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Drewa J, Lazar-Juszczak K, Adamowicz J, Juszczak K. Periprostatic Adipose Tissue as a Contributor to Prostate Cancer Pathogenesis: A Narrative Review. Cancers (Basel) 2025; 17:372. [PMID: 39941741 PMCID: PMC11816168 DOI: 10.3390/cancers17030372] [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: 12/17/2024] [Revised: 01/03/2025] [Accepted: 01/21/2025] [Indexed: 02/16/2025] Open
Abstract
Periprostatic adipose tissue (PPAT) contributes to the pathogenesis of prostate cancer. The purpose of this study was to review and summarize the literature on the role of PPAT in prostate cancer pathogenesis. Moreover, we evaluated the clinical implication of PPAT in patients with prostate cancer. We performed a scoping literature review of PubMed from January 2002 to November 2024. Search terms included "periprostatic adipose tissue", "adipokines", and "prostate cancer". Secondary search involved reference lists of eligible articles. The key criterion was to identify studies that included PPAT, adipokines, and their role in prostate cancer biology and clinical features. In total 225 publications were selected for inclusion in this review. The studies contained in publications allowed us to summarize the data on the pathogenesis of PPAT as a contributor to prostate cancer biology and its aggressiveness. The review also presents new research directions for PPAT as a new target for the treatment of prostate cancer. Based on the current review, it can be stated that PPAT plays an important role in prostate cancer pathogenesis. Moreover, PPAT seems to be a promising target point when it comes to finding new therapies in patients with more aggressive and/or advanced stages of prostate cancer.
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Affiliation(s)
- Julia Drewa
- Department of Urology and Andrology, Collegium Medicum, Nicolaus Copernicus University, 85-094 Bydgoszcz, Poland
| | - Katarzyna Lazar-Juszczak
- Primary Health Care Clinic of the Ujastek Medical Center, 31-752 Cracow, Poland
- Krakow University of Health Promotion, 31-158 Cracow, Poland
| | - Jan Adamowicz
- Department of Urology and Andrology, Collegium Medicum, Nicolaus Copernicus University, 85-094 Bydgoszcz, Poland
- Department of Regenerative Medicine, Collegium Medicum, Nicolaus Copernicus University, 85-094 Bydgoszcz, Poland
| | - Kajetan Juszczak
- Department of Urology and Andrology, Collegium Medicum, Nicolaus Copernicus University, 85-094 Bydgoszcz, Poland
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Liu Y, Zhang G, Wei D, Zhang H, Iliuk A, Xie Z, Gu Y, Gu Z, Zhang Y, Zhu Y. One-Pot Sequential Enrichment of Urinary Extracellular Vesicle and miRNAs Identifies a Noninvasive Biomarker Panel for Prostate Cancer Diagnosis. Anal Chem 2024; 96:19670-19677. [PMID: 39613483 DOI: 10.1021/acs.analchem.4c04807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2024]
Abstract
Extracellular vesicles (EVs) offer promising noninvasive alternatives for convenient and noninvasive prostate cancer (PCa) diagnosis, but inefficient EV enrichment and cargo extraction hinder discovery and validation for their clinical applications. Here, we present an integrated pipeline based on functionalized magnetic beads to streamline and enhance the efficiency of urinary EV miRNA analysis. EVs are first enriched on amphiphilic magnetic beads through chemical affinity, followed by EV lysis and the isolation of miRNAs through solid phase extraction. The new pipeline demonstrated a more than 10-fold increase in urine EV miRNA extraction efficiency compared to the traditional ultracentrifugation combined TRIzol method while reducing the sample processing time to within 1 h. The one-bead strategy further allowed us to automate the procedure on a 96-channel instrument. We applied the pipeline to analyze urine samples from 108 benign prostatic hyperplasia (BPH) controls and 92 PCa cases. Among 195 miRNA biomarkers from the literature, we prioritized 18 miRNAs for quantification and successfully validated 12 miRNAs with a ratio-based normalized method. The quantification data from BPH controls and PCa cases in the training set were subjected to a machine learning analysis of Random Forest, through which we generated a five-miRNA panel consisting of miR-148a-5p, miR-21-5p, miR-181a-5p, miR-222-3p, and miR-100-5p. This panel showed high sensitivity (89%) and specificity (72%) in the test set, highlighting immense potential of this streamlined pipeline for noninvasive diagnosis.
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Affiliation(s)
- Yufeng Liu
- School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, China
- EVLiXiR Biotech, Nanjing 210032, China
- Bell Mountain Molecular MedTech Institute, Nanjing 210032, China
| | - Guiyuan Zhang
- School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, China
- EVLiXiR Biotech, Nanjing 210032, China
- Bell Mountain Molecular MedTech Institute, Nanjing 210032, China
| | - Dong Wei
- School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, China
- Bell Mountain Molecular MedTech Institute, Nanjing 210032, China
| | - Hao Zhang
- School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, China
- EVLiXiR Biotech, Nanjing 210032, China
| | - Anton Iliuk
- Tymora Analytical Operations, West Lafayette, Indiana 47907, United States
| | - Zhuoying Xie
- School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, China
| | - Yanhong Gu
- Department of Oncology and Cancer Rehabilitation Centre, The First Affiliated Hospital of Nanjing Medical University, Nanjing 212028, China
| | - Zhongze Gu
- School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, China
| | - Ying Zhang
- Department of Chemistry and Institutes of Biomedical Sciences, Fudan University, Shanghai 200433, China
| | - Yefei Zhu
- School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, China
- Laboratory Medicine Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, China
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Moradi A, Sahebi U, Nazarian H, Majdi L, Bayat M. Oncogenic MicroRNAs: Key players in human prostate cancer pathogenesis, a narrative review. Urol Oncol 2024; 42:429-437. [PMID: 39341711 DOI: 10.1016/j.urolonc.2024.08.022] [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: 04/14/2024] [Revised: 08/25/2024] [Accepted: 08/30/2024] [Indexed: 10/01/2024]
Abstract
Prostate cancer (PC) is a leading cause of cancer-related mortality in men worldwide, and identifying key molecular players in its pathogenesis is essential for advancing effective diagnosis and therapy. MicroRNAs (miRNAs) have recently emerged as significant molecules involved in the progression of various cancers. As noncoding RNAs, miRNAs play a vital role in regulating gene expression and are implicated in several aspects of cancer pathogenesis. In the context of human PC, growing evidence suggests that certain miRNAs with oncogenic properties are key players in the initiation, progression, and metastasis of the disease. In conclusion, dysregulated miRNAs are critical in prostate cancer progression, influencing key cellular processes. Oncogenic miRNAs exhibit diagnostic and therapeutic potential in PC. Targeting these miRNAs presents novel treatment avenues, but further research is needed to fully understand their clinical utility. Additional investigation into the mechanisms of miRNA regulation and their interactions with other signaling pathways is necessary to comprehensively understand the role of oncogenic miRNAs in PC and to develop effective treatments for this disease. Overall, substantiating the role of oncogenic miRNAs in PC pathogenesis provides valuable insights into the mechanisms underlying the disease and may lead to the development of novel targeted therapies for improved patient outcomes.
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Affiliation(s)
- Ali Moradi
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Teh, Iran
| | - Unes Sahebi
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Teh, Iran
| | - Hamid Nazarian
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Teh, Iran
| | - Leila Majdi
- Preventative Gynecology Research Center, Shahid Beheshti University of Medical Sciences, Teh, Iran
| | - Mohammad Bayat
- Price Institute of Surgical Research, University of Louisville and Noveratech LLC of Louisville in Louisville, KY; Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Teh, Iran.
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4
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Jia Y, He P, Ma X, Lv K, Liu Y, Xu Y. PIK3IP1: structure, aberration, function, and regulation in diseases. Eur J Pharmacol 2024; 977:176753. [PMID: 38897445 DOI: 10.1016/j.ejphar.2024.176753] [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: 02/15/2024] [Revised: 06/01/2024] [Accepted: 06/16/2024] [Indexed: 06/21/2024]
Abstract
Phosphoinositide 3-kinase (PI3K) pathway, controlling diverse functions in cells, is one of the most frequently dysregulated pathways in cancer. Several negative regulators have been reported to intricately constrain the overactivation of PI3K pathway. Phosphatidylinoinosidine-3-kinase interacting protein 1 (PIK3IP1), as a unique transmembrane protein, is a newly discovered negative regulator of PI3K pathway. PIK3IP1 negatively regulates PI3K activity by directly binding to the p110 catalytic subunit of PI3K. It has been reported that PIK3IP1 is frequently low expressed in tumors and autoimmune diseases. In tumor cells and impaired cardiomyocyte, PIK3IP1 inhibits cell proliferation and survival. Consistently, the expression of PIK3IP1 is related with the condition of cancer. In addition, PIK3IP1 inhibits the inflammatory response and immune function via maintaining the quiescent state of immune cells. Thus, low expression of PIK3IP1 represents the severe condition of autoimmune diseases. PIK3IP1 is regulated by transcription factors, epigenetic factors or micro-RNAs to facilitate its normal function in different cellular contexts. This review integrates the total findings on PIK3IP1 in different disease, and summaries the structure, biological functions and regulatory mechanisms of PIK3IP1.
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Affiliation(s)
- Yingjie Jia
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Pengxing He
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Xubin Ma
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Kaili Lv
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Ying Liu
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Yichao Xu
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, 450001, China.
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Vogt S, Handke D, Behre HM, Greither T. Decreased Serum Levels of the Insulin Resistance-Related microRNA miR-320a in Patients with Polycystic Ovary Syndrome. Curr Issues Mol Biol 2024; 46:3379-3393. [PMID: 38666942 PMCID: PMC11049427 DOI: 10.3390/cimb46040212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 04/10/2024] [Accepted: 04/13/2024] [Indexed: 04/28/2024] Open
Abstract
Polycystic ovary syndrome (PCOS) is often associated with metabolic abnormalities in the affected patients such as obesity or a dysregulated glucose metabolism/insulin resistance (IR). IR affects the serum levels of several circulating microRNAs; however, studies on the association between IR-related microRNAs and PCOS are scarce. Therefore, we quantified the serum levels of the IR-associated microRNAs miR-93, miR-148a, miR-216a, miR-224 and miR-320a via qPCR in a cohort of 358 infertility patients, of whom 136 were diagnosed with PCOS. In bivariate correlation analyses, the serum levels of miR-93 and miR-216a were inversely associated with dipeptidyl peptidase 4 serum concentrations, and the miR-320a serum levels were significantly downregulated in PCOS patients (p = 0.02, Mann-Whitney U test). Interestingly, in all patients who achieved pregnancy after Assisted Reproductive Technology (ART) cycles, the serum levels of the five IR-associated microRNAs were significantly elevated compared to those of non-pregnant patients. In cell culture experiments, we detected a significant upregulation of miR-320a expression following testosterone stimulation over 24 and 48 h in KGN and COV434 granulosa carcinoma cells. In conclusion, we demonstrated a significantly reduced serum level of the IR-associated miR-320a in our patient cohort. This result once again demonstrates the close relationship between metabolic disorders and the dysregulation of microRNA expression patterns in PCOS.
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Affiliation(s)
| | | | | | - Thomas Greither
- Center for Reproductive Medicine and Andrology, Martin-Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle, Germany
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Li G, Liu J, Wang Y, Liu H, Fu J, Zhao Y, Huang Y. METTL3-mediated m6A modification of pri-miR-148a-3p affects prostate cancer progression by regulating TXNIP. ENVIRONMENTAL TOXICOLOGY 2023; 38:2377-2390. [PMID: 37449729 DOI: 10.1002/tox.23874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 05/30/2023] [Accepted: 06/11/2023] [Indexed: 07/18/2023]
Abstract
OBJECTIVE Prostate cancer (PCa) severely affects men's health worldwide. The mechanism of methyltransferase-like 3 (METTL3) in affecting PCa development by regulating miR-148a-3p expression via N6-methyladenosine (m6A) modification was investigated. METHODS METTL3, miR-148a-3p, and thioredoxin interacting protein (TXNIP) levels were determined using RT-qPCR and Western blotting. The m6A modification level of miR-148a-3p was observed by Me-RIP assay. Bioinformatics website predicted miR-148a-3p and TXNIP levels in PCa and their correlation, and the binding site between them was verified by dual-luciferase assay. The proliferation, migration, invasion, and apoptosis of PCa cells were examined by CCK-8 assay, Transwell assay, and flow cytometry. A transplanted tumor model was established in nude mice to observe the tumor growth ability, followed by determination of TXNIP levels in tumor tissues by immunohistochemistry. RESULTS METTL3 interference restrained the proliferation, migration, and invasion and promoted apoptosis of PCa cells. METTL3 up-regulated miR-148a-3p by promoting the m6A modification of pri-miR-148a-3p in PCa cells. miR-148a-3p overexpression nullified the inhibitory actions of silencing METTL3 on PCa cell growth. miR-148a-3p facilitated PCa cell growth by silencing TXNIP. METTL3 interference inhibited tumor growth by down-regulating miR-148a-3p and up-regulating TXNIP. CONCLUSION METTL3 promoted miR-148a-3p by mediating the m6A modification of pri-miR-148a-3p, thereby targeting TXNIP, interfering with METTL3 to inhibit the proliferation, migration and invasion of PCa cells, promote apoptosis, and inhibit tumor growth in nude mice.
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Affiliation(s)
- Guoqiang Li
- Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Junwen Liu
- Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, China
| | - Yinhuai Wang
- Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Hanqi Liu
- Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, China
| | - Jianhan Fu
- Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yuanqiao Zhao
- Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yanqing Huang
- Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, China
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Juracek J, Madrzyk M, Stanik M, Ruckova M, Trachtova K, Malcikova H, Lzicarova E, Barth DA, Pichler M, Slaby O. A tissue miRNA expression pattern is associated with disease aggressiveness of localized prostate cancer. Prostate 2023; 83:340-351. [PMID: 36478451 DOI: 10.1002/pros.24466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Revised: 11/15/2022] [Accepted: 11/21/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND Prostate cancer (PCa) is a heterogeneous malignancy with high variability in clinical course. Insufficient stratification according to the aggressiveness at the time of diagnosis causes unnecessary or delayed treatment. Current stratification systems are not effective enough because they are based on clinical, surgical or biochemical parameters, but do not take into account molecular factors driving PCa cancerogenesis. MicroRNAs (miRNAs) are important players in molecular pathogenesis of PCa and could serve as valuable biomarkers for the assessment of disease aggressiveness and its prognosis. METHODS In the study, in total, 280 PCa patients were enrolled. The miRNA expression profiles were analyzed in FFPE PCa tissue using the miRCURY LNA miRNA PCR System. The expression levels of candidate miRNAs were further verified by two-level validation using the RT-qPCR method and evaluated in relation to PCa stratification reflecting the disease aggressiveness. RESULTS MiRNA profiling revealed 172 miRNAs dysregulated between aggressive (ISUP 3-5) and indolent PCa (ISUP 1) (p < 0.05). In the training and validation cohort, miR-15b-5p and miR-106b-5p were confirmed to be significantly upregulated in tissue of aggressive PCa when their level was associated with disease aggressiveness. Furthermore, we established a prognostic score combining the level of miR-15b-5p and miR-106b-5p with serum PSA level, which discriminated indolent PCa from an aggressive form with even higher analytical parameters (AUC being 0.9338 in the training set and 0.8014 in the validation set, respectively). The score was also associated with 5-year biochemical progression-free survival (bPFS) of PCa patients. CONCLUSIONS We identified a miRNA expression pattern associated with disease aggressiveness in prostate cancer patients. These miRNAs may be of biological interest as the focus can be also set on their specific role within the molecular pathology and the molecular mechanism that underlies the aggressivity of prostate cancer.
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Affiliation(s)
- Jaroslav Juracek
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
| | - Marie Madrzyk
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
| | - Michal Stanik
- Department of Urologic Oncology, Clinic of Surgical Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - Michaela Ruckova
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
| | - Karolina Trachtova
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
| | - Hana Malcikova
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
| | - Eva Lzicarova
- Department of Oncological Pathology, Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - Dominik A Barth
- Department of Internal Medicine, Division of Oncology, Medical University of Graz, Graz, Austria
| | - Martin Pichler
- Department of Internal Medicine, Division of Oncology, Medical University of Graz, Graz, Austria
| | - Ondrej Slaby
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
- Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
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Bilal M, Javaid A, Amjad F, Youssif TA, Afzal S. An overview of prostate cancer (PCa) diagnosis: Potential role of miRNAs. Transl Oncol 2022; 26:101542. [PMID: 36148731 PMCID: PMC9493385 DOI: 10.1016/j.tranon.2022.101542] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 08/18/2022] [Accepted: 09/07/2022] [Indexed: 12/15/2022] Open
Abstract
Prostate cancer is the second most frequently diagnosed cancer among men worldwide, with the estimated sixth leading cause of cancer death. Despite major advancements in clinical biology and imaging, digital rectal examination (DRE), prostate-specific antigen (PSA), and biopsies indication remain the keystone for screening. Several kits are used to detect genomic changes and non-coding RNAs in the sample. However, its indication remains controversial for screening purposes. There is an urged need for non-invasive biomarkers to implement precision medicine. Recent research shows that miRNAs have an important role in the diagnostic, prognostic, and therapeutic agents as non-invasive biomarkers. Though prostate cancer data remains controversial in other cancer types, such as breast cancer, miR-21 expression is upregulated. Here, we reported a prolonged revision of miRNAs as prostate cancer prognostic, diagnostic, and predictive tools, including data on androgen receptor (AR) signaling, epithelial-mesenchymal transition (EMT) process, and cancer stem cells (CSCs) regulation. The combined utilization of miRNAs with other tests will help patients and clinicians to select the most appropriate personalized treatment and to avoid overdiagnosis and unnecessary biopsies. Future clinical applications of our reported novel miRNAs have a substantial role in the primary diagnosis of prostate cancer to help treatment decisions.
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Affiliation(s)
- Muhammad Bilal
- Department of Biotechnology, Graduate School of Engineering, Osaka University, Suita, Japan; SANKEN (The Institute of Scientific and Industrial Research), Osaka University, Ibaraki, Japan
| | - Aqsa Javaid
- Center of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Farhat Amjad
- Quaid-e-Azam Medical College, Bahawalpur, Pakistan
| | | | - Samia Afzal
- Center of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
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Alhammad R. Bioinformatics Analysis of the Prognostic Significance of CAND1 in ERα-Positive Breast Cancer. Diagnostics (Basel) 2022; 12:diagnostics12102327. [PMID: 36292029 PMCID: PMC9600875 DOI: 10.3390/diagnostics12102327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Revised: 09/25/2022] [Accepted: 09/26/2022] [Indexed: 12/04/2022] Open
Abstract
The identification of novel prognostic biomarkers for breast cancer is an unmet clinical need. Cullin-associated and neddylation-dissociated 1 (CAND1) has been implicated in mediating carcinogenesis in prostate and lung cancers. In addition, CAND1 is an established prognostic biomarker for worse prognosis in liver cancer. However, the prognostic significance of CAND1 in breast cancer has not yet been explored. In this study, Breast Cancer Gene-Expression Miner (Bc-GenExMiner) and TIMER2.0 were utilized to explore the mRNA expression of CAND1 in ERα-positive breast cancer patients. The Kaplan–Meier plotter was used to explore the relationship between CAND1 expression and several prognostic indicators. The Gene Set Cancer Analysis (GSCA) web server was then used to explore the pathways of the genes that correlate with CAND1 in ERα-positive breast cancer. Immune infiltration was investigated using Bc-GenExMiner. Our bioinformatics analysis illustrates that breast cancer patients have higher CAND1 compared to normal breast tissue and that ERα-positive breast cancer patients with a high expression of CAND1 have poor overall survival (OS), distant metastasis-free survival (DMFS), and relapse-free survival (RFS) outcomes. Higher CAND1 expression was observed in histologic grade 3 compared to grades 2 and 1. Our results revealed that CAND1 positively correlates with lymph nodes and negatively correlates with the infiltration of immune cells, which is in agreement with published reports. Our findings suggest that CAND1 might mediate invasion and metastasis in ERα-positive breast cancer, possibly through the activation of estrogen and androgen signaling pathways; however, experiments should be carried out to further explore the role of CAND1 in activating the androgen and estrogen signaling pathways. In conclusion, the results suggest that CAND1 could be used as a potential novel biomarker for worse prognosis in ERα-positive breast cancer.
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Affiliation(s)
- Rashed Alhammad
- Department of Pharmacology, Faculty of Medicine, Kuwait University, Kuwait City 13110, Kuwait
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10
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She K, Yu S, He S, Wang W, Chen B. CircRNA 0009043 suppresses non-small-cell lung cancer development via targeting the miR-148a-3p/DNAJB4 axis. Biomark Res 2022; 10:61. [PMID: 35974419 PMCID: PMC9380299 DOI: 10.1186/s40364-022-00407-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 08/04/2022] [Indexed: 11/13/2022] Open
Abstract
Background Circular RNAs (circRNAs) are important regulators of the development and progression of non-small-cell lung cancer (NSCLC) and many other malignancies. The functional importance of circ_0009043 in NSCLC, however, has yet to be established. Methods The expression of circ_0009043, miR-148a-3p, and DnaJ heat shock protein family (Hsp40) member B4 (DNAJB4) in NSCLC cells was assessed via qPCR. The proliferative activity of these cells was examined through EdU uptake and CCK-8 assays, while flow cytometry approaches were used to examine apoptotic cell death rates. Protein expression was measured through Western immunoblotting. Interactions between miR-148a-3p and circ_0009043 or DNAJB4 were detected through RNA immunoprecipitation (RIP) and dual-luciferase reporter assays. The in vivo importance of circ_0009043 as a regulator of oncogenic activity was assessed using murine xenograft models. Results Both NSCLC cells and tissue samples were found to exhibit circ_0009043 upregulation, and lower circ_0009043 expression levels were found to be related to poorer NSCLC patient overall survival. Knocking down circ_0009043 resulted in the enhancement of NSCLC cell proliferative activity and the suppression of apoptotic tumor cell death in vitro, while also driving more rapid in vivo tumorigenesis. Mechanistically, circ_0009043 was found to function as a molecular sponge that sequestered miR-148a-3p, which was in turn able to directly suppress DNAJB4 expression. When miR-148a-3p was overexpressed, this reversed the impact of knocking down circ_0009043 on the apoptotic death and proliferation of NSCLC cells. Conversely, miR-148a-3p inhibition resulted in the suppression of NSCLC cell apoptosis and the enhancement of tumor cell growth, while the downregulation of DNAJB4 reversed these changes. Conclusion Circ_0009043 acts as a tumor suppressor in NSCLC cells, promoting DNAJB4 upregulation via the sequestration of miR-148a-3p.
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Affiliation(s)
- Kelin She
- Department of Thoracic Surgery, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Nomal University, Changsha, Hunan, 410005, China. .,Cancer Research Institute, Central South University, Changsha, 410078, Hunan, China.
| | - Shaoqi Yu
- Department of Thoracic Surgery, The Central Hospital of Shaoyang Affiliated to University of South China, 422000, Shaoyang, China
| | - Shushuai He
- Department of Thoracic Surgery, The Central Hospital of Shaoyang Affiliated to University of South China, 422000, Shaoyang, China
| | - Wen Wang
- Department of Thoracic Surgery, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Nomal University, Changsha, Hunan, 410005, China
| | - Biao Chen
- Department of Thoracic Surgery, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Nomal University, Changsha, Hunan, 410005, China
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11
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Snipaitiene K, Bakavicius A, Lazutka JR, Ulys A, Jankevicius F, Jarmalaite S. Urinary microRNAs can predict response to abiraterone acetate in castration resistant prostate cancer: A pilot study. Prostate 2022; 82:475-482. [PMID: 34970742 DOI: 10.1002/pros.24293] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 12/06/2021] [Accepted: 12/17/2021] [Indexed: 12/25/2022]
Abstract
BACKGROUND Despite novel agents have been introduced to treat castration resistant prostate cancer (CRPC) during the last decade, up to one-third of CRPC patients face primary resistance to new generation compounds. Therefore, sensitive molecular tools are urgently needed for reliable treatment selection and response prediction. This study aimed to evaluate urinary miRNAs and blood circulating androgen receptor (AR) transcript level as a tool for noninvasive outcome prediction for CRPC patients undergoing abiraterone acetate (AA) therapy. METHODS Prostate cancer-specific miR-148a, -365, -375, and -429 were analyzed in 129 urine samples collected from 100 CRPC patients before and during AA therapy via quantitative reverse transcription PCR. To test the prognostic value, urinary miRNA levels alone, as well as combined with AR level were associated with progression-free survival (PFS) and overall survival (OS). RESULTS Level of urinary miR-375 was the highest in CRPC in comparison to noncancerous controls, as well as in combination with miR-429 was predictive for short PFS in AA-treated patients (HR = 2.2, 95% CI: 1.1-4.2, p = 0.023). Especially high prognostic power of all analyzed miRNAs was observed in CRPC cases with high blood AR levels. For PFS prediction a tandem of miR-429 and high AR reached HR of 5.0 (95% CI: 2.2-11.8, p < 0.001), while for prediction of OS the best combination was demonstrated by miR-148a and AR with HR of 3.1 (95% CI: 1.4-7.1, p = 0.006). CONCLUSIONS Urinary miRNAs could be used as prognostic biomarkers for CRPC patients to predict response to AA therapy, especially for the cases with high blood AR levels.
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Affiliation(s)
- Kristina Snipaitiene
- Life Sciences Center, Institute of Biomedical Sciences, Vilnius University, Vilnius, Lithuania
- National Cancer Institute of Lithuania, Vilnius, Lithuania
| | - Arnas Bakavicius
- National Cancer Institute of Lithuania, Vilnius, Lithuania
- Urology Centre, Vilnius University, Vilnius, Lithuania
- Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Juozas R Lazutka
- Life Sciences Center, Institute of Biomedical Sciences, Vilnius University, Vilnius, Lithuania
| | - Albertas Ulys
- National Cancer Institute of Lithuania, Vilnius, Lithuania
| | - Feliksas Jankevicius
- National Cancer Institute of Lithuania, Vilnius, Lithuania
- Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Sonata Jarmalaite
- Life Sciences Center, Institute of Biomedical Sciences, Vilnius University, Vilnius, Lithuania
- National Cancer Institute of Lithuania, Vilnius, Lithuania
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12
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Role of miRNA-145, 148, and 185 and Stem Cells in Prostate Cancer. Int J Mol Sci 2022; 23:ijms23031626. [PMID: 35163550 PMCID: PMC8835890 DOI: 10.3390/ijms23031626] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 01/11/2022] [Accepted: 01/29/2022] [Indexed: 01/27/2023] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNA molecules that play a role in cancer linked to the regulation of important cellular processes and pathways involving tumorigenesis, cell proliferation, differentiation, and apoptosis. A lot of human miRNA sequences have been identified which are linked to cancer pathogenesis. MicroRNAs, in prostate cancer (PC), play a relevant role as biomarkers, show a specific profile, and have been used as therapeutic targets. Prostate cancer (PC) is the most frequently diagnosed cancer in men. Clinical diagnoses among the gold standards for PC diagnosis and monitoring are prostate-specific antigen (PSA) testing, digital rectal examination, and prostate needle biopsies. PSA screening still has a large grey area of patients, which leads to overdiagnosis. Therefore, new biomarkers are needed to improve existing diagnostic tools. The miRNA expression profiles from tumour versus normal tissues are helpful and exhibit significant differences not only between cancerous and non-cancerous tissues, but also between different cancer types and subtypes. In this review, we focus on the role of miRNAs-145, 148, and 185 and their correlation with stem cells in prostate cancer pathogenesis. MiR-145, by modulating multiple oncogenes, regulates different cellular processes in PC, which are involved in the transition from localised to metastatic disease. MiR-148 is downregulated in high-grade tumours, suggesting that the miR-148-3 family might act as tumour suppressors in PC as a potential biomarker for detecting this disease. MiR-185 regulation is still unclear in being able to regulate tumour processes in PC. Nevertheless, other authors confirm the role of this miRNA as a tumour suppressor, suggesting its potential use as a suitable biomarker in disease prognosis. These three miRNAs are all involved in the regulation of prostate cancer stem cell behaviour (PCSCs). Within this contest, PCSCs are often involved in the onset of chemo-resistance in PC, therefore strategies for targeting this subset of cells are strongly required to control the disease. Hence, the relationship between these two players is interesting and important in prostate cancer pathogenesis and in PCSC stemness regulation, in the attempt to pave the way for novel therapeutic targets in prostate cancer.
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13
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Zhou L, Yu X, Guo Y, Liu X. LncRNA RMRP knockdown promotes proliferation and migration of Schwann cells by mediating the miR-766-5p/CAND1 axis. Neurosci Lett 2022; 770:136440. [PMID: 34974108 DOI: 10.1016/j.neulet.2021.136440] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 12/25/2021] [Accepted: 12/28/2021] [Indexed: 12/22/2022]
Abstract
The proliferation and migration of Schwann cells (SCs) promote nerve regeneration after facial nerve injury. In recent years, the role of long noncoding RNAs (lncRNAs) in regulating SC proliferation and migration has been gradually uncovered. However, there is little evidence on the function of lncRNA RMRP (lnc-RMRP) in SC growth. In the present study, we performed loss-of-function and overexpression assays to explore the function of lnc-RMRP in SCs. The relationships between lnc-RMRP, miR-766-5p and CAND1 (cullin-associated and neddylation-dissociated 1) were analyzed using bioinformatics analysis, luciferase detection, RNA binding protein immunoprecipitation and RNA pulldown methods. CCK-8, EdU, Transwell and wound healing assays were utilized for the detections of cell proliferation and migration. We found that lnc-RMRP silencing enhanced cell proliferation and migration of SCs, while lnc-RMRP overexpression showed the opposite effect. Mechanistically, lnc-RMRP directly bound to and negatively modulated the expression of miR-766-5p. MiR-766-5p knockdown decreased cell viability, proliferation and migration of SCs, and also reversed the effects of lnc-RMRP silencing. In addition, lnc-RMRP positively regulated CAND1 expression by sponging miR-766-5p. Upregulation of CAND1 rescued the function of lnc-RMRP knockdown in regulating SC proliferation and migration. These data suggested that lnc-RMRP played a significant role in SC proliferation and migration, indicating that lnc-RMRP might be a potential therapeutic target for the treatment of facial nerve injury.
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Affiliation(s)
- Long Zhou
- Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University & State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Clinical Research Center for Oral Diseases, Xi'an 710032, Shaanxi, China
| | - Xueyuan Yu
- Department of Aesthetic Plastic & Craniofacial Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China
| | - Yuan Guo
- Department of Aesthetic Plastic & Craniofacial Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China
| | - Xiangyu Liu
- Department of Aesthetic Plastic & Craniofacial Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
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14
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Deng T, Xiao Y, Dai Y, Xie L, Li X. Roles of Key Epigenetic Regulators in the Gene Transcription and Progression of Prostate Cancer. Front Mol Biosci 2021; 8:743376. [PMID: 34977151 PMCID: PMC8714908 DOI: 10.3389/fmolb.2021.743376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Accepted: 11/25/2021] [Indexed: 12/24/2022] Open
Abstract
Prostate cancer (PCa) is a top-incidence malignancy, and the second most common cause of death amongst American men and the fifth leading cause of cancer death in men around the world. Androgen receptor (AR), the key transcription factor, is critical for the progression of PCa by regulating a series of target genes by androgen stimulation. A number of co-regulators of AR, including co-activators or co-repressors, have been implicated in AR-mediated gene transcription and PCa progression. Epigenetic regulators, by modifying chromatin integrity and accessibility for transcription regulation without altering DNA sequences, influence the transcriptional activity of AR and further regulate the gene expression of AR target genes in determining cell fate, PCa progression and therapeutic response. In this review, we summarized the structural interaction of AR and epigenetic regulators including histone or DNA methylation, histone acetylation or non-coding RNA, and functional synergy in PCa progression. Importantly, epigenetic regulators have been validated as diagnostic markers and therapeutic targets. A series of epigenetic target drugs have been developed, and have demonstrated the potential to treat PCa alone or in combination with antiandrogens.
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Affiliation(s)
- Tanggang Deng
- Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- NMPA Key Laboratory for Technology Research and Evaluation of Pharmacovigilance, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yugang Xiao
- Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- NMPA Key Laboratory for Technology Research and Evaluation of Pharmacovigilance, Guangdong Pharmaceutical University, Guangzhou, China
- School of Clinical Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yi Dai
- Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- NMPA Key Laboratory for Technology Research and Evaluation of Pharmacovigilance, Guangdong Pharmaceutical University, Guangzhou, China
- School of Clinical Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China
| | - Lin Xie
- Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- NMPA Key Laboratory for Technology Research and Evaluation of Pharmacovigilance, Guangdong Pharmaceutical University, Guangzhou, China
| | - Xiong Li
- Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- NMPA Key Laboratory for Technology Research and Evaluation of Pharmacovigilance, Guangdong Pharmaceutical University, Guangzhou, China
- School of Clinical Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China
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15
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Cavallari I, Ciccarese F, Sharova E, Urso L, Raimondi V, Silic-Benussi M, D’Agostino DM, Ciminale V. The miR-200 Family of microRNAs: Fine Tuners of Epithelial-Mesenchymal Transition and Circulating Cancer Biomarkers. Cancers (Basel) 2021; 13:5874. [PMID: 34884985 PMCID: PMC8656820 DOI: 10.3390/cancers13235874] [Citation(s) in RCA: 99] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/17/2021] [Accepted: 11/18/2021] [Indexed: 12/13/2022] Open
Abstract
The miR-200 family of microRNAs (miRNAs) includes miR-200a, miR-200b, miR-200c, miR-141 and miR-429, five evolutionarily conserved miRNAs that are encoded in two clusters of hairpin precursors located on human chromosome 1 (miR-200b, miR-200a and miR-429) and chromosome 12 (miR-200c and miR-141). The mature -3p products of the precursors are abundantly expressed in epithelial cells, where they contribute to maintaining the epithelial phenotype by repressing expression of factors that favor the process of epithelial-to-mesenchymal transition (EMT), a key hallmark of oncogenic transformation. Extensive studies of the expression and interactions of these miRNAs with cell signaling pathways indicate that they can exert both tumor suppressor- and pro-metastatic functions, and may serve as biomarkers of epithelial cancers. This review provides a summary of the role of miR-200 family members in EMT, factors that regulate their expression, and important targets for miR-200-mediated repression that are involved in EMT. The second part of the review discusses the potential utility of circulating miR-200 family members as diagnostic/prognostic biomarkers for breast, colorectal, lung, ovarian, prostate and bladder cancers.
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Affiliation(s)
- Ilaria Cavallari
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
| | - Francesco Ciccarese
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
| | - Evgeniya Sharova
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
| | - Loredana Urso
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padova, Italy
| | - Vittoria Raimondi
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
| | - Micol Silic-Benussi
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
| | - Donna M. D’Agostino
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
- Department of Biomedical Sciences, University of Padua, 35131 Padova, Italy
| | - Vincenzo Ciminale
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padova, Italy
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16
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Sanwlani R, Gangoda L. Role of Extracellular Vesicles in Cell Death and Inflammation. Cells 2021; 10:2663. [PMID: 34685643 PMCID: PMC8534608 DOI: 10.3390/cells10102663] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 10/02/2021] [Accepted: 10/04/2021] [Indexed: 02/07/2023] Open
Abstract
Extracellular vesicles (EVs) have been identified as novel mediators of intercellular communication. They work via delivering the sequestered cargo to cells in the close vicinity, as well as distant sites in the body, regulating pathophysiological processes. Cell death and inflammation are biologically crucial processes in both normal physiology and pathology. These processes are indistinguishably linked with their effectors modulating the other process. For instance, during an unresolvable infection, the upregulation of specific immune mediators leads to inflammation causing cell death and tissue damage. EVs have gained considerable interest as mediators of both cell death and inflammation during conditions, such as sepsis. This review summarizes the types of extracellular vesicles known to date and their roles in mediating immune responses leading to cell death and inflammation with specific focus on sepsis and lung inflammation.
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Affiliation(s)
- Rahul Sanwlani
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3083, Australia;
| | - Lahiru Gangoda
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3083, Australia;
- The Walter and Eliza Hall Institute of Medical Research (WEHI), 1G Royal Parade, Parkville, Melbourne, VIC 3052, Australia
- Department of Medical Biology, University of Melbourne, Parkville, Melbourne, VIC 3010, Australia
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17
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Choi Y, Kim B, Ham S, Chung S, Maeng S, Kim HS, Im HI. Subanesthetic ketamine rapidly alters medial prefrontal miRNAs involved in ubiquitin-mediated proteolysis. PLoS One 2021; 16:e0256390. [PMID: 34437591 PMCID: PMC8389495 DOI: 10.1371/journal.pone.0256390] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 08/05/2021] [Indexed: 12/14/2022] Open
Abstract
Ketamine is a dissociative anesthetic and a non-competitive NMDAR antagonist. At subanesthetic dose, ketamine can relieve pain and work as a fast-acting antidepressant, but the underlying molecular mechanism remains elusive. This study aimed to investigate the mode of action underlying the effects of acute subanesthetic ketamine treatment by bioinformatics analyses of miRNAs in the medial prefrontal cortex of male C57BL/6J mice. Gene Ontology and KEGG pathway analyses of the genes putatively targeted by ketamine-responsive prefrontal miRNAs revealed that acute subanesthetic ketamine modifies ubiquitin-mediated proteolysis. Validation analysis suggested that miR-148a-3p and miR-128-3p are the main players responsible for the subanesthetic ketamine-mediated alteration of ubiquitin-mediated proteolysis through varied regulation of ubiquitin ligases E2 and E3. Collectively, our data imply that the prefrontal miRNA-dependent modulation of ubiquitin-mediated proteolysis is at least partially involved in the mode of action by acute subanesthetic ketamine treatment.
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Affiliation(s)
- Yunjung Choi
- Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology (KIST), Seoul, South Korea
- Department of Pharmacology, College of Medicine, Seoul National University, Seoul, South Korea
| | - Baeksun Kim
- Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology (KIST), Seoul, South Korea
- Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul, South Korea
| | - Suji Ham
- Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology (KIST), Seoul, South Korea
- Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul, South Korea
| | - Sooyoung Chung
- Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea
| | - Sungho Maeng
- College of East-West Medical Science, Kyung Hee University, Yongin, South Korea
| | - Hye-Sun Kim
- Department of Pharmacology, College of Medicine, Seoul National University, Seoul, South Korea
- Department of Pharmacology, Seoul National University Bundang Hospital, Seongnam, Bundang-Gu, South Korea
| | - Heh-In Im
- Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology (KIST), Seoul, South Korea
- Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul, South Korea
- Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea
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18
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Rode MP, Silva AH, Cisilotto J, Rosolen D, Creczynski-Pasa TB. miR-425-5p as an exosomal biomarker for metastatic prostate cancer. Cell Signal 2021; 87:110113. [PMID: 34371055 DOI: 10.1016/j.cellsig.2021.110113] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 08/03/2021] [Accepted: 08/04/2021] [Indexed: 12/21/2022]
Abstract
Prostate cancer-related deaths are mostly caused by metastasis, which indicates the importance of identifying clinical prognostic biomarkers. In this study, we evaluated the expression profile of exosomal microRNAs (miRNAs) derived from metastatic prostate cancer (mPCa) cell lines (LNCaP and PC-3). miRNA signatures in exosomes and cells were evaluated by miRNA microarray analysis. Fourteen miRNAs were identified as candidates for specific noninvasive biomarkers. The expression of five miRNAs was validated using RT-qPCR, which confirmed that miR-205-5p, miR-148a-3p, miR-125b-5p, miR-183-5p, and miR-425-5p were differentially expressed in mPCa exosomes. Bioinformatic analyses showed that miR-425-5p was associated with residual tumor, pathologic T and N stages, and TP53 status in PCa samples. Gene ontology analysis of negatively correlated and predicted targeted genes showed enrichment of genes related to bone development pathways. The LinkedOmics database indicated that the potential target HSPB8 has a significant negative correlation with miR-425-5p. In conclusion, this study identified a panel of exosomal miRNAs with potential value as prognostic biomarkers for prostate cancer.
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Affiliation(s)
- Michele Patrícia Rode
- Department of Pharmaceutical Sciences, Federal University of Santa Catarina, Florianópolis, SC 88040-900, Brazil
| | - Adny Henrique Silva
- Department of Pharmaceutical Sciences, Federal University of Santa Catarina, Florianópolis, SC 88040-900, Brazil
| | - Júlia Cisilotto
- Department of Pharmaceutical Sciences, Federal University of Santa Catarina, Florianópolis, SC 88040-900, Brazil
| | - Daiane Rosolen
- Department of Pharmaceutical Sciences, Federal University of Santa Catarina, Florianópolis, SC 88040-900, Brazil
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19
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Maryam Khorasani, Shahbazi S, Abolhasani M, Shahrokh H, Mahdian R. Expression Profile of MiR-200 Family Members and Their Targets in Prostate Cancer. CYTOL GENET+ 2021. [DOI: 10.3103/s009545272104006x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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20
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Novel, non-invasive markers for detecting therapy induced neuroendocrine differentiation in castration-resistant prostate cancer patients. Sci Rep 2021; 11:8279. [PMID: 33859239 PMCID: PMC8050049 DOI: 10.1038/s41598-021-87441-2] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 03/30/2021] [Indexed: 12/25/2022] Open
Abstract
Neuroendocrine prostate cancer (NEPC), a highly aggressive variant of castration-resistant prostate cancer (CRPC), often emerges upon treatment with androgen pathway inhibitors, via neuroendocrine differentiation. Currently, NEPC diagnosis is challenging as available markers are not sufficiently specific. Our objective was to identify novel, extracellular vesicles (EV)-based biomarkers for diagnosing NEPC. Towards this, we performed small RNA next generation sequencing in serum EVs isolated from a cohort of CRPC patients with adenocarcinoma characteristics (CRPC-Adeno) vs CRPC-NE and identified significant dysregulation of 182 known and 4 novel miRNAs. We employed machine learning algorithms to develop an 'EV-miRNA classifier' that could robustly stratify 'CRPC-NE' from 'CRPC-Adeno'. Examination of protein repertoire of exosomes from NEPC cellular models by mass spectrometry identified thrombospondin 1 (TSP1) as a specific biomarker. In view of our results, we propose that a miRNA panel and TSP1 can be used as novel, non-invasive tools to identify NEPC and guide treatment decisions. In conclusion, our study identifies for the first time, novel non-invasive exosomal/extracellular vesicle based biomarkers for detecting neuroendocrine differentiation in advanced castration resistant prostate cancer patients with important translational implications in clinical management of these patients that is currently extremely challenging.
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21
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Yang Y, Liu KY, Liu Q, Cao Q. Androgen Receptor-Related Non-coding RNAs in Prostate Cancer. Front Cell Dev Biol 2021; 9:660853. [PMID: 33869227 PMCID: PMC8049439 DOI: 10.3389/fcell.2021.660853] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 03/12/2021] [Indexed: 12/20/2022] Open
Abstract
Prostate cancer (PCa) is the second leading cause of cancer-related death among men in the United States. Androgen receptor (AR) signaling is the dominant oncogenic pathway in PCa and the main strategy of PCa treatment is to control the AR activity. A large number of patients acquire resistance to Androgen deprivation therapy (ADT) due to AR aberrant activation, resulting in castration-resistant prostate cancer (CRPC). Understanding the molecular mechanisms underlying AR signaling in the PCa is critical to identify new therapeutic targets for PCa patients. The recent advances in high-throughput RNA sequencing (RNA-seq) techniques identified an increasing number of non-coding RNAs (ncRNAs) that play critical roles through various mechanisms in different diseases. Some ncRNAs have shown great potentials as biomarkers and therapeutic targets. Many ncRNAs have been investigated to regulate PCa through direct association with AR. In this review, we aim to comprehensively summarize recent findings of the functional roles and molecular mechanisms of AR-related ncRNAs as AR regulators or targets in the progression of PCa.
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Affiliation(s)
- Yongyong Yang
- Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.,Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Kilia Y Liu
- Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.,Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Qi Liu
- Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.,Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Qi Cao
- Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.,Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
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22
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Jin X, Hao Z, Zhao M, Shen J, Ke N, Song Y, Qiao L, Lu Y, Hu L, Wu X, Wang J, Luo Y. MicroRNA-148a Regulates the Proliferation and Differentiation of Ovine Preadipocytes by Targeting PTEN. Animals (Basel) 2021; 11:ani11030820. [PMID: 33803986 PMCID: PMC7998426 DOI: 10.3390/ani11030820] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 03/07/2021] [Accepted: 03/08/2021] [Indexed: 12/11/2022] Open
Abstract
MicroRNAs (miRNAs) have been found to be involved in lipid deposition and metabolism. However, there have been no reports on the roles of miR-148a in the proliferation and adipogenesis of preadipocytes in sheep. In this study, the expression of miR-148a was profiled in the eight tissues of Tibetan ewes and differentiated preadipocytes, and the role of miR-148a in differentiation and proliferation of ovine preadipocytes was investigated using Oil Red O staining, CCK-8, EdU staining, cell cycle detection, and RT-qPCR. The effect of PTEN on the differentiation of ovine preadipocytes was also investigated. The miR-148a was widely expressed in the eight tissues investigated and had significantly increased expression in liver, spleen and subcutaneous adipose tissues, and the heart. The expression of miR-148a continued to increase with the differentiation of ovine preadipocytes. The over-expression of miR-148a significantly promoted differentiation but inhibited the proliferation of ovine preadipocytes. The inhibition of miR-148a had the opposite effect on the differentiation and proliferation of ovine preadipocytes with over-expressed miR-148a. The results from the dual luciferase reporter assays showed that miR-148a mimic significantly decreased the luciferase activity of PTEN-3'UTR dual luciferase reporter vector, suggesting that PTEN is a target gene of miR-148a. In over-expressed-PTEN preadipocytes, the number of lipid droplets remarkably decreased, and the expression levels of adipogenesis marker genes PPARγ, FASN, FATP4, GLUT4, C/EBPβ and LPL were also significantly down-regulated. These results suggest that miR-148a accelerated the adipogenic differentiation of ovine preadipocytes by inhibiting PTEN expression, and also inhibited the proliferation of ovine preadipocytes.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Jiqing Wang
- Correspondence: (J.W.); (Y.L.); Tel.: +86-931-763-2469 (J.W.); +86-931-763-2483 (Y.L.)
| | - Yuzhu Luo
- Correspondence: (J.W.); (Y.L.); Tel.: +86-931-763-2469 (J.W.); +86-931-763-2483 (Y.L.)
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23
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Melnik BC. Lifetime Impact of Cow's Milk on Overactivation of mTORC1: From Fetal to Childhood Overgrowth, Acne, Diabetes, Cancers, and Neurodegeneration. Biomolecules 2021; 11:404. [PMID: 33803410 PMCID: PMC8000710 DOI: 10.3390/biom11030404] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 03/04/2021] [Accepted: 03/04/2021] [Indexed: 02/07/2023] Open
Abstract
The consumption of cow's milk is a part of the basic nutritional habits of Western industrialized countries. Recent epidemiological studies associate the intake of cow's milk with an increased risk of diseases, which are associated with overactivated mechanistic target of rapamycin complex 1 (mTORC1) signaling. This review presents current epidemiological and translational evidence linking milk consumption to the regulation of mTORC1, the master-switch for eukaryotic cell growth. Epidemiological studies confirm a correlation between cow's milk consumption and birthweight, body mass index, onset of menarche, linear growth during childhood, acne vulgaris, type 2 diabetes mellitus, prostate cancer, breast cancer, hepatocellular carcinoma, diffuse large B-cell lymphoma, neurodegenerative diseases, and all-cause mortality. Thus, long-term persistent consumption of cow's milk increases the risk of mTORC1-driven diseases of civilization. Milk is a highly conserved, lactation genome-controlled signaling system that functions as a maternal-neonatal relay for optimized species-specific activation of mTORC1, the nexus for regulation of eukaryotic cell growth, and control of autophagy. A deeper understanding of milk´s impact on mTORC1 signaling is of critical importance for the prevention of common diseases of civilization.
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Affiliation(s)
- Bodo C Melnik
- Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück, Am Finkenhügel 7a, D-49076 Osnabrück, Germany
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24
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Galvão-Lima LJ, Morais AHF, Valentim RAM, Barreto EJSS. miRNAs as biomarkers for early cancer detection and their application in the development of new diagnostic tools. Biomed Eng Online 2021; 20:21. [PMID: 33593374 PMCID: PMC7885381 DOI: 10.1186/s12938-021-00857-9] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 02/05/2021] [Indexed: 02/06/2023] Open
Abstract
Over the last decades, microRNAs (miRNAs) have emerged as important molecules associated with the regulation of gene expression in humans and other organisms, expanding the strategies available to diagnose and handle several diseases. This paper presents a systematic review of literature of miRNAs related to cancer development and explores the main techniques used to quantify these molecules and their limitations as screening strategy. The bibliographic research was conducted using the online databases, PubMed, Google Scholar, Web of Science, and Science Direct searching the terms "microRNA detection", "miRNA detection", "miRNA and prostate cancer", "miRNA and cervical cancer", "miRNA and cervix cancer", "miRNA and breast cancer", and "miRNA and early cancer diagnosis". Along the systematic review over 26,000 published papers were reported, and 252 papers were returned after applying the inclusion and exclusion criteria, which were considered during this review. The aim of this study is to identify potential miRNAs related to cancer development that may be useful for early cancer diagnosis, notably in the breast, prostate, and cervical cancers. In addition, we suggest a preliminary top 20 miRNA panel according to their relevance during the respective cancer development. Considering the progressive number of new cancer cases every year worldwide, the development of new diagnostic tools is critical to refine the accuracy of screening tests, improving the life expectancy and allowing a better prognosis for the affected patients.
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Affiliation(s)
- Leonardo J. Galvão-Lima
- Advanced Nucleus of Technological Innovation (NAVI), Federal Institute of Rio Grande do Norte (IFRN), Avenue Senador Salgado Filho 1559, Natal, RN 59015-000 Brazil
| | - Antonio H. F. Morais
- Advanced Nucleus of Technological Innovation (NAVI), Federal Institute of Rio Grande do Norte (IFRN), Avenue Senador Salgado Filho 1559, Natal, RN 59015-000 Brazil
| | - Ricardo A. M. Valentim
- Laboratory of Technological Innovation in Health (LAIS), Hospital Universitário Onofre Lopes (HUOL), Federal University of Rio Grande do Norte (UFRN), Campus Lagoa Nova, Natal, RN Brazil
| | - Elio J. S. S. Barreto
- Division of Oncology and Hematology, Hospital Universitário Onofre Lopes (HUOL), Federal University of Rio Grande do Norte (UFRN), Campus Lagoa Nova, Natal, RN Brazil
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25
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Javed Z, Khan K, Rasheed A, Sadia H, Shahwani MN, Irshad A, Raza S, Salehi B, Sharifi-Rad J, Suleria HAR, Cruz-Martins N, Quispe C. Targeting androgen receptor signaling with MicroRNAs and Curcumin: a promising therapeutic approach for Prostate Cancer Prevention and intervention. Cancer Cell Int 2021; 21:77. [PMID: 33499881 PMCID: PMC7836194 DOI: 10.1186/s12935-021-01777-3] [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: 11/12/2020] [Accepted: 01/16/2021] [Indexed: 12/29/2022] Open
Abstract
Prostate cancer (PC) is a multifactorial disease characterized by the abrogation of androgen receptor signaling. Advancement in microbiology techniques has highlighted the significant role of microRNAs (miRNAs) in the progression of PC cells from an androgen-dependent to an androgen-independent state. At that stage, prostate tumors also fail to respond to currently practiced hormone therapies. So, studies in recent decades are focused on investigating the anti-tumor effects of natural compounds in PC. Curcumin is widely recognized and now of huge prestige for its anti-proliferative abilities in different types of cancer. However, its limited solubility, compatibility, and instability in the aqueous phase are major hurdles when administering. Nanoformulations have proven to be an excellent drug delivery system for various drugs and can be used as potential delivery platforms for curcumin in PC. In this review, a shed light is given on the miRNAs-mediated regulation of androgen receptor (AR) signaling and miRNA-curcumin interplay in PC, as well as on curcumin-based nanoformulations that can be used as possible therapeutic solutions for PC.
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Affiliation(s)
- Zeeshan Javed
- Office for Research Innovation and Commercialization, Lahore Garrison University, DHA, Sector-C, Phase VI, Lahore, Pakistan
| | - Khushbukhat Khan
- Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), 44000, Islamabad, Pakistan
| | - Amna Rasheed
- School of Basic Medical Sciences, Lanzhou University, 730000, Lanzhou, PR China
| | - Haleema Sadia
- Department of Biotechnology, Balochistan University of Information Technology, Engineering and Management Sciences, Quetta, Pakistan
| | - Muhammad Naeem Shahwani
- Department of Biotechnology, Balochistan University of Information Technology, Engineering and Management Sciences, Quetta, Pakistan
| | - Asma Irshad
- Department of Life Sciences, University of Management Sciences, Lahore, Pakistan
| | - Shahid Raza
- Office for Research Innovation and Commercialization, Lahore Garrison University, DHA, Sector-C, Phase VI, Lahore, Pakistan
| | - Bahare Salehi
- Medical Ethics and Law Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Javad Sharifi-Rad
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. .,Facultad de Medicina, Universidad del Azuay, Cuenca, Ecuador.
| | - Hafiz A R Suleria
- School of Agriculture and Food, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, 3010, Parkville, VIC, Australia
| | - Natália Cruz-Martins
- Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal. .,Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135, Porto, Portugal. .,Laboratory of Neuropsychophysiology, Faculty of Psychology and Education Sciences, University of Porto, 4200-135, Porto, Portugal.
| | - Cristina Quispe
- Facultad de Ciencias de la Salud, Universidad Arturo Prat, Avda. Arturo Prat 2120, 1110939, Iquique, Chile.
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26
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Yu H, Xu H, Yan C, Zhu S, Lan X, Lu Y, He Q, Yin H, Zhu Q, Zhao X, Li D, Liu Y, Wang Y. gga-miR-148a-5p-Targeting PDPK1 Inhibits Proliferation and Cell Cycle Progression of Avain Leukosis Virus Subgroup J (ALV-J)-Infected Cells. Front Cell Dev Biol 2021; 8:587889. [PMID: 33384993 PMCID: PMC7769946 DOI: 10.3389/fcell.2020.587889] [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: 07/28/2020] [Accepted: 11/17/2020] [Indexed: 11/21/2022] Open
Abstract
Avian leukosis virus subgroup J disease (ALV-J) is a contagious and immunosuppressive avian disease caused by ALV-J virus. Although miRNA participate in various biological processes of tumors, little is known about the potential role of miRNA in ALV-J. Our previous miRNA and RNA sequencing data showed that the expression of gga-miR-148a-5p was significantly different in ALV-J-infected chicken spleens compared with non-infected chickens. The aim of this study was to investigate the functional roles of gga-miR-148a-5p and identify downstream targets regulated by gga-miR-148a-5p in ALV-J-infected chickens. We found that the expression of gga-miR-148a-5p was significantly downregulated during ALV-J infection of chicken embryo fibroblasts (CEF). Dual luciferase reporter assays demonstrated that PDPK1 is a direct target gene of gga-miR-148a-5p. In vitro, overexpression of gga-miR-148a-5p significantly promoted ALV-J-infected CEF cell proliferation, included cell cycle, whereas inhibition of gga-miR-148a-5p had an opposite effect. Inhibition of PDPK1 promoted the proliferation of ALV-J-infected cells but had no effect on the activity of NF-κB. Together, these results suggested that gga-miR-148a-5p targets PDPK1 to inhibit the proliferation and cell cycle of ALV-J-infected CEF cells. Our study provides a new understanding for the tumor mechanism of ALV-J infection.
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Affiliation(s)
- Heling Yu
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Hengyong Xu
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Chaoyang Yan
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Shiliang Zhu
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Xi Lan
- College of Animal Science and Technology, Southwest University, Chongqing, China
| | - Yuxiang Lu
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Qijian He
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Huadong Yin
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Qing Zhu
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Xiaoling Zhao
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Diyan Li
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Yiping Liu
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Yan Wang
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
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27
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Al-Othman N, Alhendi A, Ihbaisha M, Barahmeh M, Alqaraleh M, Al-Momany BZ. Role of CD44 in breast cancer. Breast Dis 2020; 39:1-13. [PMID: 31839599 DOI: 10.3233/bd-190409] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Breast cancer (BC) is among the most prevalent type of malignancy affecting females worldwide. BC is classified into different types according to the status of the expression of receptors such as estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2), and progesterone receptor (PR). Androgen receptor (AR) appears to be a promising therapeutic target of BC. Binding of 5α-dihydrotestosterone (DHT) to AR controls the expression of microRNA (miRNA) molecules in BC, consequently, affecting protein expression. One of these proteins is the transmembrane glycoprotein cluster of differentiation 44 (CD44). Remarkably, CD44 is a common marker of cancer stem cells in BC. It functions as a co-receptor for a broad diversity of extracellular matrix ligands. Several ligands, primarily hyaluronic acid (HA), can interact with CD44 and mediate its functions. CD44 promotes a variety of functions independently or in cooperation with other cell-surface receptors through activation of varied signaling pathways like Rho GTPases, Ras-MAPK, and PI3K/AKT pathways to regulate cell adhesion, migration, survival, invasion, and epithelial-mesenchymal transition. In this review, we present the relations between AR, miRNA, and CD44 and their roles in BC.
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Affiliation(s)
- Nihad Al-Othman
- Division of Anatomy, Biochemistry, and Genetics, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine
| | - Ala' Alhendi
- Division of Anatomy, Biochemistry, and Genetics, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine
| | - Manal Ihbaisha
- Division of Anatomy, Biochemistry, and Genetics, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine
| | - Myassar Barahmeh
- Division of Anatomy, Biochemistry, and Genetics, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine
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28
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Robak P, Dróżdż I, Jarych D, Mikulski D, Węgłowska E, Siemieniuk-Ryś M, Misiewicz M, Stawiski K, Fendler W, Szemraj J, Smolewski P, Robak T. The Value of Serum MicroRNA Expression Signature in Predicting Refractoriness to Bortezomib-Based Therapy in Multiple Myeloma Patients. Cancers (Basel) 2020; 12:2569. [PMID: 32916955 PMCID: PMC7565855 DOI: 10.3390/cancers12092569] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 08/20/2020] [Accepted: 09/03/2020] [Indexed: 12/22/2022] Open
Abstract
Bortezomib is the first-in-class proteasome inhibitor, commonly used in the treatment of multiple myeloma (MM). The mechanisms underlying acquired bortezomib resistance in MM are poorly understood. Several cell-free miRNAs have been found to be aberrantly regulated in MM patients. The aim of this pilot study was to identify a blood-based miRNA signature that predicts bortezomib-based therapy efficacy in MM patients. Thirty MM patients treated with bortezomib-based regimens were studied, including 19 with refractory disease and 11 who were bortezomib sensitive. Serum miRNA expression patterns were identified with miRCURY LNA miRNA miRNome PCR Panels I+II (Exiqon/Qiagen). Univariate analysis found a total of 21 miRNAs to be differentially expressed in patients with MM according to bortezomib sensitivity. Multivariate logistic regression was created and allowed us to discriminate refractory from sensitive patients with a very high AUC of 0.95 (95%CI: 0.84-1.00); sensitivity, specificity and accuracy were estimated as 0.95, 0.91, and 0.93. The model used expression of 3 miRNAs: miR-215-5p, miR-181a-5p and miR-376c-3p. This study is the first to demonstrate that serum expression of several miRNAs differs between patients who are bortezomib refractory and those who are sensitive which may prove useful in studies aimed at overcoming drug resistance in MM treatment.
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Affiliation(s)
- Paweł Robak
- Department of Experimental Hematology, Medical University of Lodz, 93-510 Lodz, Poland; (P.R.); (P.S.)
| | - Izabela Dróżdż
- Department of Clinical Genetics, Medical University of Lodz, 92-213 Lodz, Poland;
| | - Dariusz Jarych
- Laboratory of Personalized Medicine, Bionanopark, Lodz, 93-465 Lodz, Poland; (D.J.); (E.W.)
| | - Damian Mikulski
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215 Lodz, Poland; (D.M.); (K.S.); (W.F.)
| | - Edyta Węgłowska
- Laboratory of Personalized Medicine, Bionanopark, Lodz, 93-465 Lodz, Poland; (D.J.); (E.W.)
| | - Monika Siemieniuk-Ryś
- Department of Hematology, Medical University of Lodz, 93-510 Lodz, Poland; (M.S.-R.); (M.M.)
| | - Małgorzata Misiewicz
- Department of Hematology, Medical University of Lodz, 93-510 Lodz, Poland; (M.S.-R.); (M.M.)
| | - Konrad Stawiski
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215 Lodz, Poland; (D.M.); (K.S.); (W.F.)
| | - Wojciech Fendler
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215 Lodz, Poland; (D.M.); (K.S.); (W.F.)
| | - Janusz Szemraj
- Department of Medical Biochemistry, Medical University of Lodz, 92-215 Lodz, Poland;
| | - Piotr Smolewski
- Department of Experimental Hematology, Medical University of Lodz, 93-510 Lodz, Poland; (P.R.); (P.S.)
| | - Tadeusz Robak
- Department of Hematology, Medical University of Lodz, 93-510 Lodz, Poland; (M.S.-R.); (M.M.)
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29
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Gurbuz V, Kiliccioglu I, Dikmen AU, Bilen CY, Sozen S, Konac E. Comparative analysis of epi-miRNA expression levels in local/locally advanced and metastatic prostate cancer patients. Gene 2020; 758:144963. [PMID: 32683077 DOI: 10.1016/j.gene.2020.144963] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 06/10/2020] [Accepted: 07/13/2020] [Indexed: 12/24/2022]
Abstract
Abnormal expression of enzymes involved in epigenetic mechanisms, such as DNA methyl transferases, can trigger large chaos in cellular gene expression networks and eventually lead to cancer progression. In our study, which is a pioneer in the literature that clinicopathologically evaluates the expression of 30 epi-miRNAs in prostate cancer (PCa), we investigated which of the new miRNA class epi-miRNAs could be an effective biomarker in the diagnosis and progression of PCa. In this study, the expression levels of 30 epi-miRNAs in whole blood samples from 25 control, 25 PCa and 40 metastatic PCa patients were investigated by the Quantitative Real-Time PCR method. Then, promoter methylation levels of 11 epi-miRNAs, whose expression levels were found to be significantly higher, were examined by methylation-specific qPCR method. The correlations between miRNA expression levels and clinicopathological parameters (Gleason Score (GS), PSA levels, TNM Staging) in different stages of PCa groups as well as disease-specific expression levels were examined. We found a hypomethylation in the promoter regions of miRNAs that showed a direct proportional increase with PSA levels (miR-34b/c, miR-148a, miR-152), GS's (miR-34a-5p, miR-34b/c, miR-101-2, miR-126, miR-148a, miR- 152, miR-185-5p) and T staging (miR-34a-5p, miR-34b/c, miR-101-2, miR-126, miR-140, miR-148a, miR-152, miR-185-5p) (p < 0.05). When miR-200a/b was evaluated according to clinicopathological parameters, it acted as an onco-miR in local/local advanced PCa and as a tumor-suppressor-miR in metastatic stage. This study is novel in the sense that our findings draw attention to the important role of miRNAs as diagnostic and prognostic biomarkers in PCa.
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Affiliation(s)
- Venhar Gurbuz
- Department of Medical Biology and Genetics, Faculty of Medicine, Gazi University, Besevler 06510, Ankara, Turkey
| | - Ilker Kiliccioglu
- Department of Medical Biology and Genetics, Faculty of Medicine, Gazi University, Besevler 06510, Ankara, Turkey; Department of Medical Biology, Faculty of Medicine, Duzce University, 81620 Duzce, Turkey
| | - Asiye Ugras Dikmen
- Department of Public Health, Faculty of Medicine, Gazi University, Besevler 06510, Ankara, Turkey
| | - Cenk Y Bilen
- Department of Urology, Faculty of Medicine, Hacettepe University, Sıhhiye 06100, Ankara, Turkey
| | - Sinan Sozen
- Department of Urology, Faculty of Medicine, Gazi University, Besevler 06510, Ankara, Turkey
| | - Ece Konac
- Department of Medical Biology and Genetics, Faculty of Medicine, Gazi University, Besevler 06510, Ankara, Turkey.
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30
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MicroRNAs as Guardians of the Prostate: Those Who Stand before Cancer. What Do We Really Know about the Role of microRNAs in Prostate Biology? Int J Mol Sci 2020; 21:ijms21134796. [PMID: 32645914 PMCID: PMC7370012 DOI: 10.3390/ijms21134796] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 06/29/2020] [Accepted: 07/02/2020] [Indexed: 12/17/2022] Open
Abstract
Prostate cancer is the second leading cause of cancer-related deaths of men in the Western world. Despite recent advancement in genomics, transcriptomics and proteomics to understand prostate cancer biology and disease progression, castration resistant metastatic prostate cancer remains a major clinical challenge and often becomes incurable. MicroRNAs (miRNAs), about 22-nucleotide-long non-coding RNAs, are a group of regulatory molecules that mainly work through post-transcriptional gene silencing via translational repression. Expression analysis studies have revealed that miRNAs are aberrantly expressed in cancers and have been recognized as regulators of prostate cancer progression. In this critical review, we provide an analysis of reported miRNA functions and conflicting studies as they relate to expression levels of specific miRNAs and prostate cancer progression; oncogenic and/or tumor suppressor roles; androgen receptor signaling; epithelial plasticity; and the current status of diagnostic and therapeutic applications. This review focuses on select miRNAs, highly expressed in normal and cancer tissue, to emphasize the current obstacles faced in utilizing miRNA data for significant impacts on prostate cancer therapeutics.
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31
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Coordinated AR and microRNA regulation in prostate cancer. Asian J Urol 2020; 7:233-250. [PMID: 32742925 PMCID: PMC7385519 DOI: 10.1016/j.ajur.2020.06.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2019] [Revised: 03/22/2020] [Accepted: 04/17/2020] [Indexed: 12/26/2022] Open
Abstract
The androgen receptor (AR) remains a key driver of prostate cancer (PCa) progression, even in the advanced castrate-resistant stage, where testicular androgens are absent. It is therefore of critical importance to understand the molecular mechanisms governing its activity and regulation during prostate tumourigenesis. MicroRNAs (miRs) are small ∼22 nt non-coding RNAs that regulate target gene, often through association with 3′ untranslated regions (3′UTRs) of transcripts. They display dysregulation during cancer progression, can function as oncogenes or tumour suppressors, and are increasingly recognised as targets or regulators of hormonal action. Thus, understanding factors which modulate miRs synthesis is essential. There is increasing evidence for complex and dynamic bi-directional cross-talk between the multi-step miR biogenesis cascade and the AR signalling axis in PCa. This review summarises the wealth of mechanisms by which miRs are regulated by AR, and conversely, how miRs impact AR's transcriptional activity, including that of AR splice variants. In addition, we assess the implications of the convergence of these pathways on the clinical employment of miRs as PCa biomarkers and therapeutic targets.
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32
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Sanwlani R, Fonseka P, Chitti SV, Mathivanan S. Milk-Derived Extracellular Vesicles in Inter-Organism, Cross-Species Communication and Drug Delivery. Proteomes 2020; 8:11. [PMID: 32414045 PMCID: PMC7356197 DOI: 10.3390/proteomes8020011] [Citation(s) in RCA: 105] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 05/07/2020] [Accepted: 05/11/2020] [Indexed: 12/13/2022] Open
Abstract
Milk is considered as more than a source of nutrition for infants and is a vector involved in the transfer of bioactive compounds and cells. Milk contains abundant quantities of extracellular vesicles (EVs) that may originate from multiple cellular sources. These nanosized vesicles have been well characterized and are known to carry a diverse cargo of proteins, nucleic acids, lipids and other biomolecules. Milk-derived EVs have been demonstrated to survive harsh and degrading conditions in gut, taken up by various cell types, cross biological barriers and reach peripheral tissues. The cargo carried by these dietary EVs has been suggested to have a role in cell growth, development, immune modulation and regulation. Hence, there is considerable interest in understanding the role of milk-derived EVs in mediating inter-organismal and cross-species communication. Furthermore, various attributes such as it being a natural source, as well as its abundance, scalability, economic viability and lack of unwarranted immunologic reactions, has generated significant interest in deploying milk-derived EVs for clinical applications such as drug delivery and disease therapy. In this review, the role of milk-derived EVs in inter-organismal, cross-species communication and in drug delivery is discussed.
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Affiliation(s)
| | | | | | - Suresh Mathivanan
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC 3083, Australia; (R.S.); (P.F.); (S.V.C.)
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33
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Jeon J, Olkhov-Mitsel E, Xie H, Yao CQ, Zhao F, Jahangiri S, Cuizon C, Scarcello S, Jeyapala R, Watson JD, Fraser M, Ray J, Commisso K, Loblaw A, Fleshner NE, Bristow RG, Downes M, Vesprini D, Liu S, Bapat B, Boutros PC. Temporal Stability and Prognostic Biomarker Potential of the Prostate Cancer Urine miRNA Transcriptome. J Natl Cancer Inst 2020; 112:247-255. [PMID: 31161221 PMCID: PMC7073919 DOI: 10.1093/jnci/djz112] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Revised: 03/01/2019] [Accepted: 05/30/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The development of noninvasive tests for the early detection of aggressive prostate tumors is a major unmet clinical need. miRNAs are promising noninvasive biomarkers: they play essential roles in tumorigenesis, are stable under diverse analytical conditions, and can be detected in body fluids. METHODS We measured the longitudinal stability of 673 miRNAs by collecting serial urine samples from 10 patients with localized prostate cancer. We then measured temporally stable miRNAs in an independent training cohort (n = 99) and created a biomarker predictive of Gleason grade using machine-learning techniques. Finally, we validated this biomarker in an independent validation cohort (n = 40). RESULTS We found that each individual has a specific urine miRNA fingerprint. These fingerprints are temporally stable and associated with specific biological functions. We identified seven miRNAs that were stable over time within individual patients and integrated them with machine-learning techniques to create a novel biomarker for prostate cancer that overcomes interindividual variability. Our urine biomarker robustly identified high-risk patients and achieved similar accuracy as tissue-based prognostic markers (area under the receiver operating characteristic = 0.72, 95% confidence interval = 0.69 to 0.76 in the training cohort, and area under the receiver operating characteristic curve = 0.74, 95% confidence interval = 0.55 to 0.92 in the validation cohort). CONCLUSIONS These data highlight the importance of quantifying intra- and intertumoral heterogeneity in biomarker development. This noninvasive biomarker may usefully supplement invasive or expensive radiologic- and tissue-based assays.
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Affiliation(s)
- Jouhyun Jeon
- Ontario Institute for Cancer Research, Toronto, ON, Canada
| | | | - Honglei Xie
- Ontario Institute for Cancer Research, Toronto, ON, Canada
| | - Cindy Q Yao
- Ontario Institute for Cancer Research, Toronto, ON, Canada
| | - Fang Zhao
- Lunenfeld-Tannenbaum Research Institute, Sinai Health System, Toronto, ON, Canada
| | - Sahar Jahangiri
- Sunnybrook Research Institute and Department of Radiation Oncology, Sunnybrook-Odette Cancer Centre, Toronto, ON, Canada
| | - Carmelle Cuizon
- Lunenfeld-Tannenbaum Research Institute, Sinai Health System, Toronto, ON, Canada
| | - Seville Scarcello
- Sunnybrook Research Institute and Department of Radiation Oncology, Sunnybrook-Odette Cancer Centre, Toronto, ON, Canada
| | - Renu Jeyapala
- Lunenfeld-Tannenbaum Research Institute, Sinai Health System, Toronto, ON, Canada
| | - John D Watson
- Ontario Institute for Cancer Research, Toronto, ON, Canada
| | - Michael Fraser
- Ontario Institute for Cancer Research, Toronto, ON, Canada
| | - Jessica Ray
- Sunnybrook Research Institute and Department of Radiation Oncology, Sunnybrook-Odette Cancer Centre, Toronto, ON, Canada
| | - Kristina Commisso
- Sunnybrook Research Institute and Department of Radiation Oncology, Sunnybrook-Odette Cancer Centre, Toronto, ON, Canada
| | - Andrew Loblaw
- Sunnybrook Research Institute and Department of Radiation Oncology, Sunnybrook-Odette Cancer Centre, Toronto, ON, Canada
| | - Neil E Fleshner
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Robert G Bristow
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
- Manchester Cancer Research Centre, University of Manchester, Manchester, UK
| | | | - Danny Vesprini
- Sunnybrook Research Institute and Department of Radiation Oncology, Sunnybrook-Odette Cancer Centre, Toronto, ON, Canada
| | - Stanley Liu
- Sunnybrook Research Institute and Department of Radiation Oncology, Sunnybrook-Odette Cancer Centre, Toronto, ON, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - Bharati Bapat
- Lunenfeld-Tannenbaum Research Institute, Sinai Health System, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Paul C Boutros
- Ontario Institute for Cancer Research, Toronto, ON, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
- Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON, Canada
- Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA
- Department of Urology, University of California, Los Angeles, Los Angeles, CA
- Broad Stem Cell Research Centre, University of California, Los Angeles, Los Angeles, CA
- Institute for Precision Health, University of California, Los Angeles, Los Angeles, CA
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA
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Eigentler A, Tymoszuk P, Zwick J, Schmitz AA, Pircher A, Kocher F, Schlicker A, Lesche R, Schäfer G, Theurl I, Klocker H, Heidegger I. The Impact of Cand1 in Prostate Cancer. Cancers (Basel) 2020; 12:cancers12020428. [PMID: 32059441 PMCID: PMC7072594 DOI: 10.3390/cancers12020428] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 02/07/2020] [Accepted: 02/09/2020] [Indexed: 02/07/2023] Open
Abstract
Evidence has accumulated asserting the importance of cullin-RING (really interesting new gene) ubiquitin ligases (CRLs) and their regulator Cullin-associated neural-precursor-cell-expressed developmentally down-regulated 8 (NEDD8) dissociated protein 1 (Cand1) in various cancer entities. However, the role of Cand1 in prostate cancer (PCa) has not been intensively investigated so far. Thus, in the present study, we aimed to assess the relevance of Cand1 in the clinical and preclinical setting. Immunohistochemical analyses of radical prostatectomy specimens of PCa patients showed that Cand1 protein levels are elevated in PCa compared to benign areas. In addition, high Cand1 levels were associated with higher Gleason Scores, as well as higher tumor recurrence and decreased overall survival. In line with clinical findings, in vitro experiments in different PCa cell lines revealed that knockdown of Cand1 reduced cell viability and proliferation and increased apoptosis, therefore underlining its role in tumor progression. We also found that the cyclin-dependent kinase inhibitor p21 is significantly upregulated upon downregulation of Cand1. Using bioinformatic tools, we detected genes encoding for proteins linked to mRNA turnover, protein polyubiquitination, and proteasomal degradation to be significantly upregulated in Cand1high tumors. Next generation sequencing of PCa cell lines resistant to the anti-androgen enzalutamide revealed that Cand1 is mutated in enzalutamide-resistant cells, however, with little functional and clinically relevant impact in the process of resistance development. To summarize the present study, we found that high Cand1 levels correlate with PCa aggressiveness.
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Affiliation(s)
- Andrea Eigentler
- Department of Urology, Medical University of Innsbruck, 6020 Innsbruck, Austria; (A.E.); (J.Z.); (H.K.)
| | - Piotr Tymoszuk
- Laboratory for Immunotherapy, Department of Internal Medicine II, Medical University of Innsbruck, 6020 Innsbruck, Austria; (P.T.); (I.T.)
| | - Johanna Zwick
- Department of Urology, Medical University of Innsbruck, 6020 Innsbruck, Austria; (A.E.); (J.Z.); (H.K.)
| | - Arndt A. Schmitz
- Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany (A.S.); (R.L.)
| | - Andreas Pircher
- Department of Internal Medicine V, Medical University of Innsbruck, 6020 Innsbruck, Austria; (A.P.); (F.K.)
| | - Florian Kocher
- Department of Internal Medicine V, Medical University of Innsbruck, 6020 Innsbruck, Austria; (A.P.); (F.K.)
| | - Andreas Schlicker
- Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany (A.S.); (R.L.)
| | - Ralf Lesche
- Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany (A.S.); (R.L.)
| | - Georg Schäfer
- Department of Pathology, Medical University of Innsbruck, 6020 Innsbruck, Austria;
| | - Igor Theurl
- Laboratory for Immunotherapy, Department of Internal Medicine II, Medical University of Innsbruck, 6020 Innsbruck, Austria; (P.T.); (I.T.)
| | - Helmut Klocker
- Department of Urology, Medical University of Innsbruck, 6020 Innsbruck, Austria; (A.E.); (J.Z.); (H.K.)
| | - Isabel Heidegger
- Department of Urology, Medical University of Innsbruck, 6020 Innsbruck, Austria; (A.E.); (J.Z.); (H.K.)
- Correspondence: ; Tel: 0043-512-504-24-808
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Androgen-Regulated microRNAs (AndroMiRs) as Novel Players in Adipogenesis. Int J Mol Sci 2019; 20:ijms20225767. [PMID: 31744106 PMCID: PMC6888160 DOI: 10.3390/ijms20225767] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 11/11/2019] [Accepted: 11/12/2019] [Indexed: 12/14/2022] Open
Abstract
The development, homeostasis, or increase of the adipose tissue is driven by the induction of the adipogenic differentiation (adipogenesis) of undifferentiated mesenchymal stem cells (MSCs). Adipogenesis can be inhibited by androgen stimulation of these MSCs resulting in the transcription initiation or repression of androgen receptor (AR) regulated genes. AR not only regulates the transcription of protein-coding genes but also the transcription of several non-coding microRNAs involved in the posttranscriptional gene regulation (herein designated as AndroMiRs). As microRNAs are largely involved in differentiation processes such as adipogenesis, the involvement of AndroMiRs in the androgen-mediated inhibition of adipogenesis is likely, however, not yet intensively studied. In this review, existing knowledge about adipogenesis-related microRNAs and AndroMiRs is summarized, and putative cross-links are drawn, which are still prone to experimental validation.
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A Novel Predictor Tool of Biochemical Recurrence after Radical Prostatectomy Based on a Five-MicroRNA Tissue Signature. Cancers (Basel) 2019; 11:cancers11101603. [PMID: 31640261 PMCID: PMC6826532 DOI: 10.3390/cancers11101603] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 10/17/2019] [Indexed: 12/24/2022] Open
Abstract
Within five to ten years after radical prostatectomy (RP), approximately 15–34% of prostate cancer (PCa) patients experience biochemical recurrence (BCR), which is defined as recurrence of serum levels of prostate-specific antigen >0.2 µg/L, indicating probable cancer recurrence. Models using clinicopathological variables for predicting this risk for patients lack accuracy. There is hope that new molecular biomarkers, like microRNAs (miRNAs), could be potential candidates to improve risk prediction. Therefore, we evaluated the BCR prognostic capability of 20 miRNAs, which were selected by a systematic literature review. MiRNA expressions were measured in formalin-fixed, paraffin-embedded (FFPE) tissue RP samples of 206 PCa patients by RT-qPCR. Univariate and multivariate Cox regression analyses were performed, to assess the independent prognostic potential of miRNAs. Internal validation was performed, using bootstrapping and the split-sample method. Five miRNAs (miR-30c-5p/31-5p/141-3p/148a-3p/miR-221-3p) were finally validated as independent prognostic biomarkers. Their prognostic ability and accuracy were evaluated using C-statistics of the obtained prognostic indices in the Cox regression, time-dependent receiver-operating characteristics, and decision curve analyses. Models of miRNAs, combined with relevant clinicopathological factors, were built. The five-miRNA-panel outperformed clinically established BCR scoring systems, while their combination significantly improved predictive power, based on clinicopathological factors alone. We conclude that this miRNA-based-predictor panel will be worth to be including in future studies.
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Zhu D, Yuan D, Guo R, Zhang L, Guo T, Zhao Y, Wang J, Chen X, Qian H, Ge H. Overexpression of miR-148a inhibits viability and invasion of ovarian cancer OVCAR3 cells by targeting FOXO3. Oncol Lett 2019; 18:402-410. [PMID: 31289511 PMCID: PMC6539956 DOI: 10.3892/ol.2019.10321] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Accepted: 03/29/2019] [Indexed: 12/31/2022] Open
Abstract
Decreased expression of microRNA (miR)-148a is associated with poor prognosis in ovarian cancer. The aim of the present study was to investigate the impact of miR-148a on tumor cell viability and invasion via targeting forkhead box protein O3 (FOXO3). Expression of miR-148a was detected in paired tumor and adjacent normal tissues. OVCAR3 cells were transfected with miR-148a mimic and inhibitor. Cell viability, apoptosis and invasion were determined. A luciferase reporter assay was used to study the association between miR-148a and FOXO3. In addition, the influence of miR-148a on tumor cell growth was investigated by performing xenograft assays in nude mice. RT-qPCR showed that miR-148a was downregulated in ovarian cancer tissues. Overexpression of miR-148a in OVCAR3 cells inhibited cell viability, suppressed invasion and promoted cellular apoptosis. The dual-luciferase assay indicated that miR-148a directly regulated the expression of FOXO3, a transcription factor of caspase-3. Western blotting confirmed that the expression of caspase-3 was regulated by the modulation of miR-148a expression. In vivo assays revealed that miR-148a overexpression inhibited the growth of OVCAR3 ×enograft tumors in nude mice. miR-148a is a tumor suppressor in ovarian cancer OVCAR3 cells and in nude mice. The suppressive effect is due to inhibiting cell viability and invasion as well as promoting apoptosis. These results may provide theoretical basis for targeting miR-148a in the treatment of ovarian cancer.
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Affiliation(s)
- Dandan Zhu
- Department of Obstetrics and Gynecology, Taizhou People's Hospital, Fifth Affiliated Hospital to Nantong University, Taizhou, Jiangsu 225300, P.R. China
| | - Donglan Yuan
- Department of Obstetrics and Gynecology, Taizhou People's Hospital, Fifth Affiliated Hospital to Nantong University, Taizhou, Jiangsu 225300, P.R. China
| | - Runfa Guo
- Department of Obstetrics and Gynecology, Taizhou People's Hospital, Fifth Affiliated Hospital to Nantong University, Taizhou, Jiangsu 225300, P.R. China
| | - Lixin Zhang
- Department of Obstetrics and Gynecology, Taizhou People's Hospital, Fifth Affiliated Hospital to Nantong University, Taizhou, Jiangsu 225300, P.R. China
| | - Ting Guo
- Central Laboratory, Taizhou People's Hospital, Fifth Affiliated Hospital to Nantong University, Taizhou, Jiangsu 225300, P.R. China
| | - Yinling Zhao
- Department of Obstetrics and Gynecology, Taizhou People's Hospital, Fifth Affiliated Hospital to Nantong University, Taizhou, Jiangsu 225300, P.R. China
| | - Jia Wang
- Department of Obstetrics and Gynecology, Taizhou People's Hospital, Fifth Affiliated Hospital to Nantong University, Taizhou, Jiangsu 225300, P.R. China
| | - Xinping Chen
- Department of Obstetrics and Gynecology, Taizhou People's Hospital, Fifth Affiliated Hospital to Nantong University, Taizhou, Jiangsu 225300, P.R. China
| | - Hua Qian
- Department of Obstetrics and Gynecology, Taizhou People's Hospital, Fifth Affiliated Hospital to Nantong University, Taizhou, Jiangsu 225300, P.R. China
| | - Hongshan Ge
- Department of Obstetrics and Gynecology, Taizhou People's Hospital, Fifth Affiliated Hospital to Nantong University, Taizhou, Jiangsu 225300, P.R. China
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Up-regulation of miRNA-148a inhibits proliferation, invasion, and migration while promoting apoptosis of cervical cancer cells by down-regulating RRS1. Biosci Rep 2019; 39:BSR20181815. [PMID: 30910849 PMCID: PMC6505193 DOI: 10.1042/bsr20181815] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 03/03/2019] [Accepted: 03/04/2019] [Indexed: 02/07/2023] Open
Abstract
The purpose of the present study is to figure out the role of miRNA-148a (miR-148a) in growth, apoptosis, invasion, and migration of cervical cancer cells by binding to regulator of ribosome synthesis 1 (RRS1). Cervical cancer and adjacent normal tissues, as well as cervical cancer cell line Caski, HeLa, C-33A, and normal cervical epithelial cell line H8 were obtained to detect the expression of miR-148a and RRS1. Relationship between miR-148a and RRS1 expression with clinicopathological characteristics was assessed. The selected Caski and HeLa cells were then transfected with miR-148a mimics, miR-148a inhibitors or RRS1 siRNA to investigate the role of miR-148a and RRS1 on proliferation, apoptosis, colony formation, invasion, and migration abilities of cervical cancer cells. Bioinformatics information and dual luciferase reporter gene assay was for used to detect the targetting relationship between miR-148a and RRS1. Down-regulated miR-148a and up-regulated RRS1 were found in cervical cancer tissues and cells. Down-regulated miR-148a and up-regulated RRS1 are closely related with prognostic factors of cervical cancer. RRS1 was determined as a target gene of miR-148a and miR-148a inhibited RRS1 expression in cervical cancer cells. Up-regulation of miR-148a inhibited cell proliferation, migration, and invasion while promoting apoptosis in Caski and HeLa cells. Our study suggests that miR-148a down-regulates RRS1 expression, thereby inhibiting the proliferation, migration, and invasion while promoting cell apoptosis of cervical cancer cells.
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39
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Fernandes RC, Hickey TE, Tilley WD, Selth LA. Interplay between the androgen receptor signaling axis and microRNAs in prostate cancer. Endocr Relat Cancer 2019; 26:R237-R257. [PMID: 30817318 DOI: 10.1530/erc-18-0571] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 02/26/2019] [Indexed: 12/29/2022]
Abstract
The androgen receptor (AR) is a ligand-activated transcription factor that drives prostate cancer. Since therapies that target the AR are the mainstay treatment for men with metastatic disease, it is essential to understand the molecular mechanisms underlying oncogenic AR signaling in the prostate. miRNAs are small, non-coding regulators of gene expression that play a key role in prostate cancer and are increasingly recognized as targets or modulators of the AR signaling axis. In this review, we examine the regulation of AR signaling by miRNAs and vice versa and discuss how this interplay influences prostate cancer growth, metastasis and resistance to therapy. Finally, we explore the potential clinical applications of miRNAs implicated in the regulation of AR signaling in this prevalent hormone-driven disease.
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Affiliation(s)
- Rayzel C Fernandes
- Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, Australia
- Freemasons Foundation Centre for Men's Health, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, Australia
| | - Theresa E Hickey
- Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, Australia
| | - Wayne D Tilley
- Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, Australia
- Freemasons Foundation Centre for Men's Health, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, Australia
| | - Luke A Selth
- Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, Australia
- Freemasons Foundation Centre for Men's Health, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, Australia
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40
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Babu KR, Muckenthaler MU. miR-148a regulates expression of the transferrin receptor 1 in hepatocellular carcinoma. Sci Rep 2019; 9:1518. [PMID: 30728365 PMCID: PMC6365501 DOI: 10.1038/s41598-018-35947-7] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Accepted: 11/10/2018] [Indexed: 02/07/2023] Open
Abstract
Transferrin receptor 1 (TFR1) is a transmembrane glycoprotein that allows for transferrin-bound iron uptake in mammalian cells. It is overexpressed in various cancers to satisfy the high iron demand of fast proliferating cells. Here we show that in hepatocellular carcinoma (HCC) TFR1 expression is regulated by miR-148a. Within the TFR1 3′UTR we identified and experimentally validated two evolutionarily conserved miRNA response elements (MREs) for miR-148/152 family members, including miR-148a. Interestingly, analyses of RNA sequencing data from patients with liver hepatocellular carcinoma (LIHC) revealed a significant inverse correlation of TFR1 mRNA levels and miR-148a. In addition, TFR1 mRNA levels were significantly increased in the tumor compared to matched normal healthy tissue, while miR-148a levels are decreased. Functional analysis demonstrated post-transcriptional regulation of TFR1 by miR-148a in HCC cells as well as decreased HCC cell proliferation upon either miR-148a overexpression or TFR1 knockdown. We hypothesize that decreased expression of miR-148a in HCC may elevate transferrin-bound iron uptake, increasing cellular iron levels and cell proliferation.
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Affiliation(s)
- Kamesh R Babu
- Department of Pediatric Hematology, Oncology, and Immunology, University of Heidelberg, Heidelberg, Germany.,Molecular Medicine Partnership Unit, University of Heidelberg, Heidelberg, Germany
| | - Martina U Muckenthaler
- Department of Pediatric Hematology, Oncology, and Immunology, University of Heidelberg, Heidelberg, Germany. .,Molecular Medicine Partnership Unit, University of Heidelberg, Heidelberg, Germany.
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41
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Complex role of miR-130a-3p and miR-148a-3p balance on drug resistance and tumor biology in esophageal squamous cell carcinoma. Sci Rep 2018; 8:17553. [PMID: 30510209 PMCID: PMC6277408 DOI: 10.1038/s41598-018-35799-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Accepted: 11/09/2018] [Indexed: 12/12/2022] Open
Abstract
miRNAs play a crucial role in cancer development and progression. However, results on the impact of miRNAs on drug sensitivity and tumor biology vary, and most studies to date focussed on either increasing or decreasing miRNA expression levels. Therefore, the current study investigated the role of different expression levels of miR-130a-3p and miR-148a-3p on drug resistance and tumor biology in four esophageal squamous cell carcinoma cell lines. Interestingly, up- and downregulation of both miRNAs significantly increased sensitivity towards chemotherapy. MiRNA modulation also reduced adherence and migration potential, and increased apoptosis rates. Target analyses showed that up- and downregulation of both miRNAs activated the apoptotic p53-pathway via increased expression of either BAX (miR-148a-3p) or Caspase 9 (miR-130a-3p). miR-148a-3p downregulation seemed to mediate its effects primarily via regulation of Bim rather than Bcl-2 levels, whereas we found the opposite scenario following miR-148a-3p upregulation. A similar effect was observed for miR-130a-3p regulating Bcl-2 and XIAP. Our data provide the first evidence that miRNA modulation in both directions may lead to similar effects on chemotherapy response and tumor biology in esophageal squamous cell carcinoma. Most interestingly, up- and downregulation seem to mediate their effects via modulating the balance of several validated or predicted targets.
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42
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Liu J, Si L, Tian H. MicroRNA-148a inhibits cell proliferation and cell cycle progression in lung adenocarcinoma via directly targeting transcription factor E2F3. Exp Ther Med 2018; 16:5400-5409. [PMID: 30546419 DOI: 10.3892/etm.2018.6845] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 09/24/2018] [Indexed: 12/14/2022] Open
Abstract
MicroRNAs (miRs) serve important roles in various human cancers, including lung adenocarcinoma. Exploring the function and regulatory mechanism of miRs underlying lung adenocarcinoma progression may contribute to identifying novel therapeutic targets and candidates. The present study aimed to examine miR-148a expression and investigate the molecular mechanisms of miR-148a in lung adenocarcinomas. The data from the current study indicated that miR-148a was significantly downregulated in lung adenocarcinoma tissues and cell lines, and low miR-148a expression was significantly associated with advanced Tumor, Node, Metastasis stages and lymph node metastasis, as well as the shorter survival time of patients. Increased miR-148a expression markedly decreased the cell proliferation, colony formation and cell cycle progression of H23 and H1975 cells. Transcription factor E2F3 (E2F3) was identified as a target of miR-148a in H23 and H1975 cells. The expression of E2F3 was negatively mediated by miR-148a in H23 and H1975 cells. In addition, E2F3 was significantly upregulated in lung adenocarcinoma tissues and cell lines, and the expression of miR-148a was inversely correlated with E2F3 expression in lung adenocarcinoma tissues. Additional experiments demonstrated that increased E2F3 expression counteracted the inhibitory effects on lung adenocarcinoma cells caused by miR-148a overexpression. In summary, the findings of the current study suggest that miR-148a may have suppressive effects on the proliferation of lung adenocarcinoma cells at least in part through directly targeting E2F3. Therefore, miR-148a may be used as a potential candidate for the treatment of lung adenocarcinoma.
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Affiliation(s)
- Jianwei Liu
- Department of Thoracic Surgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China.,Department of Thoracic Surgery, Affiliated Hospital of Binzhou Medical College, Binzhou, Shandong 256600, P.R. China
| | - Libo Si
- Department of Thoracic Surgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Hui Tian
- Department of Thoracic Surgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
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43
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Dybos SA, Flatberg A, Halgunset J, Viset T, Rolfseng T, Kvam S, Skogseth H. Increased levels of serum miR-148a-3p are associated with prostate cancer. APMIS 2018; 126:722-731. [PMID: 30160020 DOI: 10.1111/apm.12880] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Accepted: 06/11/2018] [Indexed: 02/04/2023]
Abstract
Prostate cancer (PCa) is one of the most common types of cancer and the fifth leading cause of death among men worldwide. The tools for diagnosing PCa have limited value, and to improve correct diagnosis there is a need for markers that can contribute to a more precise diagnosis, which would lead to proper treatment of only those patients who need it. Micro RNA (miRNA) plays a key role in the development of cancer and is therefore a potential marker for PCa. Next-generation sequencing was used to discover differences in miRNA expression between serum samples from PCa patients and healthy controls, and the results were validated by quantitative real-time polymerase chain reaction. Detection of the miRNA of interest was attempted in prostate tissue by in situ hybridization. All samples were collected in collaboration with Biobank1® . By miRNA sequencing of serum samples, significant expression of some miRNAs in patients with PCa and healthy controls was detected. This study showed that miR-148a-3p is upregulated in men with PCa, and the miRNA is differentially expressed in PCa patients compared to healthy controls. The results also showed that miR-148a-3p is located in prostate tissue.
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Affiliation(s)
- Sandra Amalie Dybos
- St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.,Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Arnar Flatberg
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Jostein Halgunset
- St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.,Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Trond Viset
- St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
| | - Toril Rolfseng
- St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
| | - Solveig Kvam
- St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
| | - Haakon Skogseth
- St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.,Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
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44
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ACGH detects distinct genomic alterations of primary intrahepatic cholangiocarcinomas and matched lymph node metastases and identifies a poor prognosis subclass. Sci Rep 2018; 8:10637. [PMID: 30006612 PMCID: PMC6045619 DOI: 10.1038/s41598-018-28941-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Accepted: 07/03/2018] [Indexed: 12/17/2022] Open
Abstract
Lymph node metastases (LNM) are an important prognostic factor for patients with intrahepatic cholangiocarcinoma, but underlying genetic alterations are poorly understood. Whole genome array comparative genomic hybridization (aCGH) was performed in 37 tumors and 14 matched LNM. Genomic analyses of tumors confirmed known and identified new (gains in 19q) copy number alterations (CNA). Tumors with LNM (N1) had more alterations and exclusive gains (3p, 4q, 5p, 13q) and losses (17p and 20p). LNM shared most alterations with their matched tumors (86%), but 79% acquired new isolated gains [12q14 (36%); 1p13, 2p23, 7p22, 7q11, 11q12, 13q13 and 14q12 (>20%)]. Unsupervised clustering revealed a poor prognosis subclass with increased alterations significantly associated to tumor differentiation and survival. TP53 and KRAS mutations occurred in 19% of tumors and 6% of metastases. Pathway analyses revealed association to cancer-associated pathways. Advanced tumor stage, microvascular/perineural invasion, and microscopic positive resection margin (R1) were significantly correlated to metastases, while N1-status, R1-resection, and poor tumor differentiation were significantly correlated to survival. ACGH identified clear differences between N0 (no LNM) and N1 tumors, while N1 tumors and matched LNM displayed high clonality with exclusive gains in the metastases. A novel subclass with increased CNAs and poor tumor differentiation was significantly correlated to survival.
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45
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Dankert JT, Wiesehöfer M, Czyrnik ED, Singer BB, von Ostau N, Wennemuth G. The deregulation of miR-17/CCND1 axis during neuroendocrine transdifferentiation of LNCaP prostate cancer cells. PLoS One 2018; 13:e0200472. [PMID: 30001402 PMCID: PMC6042731 DOI: 10.1371/journal.pone.0200472] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Accepted: 06/27/2018] [Indexed: 12/20/2022] Open
Abstract
Prostate carcinoma contain foci of neuroendocrine transdifferentiation, resulting in an increase of androgen-independent neuroendocrine-like (NE) tumor cells, whose number significantly correlates with tumor aggressiveness and thus lower survival rate. Neuroendocrine transdifferentiation of prostate cancer cells and a potential role of miRNAs within this process are poorly understood. MicroRNAs are small non-coding RNAs which post-transcriptionally regulate gene expression. The aim of this project was to identify new genes and miRNAs involved in neuroendocrine transdifferentiation. LNCaP prostate cancer cells were differentiated to NE-like cancer cells and microarray analyses were performed. Microarray results have been validated for the eight most deregulated mRNAs and microRNAs via qRT-PCR and analyzed with different algorithms to predict new targets for deregulated microRNAs. The induced CyclinD1 gene could be validated as new target gene for the repressed miR-17 family containing miR-17, miR-20a, miR-20b, miR-106a and miR-106b via reporter gene assays and Western Blot. Functional analysis of miR-17 family shows a high influence on cell proliferation, colony forming ability and apoptosis in LNCaP cells. Our data demonstrate wide changes in mRNA and microRNA expression during neuroendocrine transdifferentiation of LNCaP cells and confirm new mRNA-miRNA interactions with potential roles in NE-transdifferentiation of prostate carcinoma.
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Affiliation(s)
- Jaroslaw Thomas Dankert
- Institute of Anatomy, University Hospital, Duisburg-Essen University, Essen, Germany
- * E-mail:
| | - Marc Wiesehöfer
- Institute of Anatomy, University Hospital, Duisburg-Essen University, Essen, Germany
| | - Elena Dilara Czyrnik
- Institute of Anatomy, University Hospital, Duisburg-Essen University, Essen, Germany
| | - Bernhard B. Singer
- Institute of Anatomy, University Hospital, Duisburg-Essen University, Essen, Germany
| | - Nicola von Ostau
- Institute of Anatomy, University Hospital, Duisburg-Essen University, Essen, Germany
| | - Gunther Wennemuth
- Institute of Anatomy, University Hospital, Duisburg-Essen University, Essen, Germany
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Tarasov VA, Tyutyakina MG, Makhotkin MA, Shin EF, Naboka AV, Mashkarina AN, Chebotarev DA, Cherkasova EN, Kogan MI, Chibichyan MB, Matishov DG. MicroRNA-Dependent Regulation of IGF1R Gene Expression in Hormone-Sensitive and Hormone-Resistant Prostate Cancer Cells. DOKL BIOCHEM BIOPHYS 2018; 479:101-104. [PMID: 29779108 DOI: 10.1134/s1607672918020138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Indexed: 11/23/2022]
Abstract
Using multiple parallel sequencing on Illumina platform, we identified eight microRNAs that showed significant opposite changes of gene expression in cells of the hormone-sensitive LNCaP prostate cancer cell line and in cells of the hormone-resistant DU-145 cell line, in comparison to the microRNA expression in the normal prostate tissue cells. We found that the insulin-like growth factor 1 receptor (IGF1R) gene is a target of five microRNAs whose expression is increased in LNCaP cells and reduced in DU-145 cells.
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Affiliation(s)
- V A Tarasov
- Southern Scientific Center, Russian Academy of Sciences, Rostov-on-Don, 3444006, Russia
| | - M G Tyutyakina
- Southern Scientific Center, Russian Academy of Sciences, Rostov-on-Don, 3444006, Russia.
| | - M A Makhotkin
- Southern Scientific Center, Russian Academy of Sciences, Rostov-on-Don, 3444006, Russia
| | - E F Shin
- Southern Scientific Center, Russian Academy of Sciences, Rostov-on-Don, 3444006, Russia
| | - A V Naboka
- Southern Scientific Center, Russian Academy of Sciences, Rostov-on-Don, 3444006, Russia
| | - A N Mashkarina
- Southern Scientific Center, Russian Academy of Sciences, Rostov-on-Don, 3444006, Russia
| | - D A Chebotarev
- Southern Scientific Center, Russian Academy of Sciences, Rostov-on-Don, 3444006, Russia
| | - E N Cherkasova
- Southern Scientific Center, Russian Academy of Sciences, Rostov-on-Don, 3444006, Russia
| | - M I Kogan
- Southern Scientific Center, Russian Academy of Sciences, Rostov-on-Don, 3444006, Russia.,Rostov State Medical University, Ministry of Healthcare of the Russian Federation, Rostov-on-Don, Russia
| | - M B Chibichyan
- Southern Scientific Center, Russian Academy of Sciences, Rostov-on-Don, 3444006, Russia.,Rostov State Medical University, Ministry of Healthcare of the Russian Federation, Rostov-on-Don, Russia
| | - D G Matishov
- Southern Scientific Center, Russian Academy of Sciences, Rostov-on-Don, 3444006, Russia
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Bryzgunova OE, Konoshenko MY, Laktionov PP. MicroRNA-guided gene expression in prostate cancer: Literature and database overview. J Gene Med 2018; 20:e3016. [DOI: 10.1002/jgm.3016] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 03/15/2018] [Accepted: 03/17/2018] [Indexed: 12/16/2022] Open
Affiliation(s)
- Olga E. Bryzgunova
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences, Novosibirsk, Russia and ‘E. Meshalkin National Medical Research Center’ of the Ministry of Health of the Russian Federation; Novosibirsk Russia
| | - Maria Yu Konoshenko
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences, Novosibirsk, Russia and ‘E. Meshalkin National Medical Research Center’ of the Ministry of Health of the Russian Federation; Novosibirsk Russia
| | - Pavel P. Laktionov
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences, Novosibirsk, Russia and ‘E. Meshalkin National Medical Research Center’ of the Ministry of Health of the Russian Federation; Novosibirsk Russia
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48
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Mei LL, Qiu YT, Zhang B, Shi ZZ. MicroRNAs in esophageal squamous cell carcinoma: Potential biomarkers and therapeutic targets. Cancer Biomark 2018; 19:1-9. [PMID: 28269750 DOI: 10.3233/cbm-160240] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Esophageal cancer is a common cause of cancer-related deaths worldwide. Squamous cell carcinoma (SCC) is the major histological type of esophageal cancer in developing countries including China, and the prognosis is very poor. Many microRNAs are involved in several important biological and pathologic processes, and promote tumorigenesis. To better understand the prognostic and therapeutic roles of microRNAs in ESCC, we reviewed the diagnosis and prognosis associated oncogenic microRNAs (e.g. miR-21 and miR-17-92 cluster) and tumor suppressor microRNAs (e.g. miR-375, miR-133a and miR-133b), and diagnosis and prognosis associated oncogenic target genes (e.g. PDCD4 and CCND1) and tumor suppressor target genes (e.g. EZH2 and PDK1). We also summarized the prognostic microRNA and target gene pairs (e.g. miR-296 and CCND1, miR214 and EZH2). Taken together, our review highlights the opportunities and challenges for microRNAs in the molecular diagnosis and target therapy of ESCC.
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49
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Nelson PT, Wang WX, Janse SA, Thompson KL. MicroRNA expression patterns in human anterior cingulate and motor cortex: A study of dementia with Lewy bodies cases and controls. Brain Res 2017; 1678:374-383. [PMID: 29146111 DOI: 10.1016/j.brainres.2017.11.009] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Revised: 11/08/2017] [Accepted: 11/10/2017] [Indexed: 02/07/2023]
Abstract
OVERVIEW MicroRNAs (miRNAs) have been implicated in neurodegenerative diseases including Parkinson's disease and Alzheimer's disease (AD). Here, we evaluated the expression of miRNAs in anterior cingulate (AC; Brodmann area [BA] 24) and primary motor (MO; BA 4) cortical tissue from aged human brains in the University of Kentucky AD Center autopsy cohort, with a focus on dementia with Lewy bodies (DLB). METHODS RNA was isolated from gray matter of brain samples with pathology-defined DLB, AD, AD + DLB, and low-pathology controls, with n = 52 cases initially included (n = 23 with DLB), all with low (<4 h) postmortem intervals. RNA was profiled using Exiqon miRNA microarrays. Quantitative PCR for post hoc replication was performed on separate cases (n = 6 controls) and included RNA isolated from gray matter of MO, AC, primary somatosensory (BA 3), and dorsolateral prefrontal (BA 9) cortical regions. RESULTS The miRNA expression patterns differed substantially according to anatomic location: of the relatively highly-expressed miRNAs, 150/481 (31%) showed expression that was different between AC versus MO (at p < .05 following correction for multiple comparisons), most (79%) with higher expression in MO. A subset of these results were confirmed in qPCR validation focusing on miR-7, miR-153, miR-133b, miR-137, and miR-34a. No significant variation in miRNA expression was detected in association with either neuropathology or sex after correction for multiple comparisons. CONCLUSION A subset of miRNAs (some previously associated with α-synucleinopathy and/or directly targeting α-synuclein mRNA) were differentially expressed in AC and MO, which may help explain why these brain regions show differences in vulnerability to Lewy body pathology.
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Affiliation(s)
- Peter T Nelson
- Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA; Department of Pathology, University of Kentucky, Lexington, KY 40536, USA.
| | - Wang-Xia Wang
- Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA
| | - Sarah A Janse
- Department of Statistics, University of Kentucky, Lexington, KY 40536, USA
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Chen Q, Luo G, Zhang X. MiR-148a modulates HLA-G expression and influences tumor apoptosis in esophageal squamous cell carcinoma. Exp Ther Med 2017; 14:4448-4452. [PMID: 29067119 PMCID: PMC5647548 DOI: 10.3892/etm.2017.5058] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Accepted: 06/06/2017] [Indexed: 01/18/2023] Open
Abstract
Esophageal cancer (EC) is a common malignant tumor type, and esophageal squamous cell carcinoma (ESCC) accounts for the majority of EC cases. Previous studies have reported that microRNA (miR)-148a is downregulated in patients with recurrent EC. The human leukocyte antigen-G (HLA-G) is expressed to a high level in primary ESCC tissues and is associated with prognosis. A previous luciferase assay indicated that HLA-G is a target of miR-148a regulation. The aim of the current study was to investigate the expression level of miR-148a in primary ESCC. The regulatory role of miR-148a in HLA-G expression and cell proliferation in ESCC cells was also investigated. The relative expression level of miR-148a was compared between ESCC tumor tissues and adjacent normal tissues. The human ESCC cell line EC9706 was transfected with miR-148a mimic, non-homologous RNA duplex (negative control; NC) or empty vector (blank control; BC). Reverse transcription-quantitative polymerase chain reaction and western blot analysis were used to assess the level of HLA-G expression. The cells were stained with Annexin V-fluorescein isothiocyanate/propidium iodide and cell apoptosis was evaluated by flow cytometry. The level of miR-148a expression was significantly lower in primary ESCC tissues compared with adjacent normal tissues (P<0.01). In EC9706 cells transfected with miR-148a mimic, the rate of apoptosis was increased ~13-fold when compared with BC cells (P<0.01). Furthermore, the mRNA level of HLA-G was significantly reduced in cells transfected with miR-148a mimic (P<0.01). The protein levels of HLA-G were also notably decreased. Transfection with non-homologous RNA duplex did not influence the rate of cell apoptosis or expression of HLA-G when compared with the BC group. In conclusion, miR-148a was indicated to be involved in carcinogenesis in primary ESCC through the regulation of HLA-G expression. The current results suggest that miR-148a is a potential biomarker of ESCC.
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Affiliation(s)
- Quan Chen
- Department of Cardiothoracic Surgery, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, P.R. China
| | - Guanghua Luo
- Comprehensive Laboratory, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, P.R. China
| | - Xiaoying Zhang
- Department of Cardiothoracic Surgery, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, P.R. China
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