivity via reversing the resistive mechanisms in cancer cells. The dysregulatory or inactivated apoptosis mechanism involve Bcl-2 family proteins which include both pro-apoptotic members downregulation and anti-apoptotic upregulation, various inhibitors of apoptosis as inhibitory proteins (IAPs), cell cycle dysregulation, dysregulatory repair system, cell progression pathway activation of NF-κB, tumor suppressor (p53) regulation, and death receptors (DRs) of the extrinsic pathway.
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Affiliation(s)
- Gul-E-Saba Chaudhry
- Institute of Marine Biotechnology, Universiti Malaysia Terengganu, Kuala Terengganu, Malaysia.
| | - Abdah Md Akim
- Department of Biomedical Sciences, Universiti Putra Malaysia, Seri Kembangan, Selangor, Malaysia
| | - Yeong Yik Sung
- Institute of Marine Biotechnology, Universiti Malaysia Terengganu, Kuala Terengganu, Malaysia
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Durán-Vinet B, Araya-Castro K, Calderón J, Vergara L, Weber H, Retamales J, Araya-Castro P, Leal-Rojas P. CRISPR/Cas13-Based Platforms for a Potential Next-Generation Diagnosis of Colorectal Cancer through Exosomes Micro-RNA Detection: A Review. Cancers (Basel) 2021; 13:4640. [PMID: 34572866 PMCID: PMC8466426 DOI: 10.3390/cancers13184640] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 09/07/2021] [Accepted: 09/09/2021] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is the third most prevalent cancer with the second highest mortality rate worldwide. CRC is a heterogenous disease with multiple risk factors associated, including obesity, smoking, and use of alcohol. Of total CRC cases, 60% are diagnosed in late stages, where survival can drop to about 10%. CRC screening programs are based primarily on colonoscopy, yet this approach is invasive and has low patient adherence. Therefore, there is a strong incentive for developing molecular-based methods that are minimally invasive and have higher patient adherence. Recent reports have highlighted the importance of extracellular vesicles (EVs), specifically exosomes, as intercellular communication vehicles with a broad cargo, including micro-RNAs (miRNAs). These have been syndicated as robust candidates for diagnosis, primarily for their known activities in cancer cells, including immunoevasion, tumor progression, and angiogenesis, whereas miRNAs are dysregulated by cancer cells and delivered by cancer-derived exosomes (CEx). Quantitative polymerase chain reaction (qPCR) has shown good results detecting specific cancer-derived exosome micro-RNAs (CEx-miRNAs) associated with CRC, but qPCR also has several challenges, including portability and sensitivity/specificity issues regarding experiment design and sample quality. CRISPR/Cas-based platforms have been presented as cost-effective, ultrasensitive, specific, and robust clinical detection tools in the presence of potential inhibitors and capable of delivering quantitative and qualitative real-time data for enhanced decision-making to healthcare teams. Thereby, CRISPR/Cas13-based technologies have become a potential strategy for early CRC diagnosis detecting CEx-miRNAs. Moreover, CRISPR/Cas13-based platforms' ease of use, scalability, and portability also showcase them as a potential point-of-care (POC) technology for CRC early diagnosis. This study presents two potential CRISPR/Cas13-based methodologies with a proposed panel consisting of four CEx-miRNAs, including miR-126, miR-1290, miR-23a, and miR-940, to streamline novel applications which may deliver a potential early diagnosis and prognosis of CRC.
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Affiliation(s)
- Benjamín Durán-Vinet
- Scientific and Technological Bioresource Nucleus (BIOREN-UFRO), Universidad de La Frontera, Temuco 4780000, Chile; (B.D.-V.); (K.A.-C.); (H.W.)
- Center of Excellence in Translational Medicine (CEMT), Biomedicine and Translational Research Laboratory, Universidad de La Frontera, Temuco 4780000, Chile;
| | - Karla Araya-Castro
- Scientific and Technological Bioresource Nucleus (BIOREN-UFRO), Universidad de La Frontera, Temuco 4780000, Chile; (B.D.-V.); (K.A.-C.); (H.W.)
- Innovation and Entrepreneurship Institute (iDEAUFRO), Universidad de La Frontera, Temuco 4780000, Chile
| | - Juan Calderón
- Center for Genetics and Genomics, School of Medicine, Institute of Science and Innovation in Medicine (ICIM), Clínica Alemana, Universidad del Desarrollo, Santiago 8320000, Chile;
| | - Luis Vergara
- Center of Excellence in Translational Medicine (CEMT), Biomedicine and Translational Research Laboratory, Universidad de La Frontera, Temuco 4780000, Chile;
- Doctoral Program in Cell and Applied Molecular Biology, Universidad de La Frontera, Temuco 4780000, Chile
| | - Helga Weber
- Scientific and Technological Bioresource Nucleus (BIOREN-UFRO), Universidad de La Frontera, Temuco 4780000, Chile; (B.D.-V.); (K.A.-C.); (H.W.)
- Center of Excellence in Translational Medicine (CEMT), Biomedicine and Translational Research Laboratory, Universidad de La Frontera, Temuco 4780000, Chile;
| | - Javier Retamales
- Chilean Cooperative Group for Oncologic Research (GOCCHI), Santiago 8320000, Chile;
| | - Paulina Araya-Castro
- School of Medicine, Clínica Alemana, Universidad del Desarrollo, Santiago 8320000, Chile;
| | - Pamela Leal-Rojas
- Scientific and Technological Bioresource Nucleus (BIOREN-UFRO), Universidad de La Frontera, Temuco 4780000, Chile; (B.D.-V.); (K.A.-C.); (H.W.)
- Center of Excellence in Translational Medicine (CEMT), Biomedicine and Translational Research Laboratory, Universidad de La Frontera, Temuco 4780000, Chile;
- Department of Agricultural Sciences and Natural Resources, Faculty of Agricultural and Forestry Science, Universidad de La Frontera, Temuco 4780000, Chile
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Chen L, Wang Y, Lu X, Zhang L, Wang Z. miRNA-7062-5p Promoting Bone Resorption After Bone Metastasis of Colorectal Cancer Through Inhibiting GPR65. Front Cell Dev Biol 2021; 9:681968. [PMID: 34485279 PMCID: PMC8416178 DOI: 10.3389/fcell.2021.681968] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 05/06/2021] [Indexed: 11/13/2022] Open
Abstract
Bone metastasis is positively associated with a poor prognosis in patients with colorectal cancer (CRC). CRC always leads to osteolytic change, which is regulated by aberrant activation of osteoclasts. MicroRNAs are remarkedly involved in metastasis of CRC; however, their role in bone metastasis of CRC is still unclear. The aim of this study is to find key microRNAs that are critical to bone resorption in bone metastasis of CRC. In this study, bone metastasis model was established through intratibially injecting CT-26 cells or MC-38 cells. Tartrate-resistant acid phosphatase (TRAP) staining was performed to explore the osteoclastogenesis of primary early osteoclast precursors (OCPs) after stimulation by CT-26 conditioned medium (CM). Then, microarray assay was performed to find differentially expressed miRNAs and mRNAs. The target gene of miRNA was confirmed by dual-luciferase analysis. The effect of miRNA, its target gene on osteoclastogenesis, and involved pathways were explored by Western blot, immunofluorescence analysis, and TRAP staining. Finally, the effect of miRNA on bone resorption in vivo was observed. miRNA-7062-5p was upregulated in early OCPs cultured in CT-26 CM or MC-38 CM. GPR65 was proven to be the target gene of miRNA-7062-5p. Overexpression of GPR65 can rescue the osteoclastogenesis caused by miRNA-7062-5p through activation of AMPK pathway. Local injection of miRNA-7062-5p inhibitors efficiently improved the bone resorption. Our study found the role of miRNA-7062-5p in regulating osteoclast formation, and our findings provided a potential therapeutic target in treatment of bone metastasis of CRC.
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Affiliation(s)
- Liang Chen
- Department of Orthopedics, Army Medical Center, Army Medical University, Chongqing, China
| | - Yu Wang
- Department of Orthopedics, Army Medical Center, Army Medical University, Chongqing, China
| | - Xingchen Lu
- Department of Orthopedics, Army Medical Center, Army Medical University, Chongqing, China
| | - Lili Zhang
- Department of Military Psychology, College of Psychology, Army Medical University, Chongqing, China
| | - Ziming Wang
- Department of Orthopedics, Army Medical Center, Army Medical University, Chongqing, China
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11
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Wang L, Tang L, Ge T, Zhu F, Liu D, Guo H, Qian P, Xu N. LncRNA DLGAP1-AS2 regulates miR-503/cyclin D1 to promote cell proliferation in non-small cell lung cancer. BMC Pulm Med 2021; 21:277. [PMID: 34454450 PMCID: PMC8401159 DOI: 10.1186/s12890-021-01633-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 08/09/2021] [Indexed: 12/24/2022] Open
Abstract
Background LncRNA DLGAP1-AS2 plays an oncogenic role in glioma, while its role in other cancers is unknown. This study aimed to study the role of DLGAP1-AS2 in non-small cell lung cancer (NSCLC). Methods Expression of DLGAP1-AS2 in NSCLC and paired non-tumor tissues from 64 NSCLC patients and the prognostic value of DLGAP1-AS2 for NSCLC were analyzed by performing a 5-year follow-up study. The interaction between DLGAP1-AS2 and miR-503 was confirmed by dual luciferase reporter assay, and their relationship was explored in NSCLC cells transfected with DLGAP1-AS2 expression vector or miR-503 mimic. The roles of DLGAP1-AS2 and miR-503 in regulating cyclin D1 expression were analyzed by RT-qPCR and Western blot. Cell proliferation was analyzed by CCK-8 assay. Results DLGAP1-AS2 was upregulated in NSCLC and predicted poor survival. Interaction between DLGAP1-AS2 and miR-503 was confirmed by dual luciferase activity assay. Overexpression experiments showed that DLGAP1-AS2 and miR-503 overexpression failed to significantly affect the expression of each other. Interestingly, DLGAP1-AS2 overexpression upregulated cyclin D1, a target of miR-503, increased cell proliferation and reduced the effects of miR-503 overexpression on cyclin D1 expression and cell proliferation. Conclusions DLGAP1-AS2 may regulate miR-503/cyclin D1 to promote cell proliferation in NSCLC. Supplementary Information The online version contains supplementary material available at 10.1186/s12890-021-01633-0.
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Affiliation(s)
- Lu Wang
- Department of Thoracic Surgery, Anhui Chest Hospital, No. 397 Jixi Road, Shushan District, Hefei City, Anhui Province, 230022, People's Republic of China
| | - Lei Tang
- Department of Thoracic Surgery, Anhui Chest Hospital, No. 397 Jixi Road, Shushan District, Hefei City, Anhui Province, 230022, People's Republic of China
| | - Tengfei Ge
- Department of Thoracic Surgery, Anhui Chest Hospital, No. 397 Jixi Road, Shushan District, Hefei City, Anhui Province, 230022, People's Republic of China
| | - Feng Zhu
- Department of Thoracic Surgery, Anhui Chest Hospital, No. 397 Jixi Road, Shushan District, Hefei City, Anhui Province, 230022, People's Republic of China
| | - Dan Liu
- Department of Thoracic Surgery, Anhui Chest Hospital, No. 397 Jixi Road, Shushan District, Hefei City, Anhui Province, 230022, People's Republic of China
| | - Hua Guo
- Department of Thoracic Surgery, Anhui Chest Hospital, No. 397 Jixi Road, Shushan District, Hefei City, Anhui Province, 230022, People's Republic of China
| | - Peng Qian
- Department of Thoracic Surgery, Anhui Chest Hospital, No. 397 Jixi Road, Shushan District, Hefei City, Anhui Province, 230022, People's Republic of China
| | - Ning Xu
- Department of Thoracic Surgery, Anhui Chest Hospital, No. 397 Jixi Road, Shushan District, Hefei City, Anhui Province, 230022, People's Republic of China.
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12
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Emamian M, Abbaspour A, Shahani T, Biglari A, Sharafi A. Non-viral Suicide Gene Therapy: Cytosine Deaminase Gene Directed by VEGF Promoter and 5-fluorocytosine as a Gene Directed Enzyme/prodrug System in Breast Cancer Model. Drug Res (Stuttg) 2021; 71:395-406. [PMID: 34182589 DOI: 10.1055/a-1488-6054] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The present study investigated the potential of vascular endothelial growth factor (VEGF) promoter to derive cytosine deaminase (CD) transfected by polyamidoamine (G4-PAMAM) dendrimers to 4T1 murine breast cancer cell line as gene-directed enzyme/prodrug therapy. The VEGF promoter and cytosine deaminase gene were cloned into the pEGFP-N1vector from the genomic DNA of 4T1 and E. coli, respectively. The frequency of transfection for VEGF-CD-pEGFP-N1 and pEGFP-N1- CD treated groups was 35±3 and 36±4, respectively. MTT assay was perform to evaluate the cytotoxic effects of converted 5-flurocytosine on 4T1 cells. Also, the optimal concentration of 5-FC in 4T1 cells transfected by VEGF-CD-pEGFP-N1 plasmid was evaluated. The GFP expression of transfected 4T1 cells by VEGF-CD-pEGFP-N1were observed by fluorescent microscopy and flowcytometry. Results demonstrated that the suicide CD gene was successfully expressed in 4T1 cells determined by RT-PCR and GFP expression. A concentration of 200 μg/ml 5-FC was identified as optimal dose of prodrug. Furthermore, the CD/5-FC enzyme/prodrug system not only demonstrated toxicity on transformed 4T1 cells but also exerted a 'bystander effect' determined by MTT assay. The results showed that by 35% transfection with VEGF-CD-pEGFP-N1and CD-pEGFP-N1 plasmids, 80% and 90% inhibition of the cells growth occurred, respectively.
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Affiliation(s)
- Manouchehr Emamian
- Department of Genetics & Molecular Medicine, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran.,Cancer Gene Therapy Research Center, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Akbar Abbaspour
- Cancer Gene Therapy Research Center, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Tina Shahani
- Department of Genetics & Molecular Medicine, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran.,Cancer Gene Therapy Research Center, Zanjan University of Medical Sciences, Zanjan, Iran.,Zanjan Pharmaceutical Biotechnology Research Center, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Alireza Biglari
- Department of Genetics & Molecular Medicine, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran.,Zanjan Pharmaceutical Biotechnology Research Center, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Ali Sharafi
- Cancer Gene Therapy Research Center, Zanjan University of Medical Sciences, Zanjan, Iran.,Department of Pharmaceutical Biotechnology, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran.,Zanjan Pharmaceutical Biotechnology Research Center, Zanjan University of Medical Sciences, Zanjan, Iran
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13
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Ni Q, Zhang Y, Tao R, Li X, Zhu J. MicroRNA-95-3p serves as a contributor to cisplatin resistance in human gastric cancer cells by targeting EMP1/PI3K/AKT signaling. Aging (Albany NY) 2021; 13:8665-8687. [PMID: 33714198 PMCID: PMC8034895 DOI: 10.18632/aging.202679] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 01/22/2021] [Indexed: 12/11/2022]
Abstract
MicroRNAs (miRNAs) are thought to be involved in the development of cisplatin (DDP) resistance in gastric cancer (GC). Using RNA sequencing analysis (RNA-seq), we found that miR-95-3p is associated with DDP resistance in GC. We discovered that miR-95-3p is highly expressed in DDP-resistant GC tissues and cell lines (SGC7901/DDP and AGS/DDP). Furthermore, results from the BrdU and MTT assays indicated that miR-95-3p promotes GC cell proliferation. Additionally, data from transwell chamber assay, wound healing test and in vivo experiments illustrated that miR-95-3p can effectively promote invasion, migration and tumorigenic capacity, respectively, of DDP-resistant GC cells. Subsequently, results from dual luciferase assay and qRT-PCR collectively indicated that EMP1 is a target of miR-95-3p with inhibitory function through suppression of the EMT process and drug-resistance proteins. Furthermore, PI3K/AKT was identified as a downstream pathway of miR-95-3p, which promotes DDP resistance in GC. In summary, miR-95-3p helped develop DDP-resistance through down-regulation of EMP1 and increasing phosphorylation of the PI3K/Akt pathway in GC.
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Affiliation(s)
- Qingfeng Ni
- Department of General Surgery, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, PR China
| | - Yan Zhang
- Department of Chemotherapy, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, PR China
| | - Ran Tao
- Department of General Surgery, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, PR China
| | - Xiaolong Li
- Department of General Surgery, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, PR China
| | - Jianwei Zhu
- Department of General Surgery, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, PR China
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14
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He Y, Cai Y, Pai PM, Ren X, Xia Z. The Causes and Consequences of miR-503 Dysregulation and Its Impact on Cardiovascular Disease and Cancer. Front Pharmacol 2021; 12:629611. [PMID: 33762949 PMCID: PMC7982518 DOI: 10.3389/fphar.2021.629611] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Accepted: 01/20/2021] [Indexed: 12/27/2022] Open
Abstract
microRNAs (miRs) are short, non-coding RNAs that regulate gene expression by mRNA degradation or translational repression. Accumulated studies have demonstrated that miRs participate in various biological processes including cell differentiation, proliferation, apoptosis, metabolism and development, and the dysregulation of miRs expression are involved in different human diseases, such as neurological, cardiovascular disease and cancer. microRNA-503 (miR-503), one member of miR-16 family, has been studied widely in cardiovascular disease and cancer. In this review, we summarize and discuss the studies of miR-503 in vitro and in vivo, and how miR-503 regulates gene expression from different aspects of pathological processes of diseases, including carcinogenesis, angiogenesis, tissue fibrosis and oxidative stress; We will also discuss the mechanisms of dysregulation of miR-503, and whether miR-503 could be applied as a diagnostic marker or therapeutic target in cardiovascular disease or cancer.
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Affiliation(s)
- Yanjing He
- Department of Anesthesiology, The University of Hong Kong, Hong Kong, China
| | - Yin Cai
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong, China
| | - Pearl Mingchu Pai
- Department of Medicine, The University of Hong Kong - Shenzhen Hospital, Shenzhen, China
- Department of Medicine, The University of Hong Kong - Queen Mary Hospital, Hong Kong, China
| | - Xinling Ren
- Department of Respiratory Medicine, Shenzhen University General Hospital, Shenzhen, China
| | - Zhengyuan Xia
- Department of Anesthesiology, The University of Hong Kong, Hong Kong, China
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Medicine, The University of Hong Kong, Hong Kong, China
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
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15
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Dos Santos IL, Penna KGBD, Dos Santos Carneiro MA, Libera LSD, Ramos JEP, Saddi VA. Tissue micro-RNAs associated with colorectal cancer prognosis: a systematic review. Mol Biol Rep 2021; 48:1853-1867. [PMID: 33598796 DOI: 10.1007/s11033-020-06075-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 12/10/2020] [Indexed: 01/05/2023]
Abstract
Colorectal cancer (CRC) is a multifactorial disease commonly diagnosed worldwide, with high mortality rates. Several studies demonstrate important associations between differential expression of micro-RNAs (miRs) and the prognosis of CRC. The present study aimed to identify differentially expressed tissue miRs associated with prognostic factors in CRC patients, through a systematic review of the Literature. Using the PubMed database, Cochrane Library and Web of Science, studies published in English evaluating miRs differentially expressed in tumor tissue and significantly associated with the prognostic aspects of CRC were selected. All the included studies used RT-PCR (Taqman or SYBR Green) for miR expression analysis and the period of publication was from 2009 to 2018. A total of 115 articles accomplished the inclusion criteria and were included in the review. The studies investigated the expression of 100 different miRs associated with prognostic aspects in colorectal cancer patients. The most frequent oncogenic miRs investigated were miR-21, miR-181a, miR-182, miR-183, miR-210 and miR-224 and the hyperexpression of these miRs was associated with distant metastasis, lymph node metastasis and worse survival in patients with CRC. The most frequent tumor suppressor miRs were miR-126, miR-199b and miR-22 and the hypoexpression of these miRs was associated with distant metastasis, worse prognosis and a higher risk of disease relapse (worse disease-free survival). Specific tissue miRs are shown to be promising prognostic biomarkers in patients with CRC, given their strong association with the prognostic aspects of these tumors, however, new studies are necessary to establish the sensibility and specificity of the individual miRs in order to use them in clinical practice.
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Affiliation(s)
- Igor Lopes Dos Santos
- Programa de Mestrado em Ciências Ambientais e Saúde da Pontifícia Universidade Católica de Goiás, Laboratório de Genética e Biodiversidade, Escola de Ciências Médicas, Farmacêuticas e Biomédicas da Pontifícia Universidade Católica de Goiás, Área IV, Praça Universitária, 1440, Setor Leste Universitário, Goiânia, GO, 74605-010, Brazil.
| | - Karlla Greick Batista Dias Penna
- Programa de Mestrado em Ciências Ambientais e Saúde da Pontifícia Universidade Católica de Goiás, Laboratório de Genética e Biodiversidade, Escola de Ciências Médicas, Farmacêuticas e Biomédicas da Pontifícia Universidade Católica de Goiás, Área IV, Praça Universitária, 1440, Setor Leste Universitário, Goiânia, GO, 74605-010, Brazil
| | | | | | - Jéssica Enocencio Porto Ramos
- Programa de Mestrado em Ciências Ambientais e Saúde da Pontifícia Universidade Católica de Goiás, Laboratório de Genética e Biodiversidade, Escola de Ciências Médicas, Farmacêuticas e Biomédicas da Pontifícia Universidade Católica de Goiás, Área IV, Praça Universitária, 1440, Setor Leste Universitário, Goiânia, GO, 74605-010, Brazil
| | - Vera Aparecida Saddi
- Programa de Mestrado em Ciências Ambientais e Saúde da Pontifícia Universidade Católica de Goiás, Laboratório de Genética e Biodiversidade, Escola de Ciências Médicas, Farmacêuticas e Biomédicas da Pontifícia Universidade Católica de Goiás, Área IV, Praça Universitária, 1440, Setor Leste Universitário, Goiânia, GO, 74605-010, Brazil
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16
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The microRNA-424/503 cluster: A master regulator of tumorigenesis and tumor progression with paradoxical roles in cancer. Cancer Lett 2020; 494:58-72. [PMID: 32846190 DOI: 10.1016/j.canlet.2020.08.027] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 08/08/2020] [Accepted: 08/19/2020] [Indexed: 01/21/2023]
Abstract
MicroRNAs (miRNAs) are a group of non-coding RNAs that play a crucial role in post-transcriptional gene regulation and act as indispensable mediators in several critical biological processes, including tumorigenesis, tissue homeostasis, and regeneration. MiR-424 and miR-503 are intragenic miRNAs that are clustered on human chromosome Xq26.3. Previous studies have reported that both miRNAs are dysregulated and play crucial but paradoxical roles in tumor initiation and progression, involving different target genes and molecular pathways. Moreover, these two miRNAs are concomitantly expressed in several cancer cells, indicating a coordinating function as a cluster. In this review, the roles and regulatory mechanisms of miR-424, miR-503, and miR-424/503 cluster are summarized in different types of cancers.
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17
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Ahadi A. The significance of microRNA deregulation in colorectal cancer development and the clinical uses as a diagnostic and prognostic biomarker and therapeutic agent. Noncoding RNA Res 2020; 5:125-134. [PMID: 32954092 PMCID: PMC7476809 DOI: 10.1016/j.ncrna.2020.08.003] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 08/19/2020] [Accepted: 08/19/2020] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most widely recognized and deadly malignancies worldwide. Although death rates have declined over the previous decade, mainly because of enhanced screening or potential treatment alternatives, CRC remains the third leading cause of cancer-related mortality globally, with an estimated incidence of over 1 million new cases and approximately 600 000 deaths estimated yearly. Therefore, many scientific efforts are put into the development of new diagnostic biomarkers for CRC. MicroRNAs (miRNAs), one of the epigenetics categories, have demonstrated significant roles in carcinogenesis and progression through regulating epithelial-mesenchymal transition (EMT), oncogenic signaling pathways, and metastasis. Dysregulation of miRNAs expression has been reported in many cancers, including CRC. The expression profile of miRNAs is reproducibly altered in CRC, and their expression patterns are associated with diagnosis, prognosis, and therapeutic outcomes in CRC. Recently, many studies were conducted on the dysregulation of miRNAs as a diagnostic and prognostic biomarker in CRC. Among them, some miRNAs, which include miR-21, miR-34 family, miR-155, miR-224, and miR-378, have been more studied in CRC with more prominent roles in diagnosis, prognosis, and therapy. In the present review, we summarized the latest information regarding the dysregulated miRNAs in CRC and the advantages of using miRNAs as a biomarker for CRC diagnosis, treatment, and their function in different signaling pathways involved in CRC progression. Moreover, we described the translation of miRNA research to potential therapeutic applications in the management of CRC in clinical settings.
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Affiliation(s)
- Alireza Ahadi
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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18
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Kim B, Jang J, Heo YJ, Kang SY, Yoo H, Sohn I, Min BH, Kim KM. Dysregulated miRNA in a cancer-prone environment: A study of gastric non-neoplastic mucosa. Sci Rep 2020; 10:6600. [PMID: 32313120 PMCID: PMC7171080 DOI: 10.1038/s41598-020-63230-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Accepted: 03/16/2020] [Indexed: 11/09/2022] Open
Abstract
Understanding cancer-prone environments is important to efficiently detect and prevent cancers. The associations between miRNA and cancer-prone environments are still largely unknown in gastric cancer (GC). Six miRNAs that are differentially expressed during gastric carcinogenesis were selected, and quantitative real-time PCR was performed in an independent training set (fresh non-tumor and tumor samples from 18 GC patients) and validation sets (set 1 with formalin-fixed paraffin-embedded non-tumor and tumor samples from 19 solitary GC and set 2 with 37 multiple GC patients). The results were compared with those of 37 gastric mucosa from 20 healthy volunteers. The expression levels of miR-26a, miR-375, and miR-1260 in gastric mucosa from healthy volunteers were statistically higher than that of non-tumorous gastric mucosa located 3 cm apart from the GC in the training set (miR-26a, P < 0.0001; miR-375, P = 0.0049; miR-1260, P = 0.0172), validation set 1 (miR-26a and miR-375, P < 0.0001; miR-1260, P = 0.0008), and validation set 2 (miR-26a, miR-375, and miR-1260, P < 0.0001). And a combination of miR-26a and miR-1260 showed the highest area under the curve value of 0.89. miRNAs are differentially expressed in non-neoplastic gastric mucosa and can be used as a biomarker to predict cancer-prone environments.
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Affiliation(s)
- Binnari Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.,Center of Companion Diagnostics, Samsung Medical Center, Seoul, Republic of Korea
| | - Jiryeon Jang
- The Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - You Jeong Heo
- The Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - So Young Kang
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Heejin Yoo
- Statistics and Data Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Insuk Sohn
- Statistics and Data Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Byung-Hoon Min
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
| | - Kyoung-Mee Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. .,Center of Companion Diagnostics, Samsung Medical Center, Seoul, Republic of Korea.
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19
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Cheng Y, Liu W. MicroRNA-503 serves an oncogenic role in retinoblastoma progression by directly targeting PTPN12. Exp Ther Med 2019; 18:2285-2292. [PMID: 31410179 DOI: 10.3892/etm.2019.7795] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Accepted: 04/05/2019] [Indexed: 12/16/2022] Open
Abstract
Numerous studies have demonstrated that microRNAs (miRNAs or miRs) are abnormally expressed in retinoblastoma (RB). miRNAs may serve a role in oncogene or tumor-suppressor activity in RB genesis and development by modulating various biological processes. miRNAs therefore, may be effective therapeutic targets for miRNA-based therapy in patients with RB. Recently it has been revealed that miR-503 may serve a role in various types of human cancer. However, the expression and functional roles of miR-503 are rarely reported in RB. In the current study, the expression of miR-503 was significantly upregulated in RB tissues and cell lines. In addition, Cell Counting Kit-8 and in vitro invasion assays were performed to assess cell proliferation and invasion, respectively. The results of the present study revealed that miR-503 inhibition impeded RB in vitro cell proliferation and invasion. Furthermore, protein tyrosine phosphatase nonreceptor type 12 (PTPN12) was demonstrated to be a direct target gene of miR-503 in RB cells. PTPN12 overexpression also led to the downregulation of miR-503 in RB cell proliferation and invasion. PTPN12 knockdown could therefore abrogate the effects of miR-503 downregulation in RB cells. In conclusion, the results demonstrated that miR-503 may serve a role in RB oncogenic activity progression by directly targeting PTPN12. Therefore, miR-503 may be a target for effective therapy in patients with RB.
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Affiliation(s)
- Yang Cheng
- Department of Ophthalmology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Wei Liu
- Department of Ophthalmology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
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20
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Fu Y, Meng Y, Gu X, Tian S, Hou X, Ji M. miR-503 expression is downregulated in cervical cancer and suppresses tumor growth by targeting AKT2. J Cell Biochem 2019; 120:8177-8184. [PMID: 30697802 DOI: 10.1002/jcb.28099] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Accepted: 10/29/2018] [Indexed: 01/24/2023]
Abstract
Previous studies have reported that microRNAs function as key regulators in tumor development and progression. This study aims to investigate the functional effects of miR-503 expression in cervical cancer (CC) progression. We detected the expression of miR-503 in CC tissues and cell lines using quantitative real-time polymerase chain reaction. Synthesized miR-503 mimics or inhibitors were used to upregulate or downregulate the expression of miR-503 in HeLa or SiHa cells. Cell Counting Kit-8 and colony formation assay were used to detect the ability of cell proliferation. Furthermore, luciferase assay and Western blot were applied to confirm the target of miR-503 in CC cells. Here, we demonstrated that miR-503 expression was significantly downregulated in CC tissues, compared with adjacent normal tissues. miR-503 expression was significantly associated with tumor size and International Federation of Gynecology and Obstetrics stage. Furthermore, increasing miR-503 expression in CC cells dramatically inhibited cell proliferation, colony formation ability of CC. However, reducing miR-503 had reverse effects on these malignant behaviors. Moreover, we demonstrated that miR-503 inhibited cell proliferation by targeting AKT2 3'-untranslated region and affected its expression. Overexpression of AKT2 rescued the effects induced by miR-503 on cell proliferation. Therefore, our results indicated that miR-503 may serve as a tumor suppressor in CC and provide a potential value for CC treatment.
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Affiliation(s)
- Yuanyuan Fu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yuejin Meng
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiaoli Gu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shuxuan Tian
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiaoying Hou
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Mengge Ji
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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21
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Espelt MV, Bacigalupo ML, Carabias P, Troncoso MF. MicroRNAs contribute to ATP-binding cassette transporter- and autophagy-mediated chemoresistance in hepatocellular carcinoma. World J Hepatol 2019; 11:344-358. [PMID: 31114639 PMCID: PMC6504855 DOI: 10.4254/wjh.v11.i4.344] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 02/21/2019] [Accepted: 03/25/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) has an elevated mortality rate, largely because of high recurrence and metastasis. Additionally, the main obstacle during treatment of HCC is that patients usually develop resistance to chemotherapy. Cancer drug resistance involves many different mechanisms, including alterations in drug metabolism and processing, impairment of the apoptotic machine, activation of cell survival signaling, decreased drug sensitivity and autophagy, among others. Nowadays, miRNAs are emerging as master regulators of normal physiology- and tumor-related gene expression. In HCC, aberrant expression of many miRNAs leads to chemoresistance. Herein, we particularly analyzed miRNA impact on HCC resistance to drug therapy. Certain miRNAs target ABC (ATP-binding cassette) transporter genes. As most of these miRNAs are downregulated in HCC, transporter levels increase and intracellular drug accumulation decrease, turning cells less sensitive to death. Others miRNAs target autophagy-related gene expression, inhibiting autophagy and acting as tumor suppressors. Nevertheless, due to its downregulation in HCC, these miRNAs do not inhibit autophagy or tumor growth and, resistance is favored. Concluding, modulation of ABC transporter and/or autophagy-related gene expression or function by miRNAs could be determinant for HCC cell survival under chemotherapeutic drug treatment. Undoubtedly, more insights on the biological processes, signaling pathways and/or molecular mechanisms regulated by miRNAs are needed. Anyway, miRNA-based therapy together with conventional chemotherapeutic drugs has a great future in cancer therapy.
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Affiliation(s)
- María V Espelt
- Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas, Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad de Buenos Aires, Buenos Aires C1113AAD, Argentina
| | - María L Bacigalupo
- Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas, Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad de Buenos Aires, Buenos Aires C1113AAD, Argentina
| | - Pablo Carabias
- Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas, Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad de Buenos Aires, Buenos Aires C1113AAD, Argentina
| | - María F Troncoso
- Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas, Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad de Buenos Aires, Buenos Aires C1113AAD, Argentina
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22
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Gorbatenko A, Søkilde R, Sorensen EE, Newie I, Persson H, Morancho B, Arribas J, Litman T, Rovira C, Pedersen SF. HER2 and p95HER2 differentially regulate miRNA expression in MCF-7 breast cancer cells and downregulate MYB proteins through miR-221/222 and miR-503. Sci Rep 2019; 9:3352. [PMID: 30833639 PMCID: PMC6399295 DOI: 10.1038/s41598-019-39733-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Accepted: 02/04/2019] [Indexed: 12/18/2022] Open
Abstract
The HER2 oncogene and its truncated form p95HER2 play central roles in breast cancer. Here, we show that although HER2 and p95HER2 generally elicit qualitatively similar changes in miRNA profile in MCF-7 breast cancer cells, a subset of changes are distinct and p95HER2 shifts the miRNA profile towards the basal breast cancer subtype. High-throughput miRNA profiling was carried out 15, 36 and 60 h after HER2 or p95HER2 expression and central hits validated by RT-qPCR. miRNAs strongly regulated by p95HER2 yet not by HER2, included miR-221, miR-222, miR-503, miR-29a, miR-149, miR-196 and miR-361. Estrogen receptor-α (ESR1) expression was essentially ablated by p95HER2 expression, in a manner recapitulated by miR-221/-222 mimics. c-Myb family transcription factors MYB and MYBL1, but not MYBL2, were downregulated by p95HER2 and by miR-503 or miR-221/-222 mimics. MYBL1 3′UTR inhibition by miR-221/222 was lost by deletion of a single putative miR-221/222 binding sites. p95HER2 expression, or knockdown of either MYB protein, elicited upregulation of tissue inhibitor of matrix metalloprotease-2 (TIMP2). miR-221/222 and -503 mimics increased, and TIMP2 knockdown decreased, cell migration and invasion. A similar pathway was operational in T47D- and SKBr-3 cells. This work reveals important differences between HER2- and p95HER2- mediated miRNA changes in breast cancer cells, provides novel mechanistic insight into regulation of MYB family transcription factors by p95HER2, and points to a role for a miR-221/222– MYB family–TIMP2 axis in regulation of motility in breast cancer cells.
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Affiliation(s)
- Andrej Gorbatenko
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, 10029, USA.,Section for Cell Biology and Physiology, Department of Biology, Faculty of Science, University of Copenhagen, Universitetsparken 13, DK-2100, Copenhagen, Denmark
| | - Rolf Søkilde
- BioCare, Strategic Cancer Research Program, Lund, Sweden.,Department of Clinical Sciences Lund, Oncology and Pathology, Faculty of Medicine, Lund University, Lund, Sweden
| | - Ester E Sorensen
- Section for Cell Biology and Physiology, Department of Biology, Faculty of Science, University of Copenhagen, Universitetsparken 13, DK-2100, Copenhagen, Denmark
| | - Inga Newie
- BioCare, Strategic Cancer Research Program, Lund, Sweden.,Department of Clinical Sciences Lund, Oncology and Pathology, Faculty of Medicine, Lund University, Lund, Sweden
| | - Helena Persson
- BioCare, Strategic Cancer Research Program, Lund, Sweden.,Department of Clinical Sciences Lund, Oncology and Pathology, Faculty of Medicine, Lund University, Lund, Sweden
| | - Beatriz Morancho
- Preclinical Research Program, Vall d'Hebron Institute of Oncology and CIBERONC, 08035, Barcelona, Spain
| | - Joaquin Arribas
- Preclinical Research Program, Vall d'Hebron Institute of Oncology and CIBERONC, 08035, Barcelona, Spain.,Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, JA, Bellaterra, Spain.,Institució Catalana de Recerca i Estudis Avançats, JA, Barcelona, Spain
| | - Thomas Litman
- Department of International Health, Immunology and Microbiology, University of Copenhagen, Blegdamsvej 3B, DK-2200, Copenhagen, Denmark
| | - Carlos Rovira
- BioCare, Strategic Cancer Research Program, Lund, Sweden.,Department of Clinical Sciences Lund, Oncology and Pathology, Faculty of Medicine, Lund University, Lund, Sweden
| | - Stine Falsig Pedersen
- Section for Cell Biology and Physiology, Department of Biology, Faculty of Science, University of Copenhagen, Universitetsparken 13, DK-2100, Copenhagen, Denmark.
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23
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MicroRNA Expression Profiles in Upper Tract Urothelial Carcinoma Differentiate Tumor Grade, Stage, and Survival: Implications for Clinical Decision-Making. Urology 2019; 123:93-100. [DOI: 10.1016/j.urology.2018.10.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Revised: 08/05/2018] [Accepted: 10/02/2018] [Indexed: 12/14/2022]
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24
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Iamartino L, Elajnaf T, Kallay E, Schepelmann M. Calcium-sensing receptor in colorectal inflammation and cancer: Current insights and future perspectives. World J Gastroenterol 2018; 24:4119-4131. [PMID: 30271078 PMCID: PMC6158479 DOI: 10.3748/wjg.v24.i36.4119] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Revised: 07/11/2018] [Accepted: 08/01/2018] [Indexed: 02/06/2023] Open
Abstract
The extracellular calcium-sensing receptor (CaSR) is best known for its action in the parathyroid gland and kidneys where it controls body calcium homeostasis. However, the CaSR has different roles in the gastrointestinal tract, where it is ubiquitously expressed. In the colon, the CaSR is involved in controlling multiple mechanisms, including fluid transport, inflammation, cell proliferation and differentiation. Although the expression pattern and functions of the CaSR in the colonic microenvironment are far from being completely understood, evidence has been accumulating that the CaSR might play a protective role against both colonic inflammation and colorectal cancer. For example, CaSR agonists such as dipeptides have been suggested to reduce colonic inflammation, while dietary calcium was shown to reduce the risk of colorectal cancer. CaSR expression is lost in colonic malignancies, indicating that the CaSR is a biomarker for colonic cancer progression. This dual anti-inflammatory and anti-tumourigenic role of the CaSR makes it especially interesting in colitis-associated colorectal cancer. In this review, we describe the clinical and experimental evidence for the role of the CaSR in colonic inflammation and colorectal cancer, the intracellular signalling pathways which are putatively involved in these actions, and the possibilities to exploit these actions of the CaSR for future therapies of colonic inflammation and cancer.
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Affiliation(s)
- Luca Iamartino
- Institute of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna 1090, Austria
| | - Taha Elajnaf
- Institute of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna 1090, Austria
| | - Enikö Kallay
- Institute of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna 1090, Austria
| | - Martin Schepelmann
- Institute of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna 1090, Austria
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25
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Deciphering the Far-Reaching Functions of Non-coding RNA in Colorectal Cancer. CURRENT COLORECTAL CANCER REPORTS 2018. [DOI: 10.1007/s11888-018-0408-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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26
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Sun Y, Li L, Xing S, Pan Y, Shi Y, Zhang L, Shen Q. miR-503-3p induces apoptosis of lung cancer cells by regulating p21 and CDK4 expression. Cancer Biomark 2018; 20:597-608. [PMID: 28800319 DOI: 10.3233/cbm-170585] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Studies have shown that microRNAs (miRNAs) can promote or suppress tumor growth and therefore act as targets for cancer therapy. Hsa-miR-503-5p, a mature miRNA derived from 5' ends of pre-miR-503, has been proved to regulate cell proliferation, transformation, migration and invasion. However, the biological function of miR-503-3p derived from 3' ends of pre-miR-503 has never been reported. In current study, we found that miR-503-3p inhibits lung cancer cell viability and induces cell apoptosis. To better understand the molecular mechanism underlying the miR-503-3p participating in this process, PCR array and RNA-sequencing (RNA-seq) were performed and some differential expression genes were discovered between NC and miR-503-3p treated groups. Biological interaction network showed that p21 and CDK4 are the most important proteins involving miR-503-3p signal pathway. Dual-luciferase assay results shown miR-503-3p directly regulates the expression of p21 by targeting 3'-UTR of its mRNA. These results shed light on the potential roles of miR-503-3p, indicating that it may act as an anti-oncogene factor to inhibit lung cancer cell viability.
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Affiliation(s)
- Yi Sun
- Department of Chest Surgery, the Central Hospital of Linyi, Yishui, Shandong, China
| | - Li Li
- Department of Health, Linyi University Yishui, Yishui, Shandong, China
| | - Shigang Xing
- Department of Chest Surgery, the Central Hospital of Linyi, Yishui, Shandong, China
| | - Yinghua Pan
- Department of Radiotherapy, the Second Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Yunxiang Shi
- Department of Chest Surgery, the Central Hospital of Linyi, Yishui, Shandong, China
| | - Linghua Zhang
- Department of Clinical Laboratory, Yantaishan Hospital, Yantai, Shandong, China
| | - Qiang Shen
- Department of Clinical Laboratory, Yantaishan Hospital, Yantai, Shandong, China.,Department of Emergency Surgery, Qingdao Medical Center, Qingdao, Shandong, China
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27
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CPT1A-mediated fatty acid oxidation promotes colorectal cancer cell metastasis by inhibiting anoikis. Oncogene 2018; 37:6025-6040. [DOI: 10.1038/s41388-018-0384-z] [Citation(s) in RCA: 115] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Revised: 05/31/2018] [Accepted: 06/02/2018] [Indexed: 12/15/2022]
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28
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Liu W, Song Y, Zhang C, Gao P, Huang B, Yang J. The protective role of all-transretinoic acid (ATRA) against colorectal cancer development is achieved via increasing miR-3666 expression and decreasing E2F7 expression. Biomed Pharmacother 2018; 104:94-101. [PMID: 29772445 DOI: 10.1016/j.biopha.2018.05.015] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 05/04/2018] [Accepted: 05/07/2018] [Indexed: 12/22/2022] Open
Abstract
OBJECTIVE Colorectal cancer (CRC) is one of the most common malignancies with high morbidity and mortality rates worldwide. This study aimed to investigate whether miR-3666 was involved in inhibitory effects of all-transretinoic acid (ATRA) on the development of colorectal cancer (CRC). MATERIAL AND METHODS Surgical specimens of CRC tissues and adjacent non-tumor mucosa were collected for determining miR-3666 expression. Human CRC HCT116 cells were treated with different doses of ATRA (10, 20, 40, and 60 μM, respectively) and/or transfected with miR-3666 mimic, miR-3666 inhibitor, E2F7 siRNAs or their controls, respectively. After different treatments, cell viability, apoptosis, migration and invasion were detected. The regulatory relationship between miR-3666 and E2F7 was investigated. Furthermore, the association between MAPK/ERK pathway and ATRA or miR-3666/E2F7 was explored. RESULTS The miR-3666 was lowly expressed in CRC tissues, while E2F7 was highly expressed. ATRA decreased HCT116 cell viability, migration, and invasion, and induced apoptosis, indicating that ATRA inhibited the malignant behaviors of HCT116 cells. Moreover, ATRA increased miR-3666 expression, and effects of ATRA on the malignant behaviors of HCT116 cells were achieved by positive regulating miR-3666 expression. Furthermore, E2F7 was a target gene of miR-3666, and knockdown of E2F7 reversed the combined effects of ATRA and miR-3666 inhibitor on the malignant behaviors of HCT116 cells. Besides, ATRA inhibited the activation of MAPK/ERK signaling pathway, which was reversed by inhibition of miR-3666. CONCLUSIONS Our results reveal that ATRA protects against CRC development possible via increasing miR-3666 expression and decreasing E2F7 expression. MiR-3666/E2F7 may play a key role in regulating the inhibitory effects of ATRA on HCT116 cells via suppressing the activation of MAPK/ERK signaling pathway.
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Affiliation(s)
- Weihong Liu
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical Research and Development, Dali University, Dali, Yunnan, 671000, China; The Libraries of Dali University, Dali, Yunnan, 671003, China
| | - Yanqiu Song
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical Research and Development, Dali University, Dali, Yunnan, 671000, China
| | - Chenggui Zhang
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical Research and Development, Dali University, Dali, Yunnan, 671000, China
| | - Pengfei Gao
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical Research and Development, Dali University, Dali, Yunnan, 671000, China
| | - Bisheng Huang
- Department of Agriculture and biological Science, Dali University, Dali, Yunnan, 671003, China
| | - Jianfang Yang
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical Research and Development, Dali University, Dali, Yunnan, 671000, China; School of Foreign Languages, Dali University, Dali, Yunnan, 671003, China.
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29
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Huang PS, Chung IH, Lin YH, Lin TK, Chen WJ, Lin KH. The Long Non-Coding RNA MIR503HG Enhances Proliferation of Human ALK-Negative Anaplastic Large-Cell Lymphoma. Int J Mol Sci 2018; 19:ijms19051463. [PMID: 29758012 PMCID: PMC5983830 DOI: 10.3390/ijms19051463] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Revised: 05/10/2018] [Accepted: 05/12/2018] [Indexed: 02/07/2023] Open
Abstract
Anaplastic lymphoma kinase (ALK)-negative anaplastic large-cell lymphoma (ALCL) is a rare type of highly malignant, non-Hodgkin lymphoma. Currently, only a few gene rearrangements have been linked to ALK-negative ALCL progression. However, the specific molecular mechanisms underlying the growth of ALK-negative ALCL tumors remain unclear. Here, we investigated aberrantly expressed, long non-coding RNAs (lncRNAs) in ALK-negative ALCL and assessed their potential biological function. MIR503HG (miR-503 host gene) was highly expressed in ALK-negative cell lines and was significantly upregulated in tumors in mice formed from ALK-negative ALCL cell lines. Depletion of MIR503HG suppressed tumor cell proliferation in vivo and in vitro; conversely, its overexpression enhanced tumor cell growth. MIR503HG-induced proliferation was mediated by the induction of microRNA-503 (miR-503) and suppression of Smurf2, resulting in stabilization of the tumor growth factor-β receptor (TGFBR) and enhanced tumor cell growth. Collectively, these findings support a potential role for MIR503HG in cancer cell proliferation through the miR-503/Smurf2/TGFBR axis and indicate that MIR503HG is a potential marker in ALK-negative ALCL.
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MESH Headings
- Anaplastic Lymphoma Kinase
- Animals
- Cell Line, Tumor
- Cell Proliferation
- Disease Models, Animal
- Gene Expression Regulation, Neoplastic
- Heterografts
- Humans
- Lymphoma, Large-Cell, Anaplastic/genetics
- Lymphoma, Large-Cell, Anaplastic/metabolism
- Lymphoma, Large-Cell, Anaplastic/pathology
- Mice
- MicroRNAs/genetics
- RNA Interference
- RNA, Long Noncoding/genetics
- Receptor Protein-Tyrosine Kinases/deficiency
- Receptors, Transforming Growth Factor beta
- Ubiquitin-Protein Ligases/genetics
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Affiliation(s)
- Po-Shuan Huang
- Department of Biochemistry, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.
| | - I-Hsiao Chung
- Department of Biochemistry, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.
| | - Yang-Hsiang Lin
- Department of Biochemistry, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan.
| | - Tzu-Kang Lin
- Neurosurgery, Fu Jen Catholic University Hospital and School of Medicine, Fu Jen Catholic University, New Taipei City 24250, Taiwan.
| | - Wei-Jan Chen
- Cardiovascular Division, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan 333, Taiwan.
| | - Kwang-Huei Lin
- Department of Biochemistry, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan.
- Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan.
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30
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Gao S, Zhao ZY, Wu R, Zhang Y, Zhang ZY. Prognostic value of microRNAs in colorectal cancer: a meta-analysis. Cancer Manag Res 2018; 10:907-929. [PMID: 29750053 PMCID: PMC5935085 DOI: 10.2147/cmar.s157493] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Background Numerous studies have shown that miRNA levels are closely related to the survival time of patients with colon, rectal, or colorectal cancer (CRC). However, the outcomes of different investigations have been inconsistent. Accordingly, a meta-analysis was conducted to study associations among the three types of cancers. Materials and methods Studies published in English that estimated the expression levels of miRNAs with survival curves in CRC were identified until May 20, 2017 by online searches in PubMed, Embase, Web of Science, and the Cochrane Library by two independent authors. Pooled HRs with 95% CIs were used to estimate the correlation between miRNA expression and overall survival. Results A total of 63 relevant articles regarding 13 different miRNAs, with 10,254 patients were ultimately included. CRC patients with high expression of blood miR141 (HR 2.52, 95% CI 1.68-3.77), tissue miR21 (HR 1.31, 95% CI 1.12-1.53), miR181a (HR 1.52, 95% CI 1.26-1.83), or miR224 (HR 2.12, 95% CI 1.04-4.34), or low expression of tissue miR126 (HR 1.55, 95% CI 1.24-1.93) had significantly poor overall survival (P<0.05). Conclusion In general, blood miR141 and tissue miR21, miR181a, miR224, and miR126 had significant prognostic value. Among these, blood miR141 and tissue miR224 were strong biomarkers of prognosis for CRC.
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Affiliation(s)
- Song Gao
- Second Department of Clinical Oncology, Shengjing Hospital of China Medical University
| | - Zhi-Ying Zhao
- School of Computer Science and Engineering, Northeastern University, Shenyang
| | - Rong Wu
- Second Department of Clinical Oncology, Shengjing Hospital of China Medical University
| | - Yue Zhang
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Zhen-Yong Zhang
- Second Department of Clinical Oncology, Shengjing Hospital of China Medical University
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31
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Wu D, Lu P, Mi X, Miao J. Downregulation of miR-503 contributes to the development of drug resistance in ovarian cancer by targeting PI3K p85. Arch Gynecol Obstet 2018; 297:699-707. [DOI: 10.1007/s00404-018-4649-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Accepted: 01/03/2018] [Indexed: 02/01/2023]
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32
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Farhana L, Banerjee HN, Verma M, Majumdar APN. Role of Microbiome in Carcinogenesis Process and Epigenetic Regulation of Colorectal Cancer. Methods Mol Biol 2018; 1856:35-55. [PMID: 30178245 DOI: 10.1007/978-1-4939-8751-1_3] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Epigenetic changes during the development of colorectal cancer (CRC) play a significant role. Along with factors such as diet, lifestyle, and genetics, oncogenic infection, bacteria alone or whole microbiome, has been associated with this tumor type. How gut microbiome contributes to CRC pathogenesis in the host is not fully understood. Most of the epigenetic studies in CRC have been conducted in populations infected with Helicobacter pylori. In the current review, we summarize how the gut microbiota contributes in colon carcinogenesis and the potential role of epigenetic mechanism in gene regulation. We discuss microbiota-mediated initiation and progression of colon tumorigenesis and have also touched upon the role of microbial metabolites as an initiator or an inhibitor for procarcinogenic or antioncogenic activities. The hypothesis of gut microbiota associated CRC revealed the dynamic and complexity of microbial interaction in initiating the development of CRC. In the multifaceted processes of colonic carcinogenesis, gradual alteration of microbiota along with their microenvironment and the potential oncopathogenic microbes mediated modulation of cancer therapy and other factors involved in microbiome dysbiosis leading to the CRC have also been discussed. This review provides a comprehensive summary of the mechanisms of CRC development, the role of microbiome or single bacterial infection in regulating the processes of carcinogenesis, and the intervention by novel therapeutics. Epigenetic mechanism involved in CRC is also discussed.
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Affiliation(s)
- Lulu Farhana
- Veterans Affairs Medical Center, Research Service, Detroit, MI, USA
- Department of Internal Medicine, Wayne State University, Detroit, MI, USA
| | | | - Mukesh Verma
- Epidemiology and Genomics Research Program, National Cancer Institute, Rockville, MD, USA
| | - Adhip P N Majumdar
- Veterans Affairs Medical Center, Research Service, Detroit, MI, USA.
- Department of Internal Medicine, Wayne State University, Detroit, MI, USA.
- Karmanos Cancer Institute, Wayne State University-School of Medicine, Detroit, MI, USA.
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33
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Nunez Lopez YO, Victoria B, Golusinski P, Golusinski W, Masternak MM. Characteristic miRNA expression signature and random forest survival analysis identify potential cancer-driving miRNAs in a broad range of head and neck squamous cell carcinoma subtypes. Rep Pract Oncol Radiother 2018; 23:6-20. [PMID: 29187807 PMCID: PMC5698002 DOI: 10.1016/j.rpor.2017.10.003] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Revised: 08/27/2017] [Accepted: 10/22/2017] [Indexed: 12/13/2022] Open
Abstract
AIM To characterize the miRNA expression profile in head and neck squamous cell carcinoma (HNSSC) accounting for a broad range of cancer subtypes and consequently identify an optimal miRNA signature with prognostic value. BACKGROUND HNSCC is consistently among the most common cancers worldwide. Its mortality rate is about 50% because of the characteristic aggressive behavior of these cancers and the prevalent late diagnosis. The heterogeneity of the disease has hampered the development of robust prognostic tools with broad clinical utility. MATERIALS AND METHODS The Cancer Genome Atlas HNSC dataset was used to analyze level 3 miRNA-Seq data from 497 HNSCC patients. Differential expression (DE) analysis was implemented using the limma package and multivariate linear model that adjusted for the confounding effects of age at diagnosis, gender, race, alcohol history, anatomic neoplasm subdivision, pathologic stage, T and N stages, and vital status. Random forest (RF) for survival analysis was implemented using the randomForestSRC package. RESULTS A characteristic DE miRNA signature of HNSCC, comprised of 11 upregulated (i.e., miR-196b-5p, miR-1269a, miR-196a-5p, miR-4652-3p, miR-210-3p, miR-1293, miR-615-3p, miR-503-5p, miR-455-3p, miR-205-5p, and miR-21-5p) and 9 downregulated (miR-376c-3p, miR-378c, miR-29c-3p, miR-101-3p, miR-195-5p, miR-299-5p, miR-139-5p, miR-6510-3p, miR-375) miRNAs was identified. An optimal RF survival model was built from seven variables including age at diagnosis, miR-378c, miR-6510-3p, stage N, pathologic stage, gender, and race (listed in order of variable importance). CONCLUSIONS The joint differential miRNA expression and survival analysis controlling for multiple confounding covariates implemented in this study allowed for the identification of a previously undetected prognostic miRNA signature characteristic of a broad range of HNSCC.
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Affiliation(s)
- Yury O. Nunez Lopez
- Translational Research Institute for Metabolism & Diabetes, Florida Hospital, 301 East Princeton St., Orlando, FL 32804, USA
| | - Berta Victoria
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 6900 Lake Nona Blvd., Orlando, FL 32827, USA
| | - Pawel Golusinski
- Department of Head and Neck Surgery, The Greater Poland Cancer Centre, 15 Garbary St., 61-866 Poznan, Poland
| | - Wojciech Golusinski
- Department of Head and Neck Surgery, The Greater Poland Cancer Centre, 15 Garbary St., 61-866 Poznan, Poland
| | - Michal M. Masternak
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 6900 Lake Nona Blvd., Orlando, FL 32827, USA
- Department of Head and Neck Surgery, The Greater Poland Cancer Centre, 15 Garbary St., 61-866 Poznan, Poland
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34
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Kim YJ, Hwang KC, Kim SW, Lee YC. Potential miRNA-target interactions for the screening of gastric carcinoma development in gastric adenoma/dysplasia. Int J Med Sci 2018; 15:610-616. [PMID: 29725252 PMCID: PMC5930463 DOI: 10.7150/ijms.24061] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Accepted: 03/01/2018] [Indexed: 12/14/2022] Open
Abstract
Although miRNA markers have been identified for the pathological development of gastric adenocarcinoma (GAC), the underlying molecule mechanism are still not fully understood. Moreover, some gastric adenoma/dysplasia may progress to GAC. In this study, the miRNA expression profiles in normal and paired low-/high-grade dysplasia were analyzed using Affymetrix Gene-Chip miRNA arrays. Of the total 2578 mature miRNA probe sets, ~1600 showed positive signals when the between normal and paired low-/high-grade dysplasia were compared. To verify the miRNA expression, qRT-PCR analysis was performed to quantify the expression of altered miRNAs between normal and paired low-/high-grade dysplasia. The analysis revealed that hsa-miR-421, hsa-miR-29b-1-5p, and hsa-miR-27b-5p were overexpressed in gastric low-/high-grade dysplasia and that based on these miRNA-target interactions, FBXO11 and CREBZF could be considered convincing markers for gastric cancer (GC) progression. Thus, we identified three miRNAs (hsa-miR-421, hsa-miR-29b-1-5p, and hsa-miR-27b-5p) with two mRNAs (FBXO11 and CREBZF) that might play an important role in the GC development from premalignant adenomas. Furthermore, these two target mRNAs and three miRNAs were predicted to be potential biomarkers for the progression of GC by miRNA-target interaction analysis.
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Affiliation(s)
- Yu Jin Kim
- Department of Internal Medicine, Catholic Kwandong University, International St. Mary's Hospital, Incheon Metropolitan City, 404-834, Republic of Korea.,Yonsei University College of Medicine, 50-Yonsei-ro, Seodaemun-gu, Seoul, Republic of Korea
| | - Ki-Chul Hwang
- Catholic Kwandong University, International St. Mary's Hospital, Incheon Metropolitan City, 404-834, Republic of Korea.,Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do 210-701, Republic of Korea
| | - Sang Woo Kim
- Catholic Kwandong University, International St. Mary's Hospital, Incheon Metropolitan City, 404-834, Republic of Korea.,Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do 210-701, Republic of Korea
| | - Yong Chan Lee
- Division of Gastroenterology, Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, 50-Yonsei-ro, Seodaemun-gu, Seoul, Republic of Korea
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Vaira V, Verdelli C, Forno I, Corbetta S. MicroRNAs in parathyroid physiopathology. Mol Cell Endocrinol 2017; 456:9-15. [PMID: 27816765 DOI: 10.1016/j.mce.2016.10.035] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Revised: 10/30/2016] [Accepted: 10/31/2016] [Indexed: 12/19/2022]
Abstract
Parathyroid glands regulate calcium homeostasis through synthesis and secretion of parathormone (PTH). They sense the extracellular calcium concentration through the G-protein coupled calcium sensing receptor (CASR) and release PTH in order to preserve calcium concentration in the physiological range. Tumors of the parathyroid glands are common endocrine neoplasia associated with primary or secondary/tertiary hyperparathyroidisms. Small non-coding RNAs are regulators of gene expression able to modulate hormone synthesis, hormone release and endocrine cell proliferation. In this scenario, microRNA (miRNA) expression profiles have been investigated in parathyroid tumors, while miRNAs are involved in hypocalcemia and uremia-induced PTH release from normal parathyroid cells. Here we reviewed data about the role of miRNAs in the regulation of: 1) PTH synthesis and secretion; 2) CASR expression; 3) parathyroid cell tumorigenesis. Though studies about miRNAs in parathyroid gland pathophysiology are limited, they contribute in elucidating regulatory pathways involved in PTH release and parathyroid cell tumorigenesis.
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Affiliation(s)
- V Vaira
- Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - C Verdelli
- Laboratory of Experimental Endocrinology, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
| | - I Forno
- Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - S Corbetta
- Endocrinology Service, Department of Biomedical Sciences for Health, University of Milan, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy.
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Shuang Y, Zhou X, Li C, Huang Y, Zhang L. MicroRNA‑503 serves an oncogenic role in laryngeal squamous cell carcinoma via targeting programmed cell death protein 4. Mol Med Rep 2017; 16:5249-5256. [PMID: 28849168 PMCID: PMC5647079 DOI: 10.3892/mmr.2017.7278] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Accepted: 06/22/2017] [Indexed: 12/23/2022] Open
Abstract
Laryngeal squamous cell carcinoma (LSCC), the most common form of laryngeal carcinoma, is an aggressive malignancy that demonstrates the second highest rate of morbidity of all head and neck squamous cell carcinomas. The abnormal expression of microRNAs (miRs) has been demonstrated in a number of types of human cancer, and they have been demonstrated to be oncogenes or tumour suppressor genes. miR-503 has been studied in various types of human cancer; however, the expression level, roles and underlying mechanisms in LSCC remain unknown. In the present study, it was demonstrated that miR-503 was significantly upregulated in LSCC tissues and cell lines. The level of miR-503 in LSCC tissues was correlated with thyroid cartilage invasion, lymph node metastasis, and tumour, node and metastasis stage. In addition, down-regulation of miR-503 inhibited cell proliferation and invasion in LSCC. Programmed cell death protein 4 (PDCD4) was identified to be a direct target gene of miR-503. PDCD4 overexpression could mimic the roles of miR-503 underexpression in LSCC. Furthermore, PDCD4 was down-regulated in LSCC tissues and this correlated with the miR-503 expression level. In conclusion, these results suggested that miR-503 promotes tumour growth and invasion by directly targeting PDCD4. The identification of the miR-503/PDCD4 axis may provide novel targets for LSCC treatment and improve prognosis.
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Affiliation(s)
- Yu Shuang
- Department of Otorhinolaryngology and Maxillofacial Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute, National Clinical Research Center of Cancer, Tianjin 300060, P.R. China
| | - Xuan Zhou
- Department of Otorhinolaryngology and Maxillofacial Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute, National Clinical Research Center of Cancer, Tianjin 300060, P.R. China
| | - Chao Li
- Department of Otorhinolaryngology, Head and Neck Surgery, The Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
| | - Yongwang Huang
- Department of Otorhinolaryngology, Head and Neck Surgery, The Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
| | - Lun Zhang
- Department of Otorhinolaryngology and Maxillofacial Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute, National Clinical Research Center of Cancer, Tianjin 300060, P.R. China
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Torres S, Garcia-Palmero I, Bartolomé RA, Fernandez-Aceñero MJ, Molina E, Calviño E, Segura MF, Casal JI. Combined miRNA profiling and proteomics demonstrates that different miRNAs target a common set of proteins to promote colorectal cancer metastasis. J Pathol 2017; 242:39-51. [PMID: 28054337 DOI: 10.1002/path.4874] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Revised: 12/13/2016] [Accepted: 01/02/2017] [Indexed: 12/13/2022]
Abstract
The process of liver colonization in colorectal cancer remains poorly characterized. Here, we addressed the role of microRNA (miRNA) dysregulation in metastasis. We first compared miRNA expression profiles between colorectal cancer cell lines with different metastatic properties and then identified target proteins of the dysregulated miRNAs to establish their functions and prognostic value. We found that 38 miRNAs were differentially expressed between highly metastatic (KM12SM/SW620) and poorly metastatic (KM12C/SW480) cancer cell lines. After initial validation, we determined that three miRNAs (miR-424-3p, -503, and -1292) were overexpressed in metastatic colorectal cancer cell lines and human samples. Stable transduction of non-metastatic cells with each of the three miRNAs promoted metastatic properties in culture and increased liver colonization in vivo. Moreover, miR-424-3p and miR-1292 were associated with poor prognosis in human patients. A quantitative proteomic analysis of colorectal cancer cells transfected with miR-424-3p, miR-503, or miR-1292 identified alterations in 149, 129, or 121 proteins, respectively, with an extensive overlap of the target proteins of the three miRNAs. Importantly, down-regulation of two of these shared target proteins, CKB and UBA2, increased cell adhesion and proliferation in colorectal cancer cells. The capacity of distinct miRNAs to regulate the same mRNAs boosts the capacity of miRNAs to regulate cancer metastasis and underscores the necessity of targeting multiple miRNAs for effective cancer therapy. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Sofía Torres
- Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain
| | - Irene Garcia-Palmero
- Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain
| | - Rubén A Bartolomé
- Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain
| | | | - Elena Molina
- Surgical Pathology Department, Hospital Clínico, Madrid, Spain
| | - Eva Calviño
- Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain
| | - Miguel F Segura
- Laboratory of Translational Research in Child and Adolescent Cancer, Vall d'Hebron Institut de Recerca, Barcelona, Spain
| | - J Ignacio Casal
- Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain
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Colorectal Carcinoma: A General Overview and Future Perspectives in Colorectal Cancer. Int J Mol Sci 2017; 18:ijms18010197. [PMID: 28106826 PMCID: PMC5297828 DOI: 10.3390/ijms18010197] [Citation(s) in RCA: 857] [Impact Index Per Article: 107.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Revised: 01/06/2017] [Accepted: 01/11/2017] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer-related death. Most cases of CRC are detected in Western countries, with its incidence increasing year by year. The probability of suffering from colorectal cancer is about 4%–5% and the risk for developing CRC is associated with personal features or habits such as age, chronic disease history and lifestyle. In this context, the gut microbiota has a relevant role, and dysbiosis situations can induce colonic carcinogenesis through a chronic inflammation mechanism. Some of the bacteria responsible for this multiphase process include Fusobacterium spp, Bacteroides fragilis and enteropathogenic Escherichia coli. CRC is caused by mutations that target oncogenes, tumour suppressor genes and genes related to DNA repair mechanisms. Depending on the origin of the mutation, colorectal carcinomas can be classified as sporadic (70%); inherited (5%) and familial (25%). The pathogenic mechanisms leading to this situation can be included in three types, namely chromosomal instability (CIN), microsatellite instability (MSI) and CpG island methylator phenotype (CIMP). Within these types of CRC, common mutations, chromosomal changes and translocations have been reported to affect important pathways (WNT, MAPK/PI3K, TGF-β, TP53), and mutations; in particular, genes such as c-MYC, KRAS, BRAF, PIK3CA, PTEN, SMAD2 and SMAD4 can be used as predictive markers for patient outcome. In addition to gene mutations, alterations in ncRNAs, such as lncRNA or miRNA, can also contribute to different steps of the carcinogenesis process and have a predictive value when used as biomarkers. In consequence, different panels of genes and mRNA are being developed to improve prognosis and treatment selection. The choice of first-line treatment in CRC follows a multimodal approach based on tumour-related characteristics and usually comprises surgical resection followed by chemotherapy combined with monoclonal antibodies or proteins against vascular endothelial growth factor (VEGF) and epidermal growth receptor (EGFR). Besides traditional chemotherapy, alternative therapies (such as agarose tumour macrobeads, anti-inflammatory drugs, probiotics, and gold-based drugs) are currently being studied to increase treatment effectiveness and reduce side effects.
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Zamani M, Hosseini SV, Mokarram P. Epigenetic biomarkers in colorectal cancer: premises and prospects. Biomarkers 2016; 23:105-114. [PMID: 27788596 DOI: 10.1080/1354750x.2016.1252961] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
CONTEXT Colorectal cancer is one of the most common cancers worldwide. Epigenetic alterations play an important role in the pathogenesis of the colorectal cancer. OBJECTIVE This review has focused on the most recent investigations, which has suggested potential epigenetic biomarkers in colorectal cancer. METHODS Evidences were achieved by searching online medical databases including Google scholar, Pubmed, Scopus and Science Direct. RESULTS Extensive studies have indicated that aberrant epigenetic modifications could serve as potential biomarkers for diagnosis, prognosis and prediction of colorectal cancer. CONCLUSION Advances in aberrant epigenetic modifications can open new avenues for exploration of reliable and robust biomarkers to improve the management of CRC patients.
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Affiliation(s)
- Mozhdeh Zamani
- a Colorectal Research Center , Shiraz University of Medical Sciences , Shiraz , IR Iran
| | - Seyed Vahid Hosseini
- a Colorectal Research Center , Shiraz University of Medical Sciences , Shiraz , IR Iran
| | - Pooneh Mokarram
- b Gasteroenterohepatology Research Center , Nemazee Hospital, School of Medicine, Shiraz University of Medical Sciences , Shiraz , Iran.,c Department of Biochemistry, Faculty of Medicine , Shiraz University of Medical Sciences , Shiraz , Iran
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Longqiu Y, Pengcheng L, Xuejie F, Peng Z. A miRNAs panel promotes the proliferation and invasion of colorectal cancer cells by targeting GABBR1. Cancer Med 2016; 5:2022-31. [PMID: 27230463 PMCID: PMC4884921 DOI: 10.1002/cam4.760] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2016] [Revised: 04/05/2016] [Accepted: 04/06/2016] [Indexed: 01/09/2023] Open
Abstract
MicroRNAs (miRNAs) have been implicated in the regulation of colorectal cancer. Despite the expression of miR-17-92 cluster in cancer has been gradually revealed, the role of each individual miRNAs in colorectal cancer still remains unclear. We studied the impact of miR-106a/b, miR-20a/b, and miR-17 of miR-17-92 cluster on colorectal cancer cells. Real-time quantitative polymerase chain reactions (RT-PCR) were used to test these five miRNAs expression in colorectal cancer cell line HCT116. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assays, Bromodeoxyuridine (BrdU), and Transwell invasion assays were used to explore the effects of these five miRNAs in colorectal cancer cells. Luciferase reporter assay, RT-PCR, and western blotting were performed to validate the interaction of these five miRNAs with the gamma-amino-butyric acid type B receptor 1(GABBR1). We found that these five miRNAs were significantly upregulated in colorectal cancer samples compared with normal tissues. Forced expression of these five miRNAs significantly promoted HCT116 and HT-29 cells proliferation and invasion. We further found that these five miRNAs function as oncogenes in colorectal cancer by specifically binding to the 3-untranslated regions (3'UTR) of GABBR1.Furthermore, inhibition of GABBR1 could mimic the function of miRNAs in HCT116 cells, while overexpression of GABBR1 blocked the function of miRNAs-promoted proliferation and invasion. In conclusion, miR-106a/b, miR-20a/b, and miR-17 contribute to the proliferation and invasion of colorectal cancer by targeting their common target gene, GABBR1, and played a critical role in the proliferation and invasion of colorectal cancer.
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Affiliation(s)
- Yang Longqiu
- Department of AnesthesiologyHuangshi Central HospitalAffiliated Hospital of Hubei Polytechnic UniversityEdong Healthcare GroupHuangshi435000China
| | - Luo Pengcheng
- Department of Urology SurgeryHuangshi Central HospitalAffiliated Hospital of Hubei Polytechnic UniversityEdong Healthcare GroupHuangshi435000China
| | - Fei Xuejie
- Department of Intensive Care UnitShuguang Hospital Affiliated with Shanghai University of Traditional Chinese MedicineShanghai200021China
| | - Zhang Peng
- Department of OncologyThe Center Hospital of Zaozhuang Mining GroupZaozhuang277000China
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