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Wu T, Chen Y, You Q, Jiang Z, Chen X. Targeting bromodomian-containing protein 8 (BRD8): An advanced tool to interrogate BRD8. Eur J Med Chem 2024; 268:116271. [PMID: 38401187 DOI: 10.1016/j.ejmech.2024.116271] [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: 01/11/2024] [Revised: 02/07/2024] [Accepted: 02/19/2024] [Indexed: 02/26/2024]
Abstract
Epigenetic modifications play crucial roles in physiological processes, including cell differentiation, proliferation, and death. Bromodomain/Brd-containing proteins (BCPs) regulate abnormal gene expression in various diseases by recognizing the lysine-ε-N-acetylated residues (KAc) or by acting as transcriptional co-activators. Small molecule inhibitors targeting BCPs offer an attractive strategy for modulating aberrant gene expression. Besides the extensive research on the bromodomain and extra-terminal (BET) domain family proteins, the non-BET proteins have gained increasing attention. Bromodomain containing protein 8 (BRD8), a reader of KAc and co-activator of nuclear receptors (NRs), plays a key role in various cancers. This review provides a comprehensive analysis of the structure, disease-related functions, and inhibitor development of BRD8. Opportunities and challenges for future studies targeting BRD8 in disease treatment are discussed.
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Affiliation(s)
- Tingting Wu
- Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Yali Chen
- Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Qidong You
- Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Zhengyu Jiang
- Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
| | - Xuetao Chen
- Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
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2
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Fadl J, Aljuhani RA, Albog YH, Khraisat AF, Alsubaie KA. Role of microRNA in Sex Steroid Hormones Signaling and Its Effect in Regulation of Endometrial, Ovarian, and Cervical Cancer: A Literature Review. Cureus 2024; 16:e54773. [PMID: 38523927 PMCID: PMC10961145 DOI: 10.7759/cureus.54773] [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] [Accepted: 02/22/2024] [Indexed: 03/26/2024] Open
Abstract
Worldwide, in 2020, an estimated 417,367 people were diagnosed with uterine cancer. Endometrial cancer accounts for more than 90% of all uterine cancers. The 15th most frequent cancer overall and the sixth most frequent cancer in women is endometrial cancer. Global ovarian cancer Incidence was diagnosed estimated at 313,959 new cases worldwide in 2020. Cervical cancer is the fourth most common malignancy in women worldwide. It has been demonstrated that sex steroid hormones (SSHs) have an essential role in regulating the susceptibility of cancer to cytotoxic therapy. Dysregulation of DNA repair contributes to genomic instability, aberrant cell survival, and cancer development as well as therapy resistance. Several crucial DNA repair components have been discovered to interact with the three main SSHs: androgen, estrogen, and progesterone. MicroRNA (miRNA) dysregulation has been associated with aberrant sex steroid hormone signaling as well as an increased risk of endometrial, cervical, and ovarian cancer. The expression of estrogen and progesterone receptors is modulated by a number of miRNAs, and it has been demonstrated that the miRNA expression profile may predict the way a patient would respond to hormone therapy. Additionally, particular miRNAs have been linked to the control of genes involved in signaling pathways connected to hormones. Recent research has shown that miRNAs can modify hormone signaling pathways and affect the expression of sex steroid hormone receptors. Our goal in this literature review is to present an overview of current knowledge regarding the role of miRNAs in cancers regulated by sex steroid hormone pathways, as well as to identify particular miRNA targets for hormonal therapy.
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Affiliation(s)
- Jina Fadl
- Obstetrics and Gynaecology, Batterjee Medical College, Jeddah, SAU
| | | | - Yusef H Albog
- Obstetrics and Gynaecology, Batterjee Medical College, Jeddah, SAU
| | - Ayda F Khraisat
- Obstetrics and Gynaecology, Batterjee Medical College, Jeddah, SAU
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3
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Pordel S, Khorrami M, Saadatpour F, Rezaee D, Cho WC, Jahani S, Aghaei-Zarch SM, Hashemi E, Najafi S. The role of microRNA-185 in the pathogenesis of human diseases: A focus on cancer. Pathol Res Pract 2023; 249:154729. [PMID: 37639952 DOI: 10.1016/j.prp.2023.154729] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 07/29/2023] [Indexed: 08/31/2023]
Abstract
MicroRNAs (miRNAs) are a widely-studied class of non-coding RNAs characterized by their short length (18-25 nucleotides). The precise functions of miRNAs are not well-elucidated; however, an increasing number of studies suggest their involvement in various physiologic processes and deregulation in pathologic conditions. miRNA-185 (miR-185) is among the mostly-studied miRNAs in human diseases, which is found to play putative roles in conditions like metabolic disorders, asthma, frailty, schizophrenia, and hepatitis. Notably, many cancer studies report the downregulation of miR-185 in cell lines, tumor tissues, and plasma specimens of patients, while it demonstrates a suppressing role on the malignant properties of cancer cells in vitro and in vivo. Accordingly, miR-185 can be considered a tumor suppressor miRNA in human malignancies, while a few studies also report inconsistent findings. Being suggested as a prognostic/diagnostic biomarker, mi-185 is also found to offer clinical potentials, particularly for early diagnosis and prediction of the prognosis of cancer patients. In this review, we have outlined the studies that have evaluated the functions and clinical significance of miR-185 in different human diseases with a particular focus on cancer.
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Affiliation(s)
- Safoora Pordel
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Immunology and Allergy, The Persian Gulf Tropical Medicine Research Center, The Persian Gulf Biomedical Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Motahare Khorrami
- Immunology Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fatemeh Saadatpour
- Pharmaceutical Biotechnology Lab, Department of Microbiology, School of Biology and Center of Excellence in Phylogeny of Living Organisms, College of Science, University of Tehran, Tehran, Iran
| | - Delsuz Rezaee
- School of Allied Medical Sciences, Ilam University of Medical Sciences, Ilam, Iran
| | - William C Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, 30 Gascoigne Road, Hong Kong, China
| | | | - Seyed Mohsen Aghaei-Zarch
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Elham Hashemi
- Department of Anatomical Sciences, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Sajad Najafi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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4
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Ghamlouche F, Yehya A, Zeid Y, Fakhereddine H, Fawaz J, Liu YN, Al-Sayegh M, Abou-Kheir W. MicroRNAs as clinical tools for diagnosis, prognosis, and therapy in prostate cancer. Transl Oncol 2023; 28:101613. [PMID: 36608541 PMCID: PMC9827391 DOI: 10.1016/j.tranon.2022.101613] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 12/05/2022] [Accepted: 12/24/2022] [Indexed: 01/06/2023] Open
Abstract
Prostate cancer (PCa) is one of the most commonly diagnosed cancers among men worldwide. Despite the presence of accumulated clinical strategies for PCa management, limited prognostic/sensitive biomarkers are available to follow up on disease occurrence and progression. MicroRNAs (miRNAs) are small non-coding RNAs that control gene expression through post-transcriptional regulation of their complementary target messenger RNA (mRNA). MiRNAs modulate fundamental biological processes and play crucial roles in the pathology of various diseases, including PCa. Multiple evidence proved an aberrant miRNA expression profile in PCa, which is actively involved in the carcinogenic process. The robust and pleiotropic impact of miRNAs on PCa suggests them as potential candidates to help more understand the molecular landscape of the disease, which is likely to provide tools for early diagnosis and prognosis as well as additional therapeutic strategies to manage prostate tumors. Here, we emphasize the most consistently reported dysregulated miRNAs and highlight the contribution of their altered downstream targets with PCa hallmarks. Also, we report the potential effectiveness of using miRNAs as diagnostic/prognostic biomarkers in PCa and the high-throughput profiling technologies that are being used in their detection. Another key aspect to be discussed in this review is the promising implication of miRNAs molecules as therapeutic tools and targets for fighting PCa.
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Affiliation(s)
- Fatima Ghamlouche
- Department of Anatomy, Cell Biology, and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Amani Yehya
- Department of Anatomy, Cell Biology, and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Yousef Zeid
- Department of Anatomy, Cell Biology, and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Hiam Fakhereddine
- Department of Anatomy, Cell Biology, and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Jhonny Fawaz
- Department of Anatomy, Cell Biology, and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Yen-Nien Liu
- International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
| | - Mohamed Al-Sayegh
- Biology Division, New York University Abu Dhabi, Abu Dhabi 2460, United Arab Emirates.
| | - Wassim Abou-Kheir
- Department of Anatomy, Cell Biology, and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107-2020, Lebanon.
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Genchi G, Lauria G, Catalano A, Sinicropi MS, Carocci A. Biological Activity of Selenium and Its Impact on Human Health. Int J Mol Sci 2023; 24:2633. [PMID: 36768955 PMCID: PMC9917223 DOI: 10.3390/ijms24032633] [Citation(s) in RCA: 114] [Impact Index Per Article: 57.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 01/25/2023] [Accepted: 01/26/2023] [Indexed: 02/03/2023] Open
Abstract
Selenium (Se) is a naturally occurring metalloid element essential to human and animal health in trace amounts but it is harmful in excess. Se plays a substantial role in the functioning of the human organism. It is incorporated into selenoproteins, thus supporting antioxidant defense systems. Selenoproteins participate in the metabolism of thyroid hormones, control reproductive functions and exert neuroprotective effects. Among the elements, Se has one of the narrowest ranges between dietary deficiency and toxic levels. Its level of toxicity may depend on chemical form, as inorganic and organic species have distinct biological properties. Over the last decades, optimization of population Se intake for the prevention of diseases related to Se deficiency or excess has been recognized as a pressing issue in modern healthcare worldwide. Low selenium status has been associated with an increased risk of mortality, poor immune function, cognitive decline, and thyroid dysfunction. On the other hand, Se concentrations slightly above its nutritional levels have been shown to have adverse effects on a broad spectrum of neurological functions and to increase the risk of type-2 diabetes. Comprehension of the selenium biochemical pathways under normal physiological conditions is therefore an important issue to elucidate its effect on human diseases. This review gives an overview of the role of Se in human health highlighting the effects of its deficiency and excess in the body. The biological activity of Se, mainly performed through selenoproteins, and its epigenetic effect is discussed. Moreover, a brief overview of selenium phytoremediation and rhizofiltration approaches is reported.
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Affiliation(s)
- Giuseppe Genchi
- Dipartimento di Farmacia e Scienze della Salute e della Nutrizione, Università della Calabria, Arcavacata di Rende, 87036 Cosenza, Italy
| | - Graziantonio Lauria
- Dipartimento di Farmacia e Scienze della Salute e della Nutrizione, Università della Calabria, Arcavacata di Rende, 87036 Cosenza, Italy
| | - Alessia Catalano
- Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari “A. Moro”, 70125 Bari, Italy
| | - Maria Stefania Sinicropi
- Dipartimento di Farmacia e Scienze della Salute e della Nutrizione, Università della Calabria, Arcavacata di Rende, 87036 Cosenza, Italy
| | - Alessia Carocci
- Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari “A. Moro”, 70125 Bari, Italy
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Coradduzza D, Solinas T, Balzano F, Culeddu N, Rossi N, Cruciani S, Azara E, Maioli M, Zinellu A, De Miglio MR, Madonia M, Falchi M, Carru C. miRNAs as molecular biomarkers for prostate cancer. J Mol Diagn 2022; 24:1171-1180. [PMID: 35835374 DOI: 10.1016/j.jmoldx.2022.05.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 04/05/2022] [Accepted: 05/23/2022] [Indexed: 01/10/2023] Open
Abstract
MicroRNAs (miRNAs) are short noncoding RNA able to regulate specific mRNA stability, thus influencing target gene expression. Disrupted levels of several miRNA have been associated with prostate cancer, the leading cause of cancer death among men and the fifth leading cause of death worldwide. Here, we investigated whether miR-145, miR-148, and miR-185 circulating levels in plasma could be used as molecular biomarkers, to allow distinguishing between individuals with benign prostatic hyperplasia, precancerous lesion, and prostate cancer. In this study, we recruited 170 urological clinic patients with suspected prostate cancer who underwent prostate biopsy. Total RNA was isolated from plasma, and TaqMan MicroRNA assays were used to analyze miR-145, miR-185, and miR-148 expression. First, differential miRNA expression among patient groups was evaluated. Then, miRNA levels were combined with clinical assessment outcomes, including results from invasive tests, using multivariate analysis to examine their ability in discriminating among the three patient groups. Our results suggest that miRNA is a promising molecular tool for clinical management of at-risk patients.
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Affiliation(s)
| | - Tatiana Solinas
- Urologic Clinic, Dep. of Clinical and Experimental Medicine, University of Sassari
| | - Francesca Balzano
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Nicola Culeddu
- Institute of Biomolecular Chemistry, National Research Council, Sassari, Italy
| | - Niccolò Rossi
- Department of Twin Research and Genetic Epidemiology, King's College London, London, UK
| | - Sara Cruciani
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Emanuela Azara
- Institute of Biomolecular Chemistry, National Research Council, Sassari, Italy
| | - Margherita Maioli
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Angelo Zinellu
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | | | - Massimo Madonia
- Urologic Clinic, Dep. of Clinical and Experimental Medicine, University of Sassari
| | - Mario Falchi
- Department of Twin Research and Genetic Epidemiology, King's College London, London, UK
| | - Ciriaco Carru
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy; University Hospital of Sassari (AOU), Sassari, Italy.
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Sun J, Zhu YM, Liu Q, Hu YH, Li C, Jie HH, Xu GH, Xiao RJ, Xing XL, Yu SC, Liang YP. LncRNA ROR modulates myocardial ischemia-reperfusion injury mediated by the miR-185-5p/CDK6 axis. J Transl Med 2022; 102:505-514. [PMID: 35066566 DOI: 10.1038/s41374-021-00722-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 12/06/2021] [Accepted: 12/09/2021] [Indexed: 02/07/2023] Open
Abstract
LncRNAs and miRNAs are correlated with the pathogenesis of myocardial ischemia-reperfusion injury (MIRI). Whether lncRNA ROR or miR-185-5p plays a crucial role in MIRI is still unclear. In in-vitro, human cardiac myocytes (HCMs) were treated with hypoxia/reoxygenation (H/R). Wistar rats were used to set up an in-vitro I/R model by means of recanalization after ligation. Evaluation of the myocardial injury marker lactate dehydrogenase (LDH) in HCMs cells was performed. The expression of miR-185-5p and ROR, IL-1β, and IL-18 were detected by qRT-PCR. ELISA was also performed to evaluate the secretion of IL-1β and IL-18. Western blotting was carried out to determine CDK6, NLRP3, GSDMD-N, ASC, and cleaved-caspase1 protein expression. The relationship between miR-185-5p and CDK6 or ROR was confirmed by a dual-luciferase reporter assay. Our findings revealed that H/R treated HCMs showed a significantly decreased miR-185-5p expression and increased expression of CDK6 and ROR. ROR knockdown reduced H/R induced pyroptosis and inflammation, while knockdown of miR-185-5p accelerated the effect. Furthermore, miR-185-5p was negatively regulated and absorbed by ROR in HCMs. Overexpression of miR-185-5p reversed the H/R-induced cell pyroptosis and upregulation of LDH, IL-1β, and IL-18. In HCMs, miR-185-5p was also negatively regulated and related to CDK6 expression. Moreover, overexpression of CDK6 significantly inhibited the effects of miR-185-5p mimics on the inflammatory response and pyroptosis of HCMs. Knockdown of ROR alleviated H/R-induced myocardial injury by elevating miR-185-5p and inhibiting CDK6 expression. Taken together, our results show that the ROR/miR-185-5p/CDK6 axis modulates cell pyroptosis induced by H/R and the inflammatory response of HCMs.
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Affiliation(s)
- Jing Sun
- Department of Anesthesiology, Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, P.R. China
| | - Yan-Meng Zhu
- Queen Mary School, Nanchang University, Nanchang, 330006, Jiangxi Province, P.R. China
| | - Qin Liu
- Department of Anesthesiology, Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, P.R. China
| | - Yan-Hui Hu
- Department of Anesthesiology, Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, P.R. China
| | - Chang Li
- Department of Anesthesiology, Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, P.R. China
| | - Huan-Huan Jie
- Department of Anesthesiology, Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, P.R. China
| | - Guo-Hai Xu
- Department of Anesthesiology, Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, P.R. China
| | - Ren-Jie Xiao
- Department of Anesthesiology, Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, P.R. China
| | - Xian-Liang Xing
- Department of Anesthesiology, Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, P.R. China
| | - Shu-Chun Yu
- Department of Anesthesiology, Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, P.R. China
| | - Ying-Ping Liang
- Department of Anesthesiology, Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, P.R. China.
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Doghish AS, Ismail A, El-Mahdy HA, Elkady MA, Elrebehy MA, Sallam AAM. A review of the biological role of miRNAs in prostate cancer suppression and progression. Int J Biol Macromol 2022; 197:141-156. [PMID: 34968539 DOI: 10.1016/j.ijbiomac.2021.12.141] [Citation(s) in RCA: 75] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 12/20/2021] [Accepted: 12/21/2021] [Indexed: 02/06/2023]
Abstract
Prostate cancer (PC) is the third-leading cause of cancer-related deaths worldwide. Although the current treatment strategies are progressing rapidly, PC is still representing a substantial medical problem for affected patients. Several factors are involved in PC initiation, progression, and treatments failure including microRNAs (miRNAs). The miRNAs are endogenous short non-coding RNA sequence negatively regulating target mRNA expression via degradation or translation repression. miRNAs play a pivotal role in PC pathogenesis through its ability to initiate the induction of cancer stem cells (CSCs) and proliferation, as well as sustained cell cycle, evading apoptosis, invasion, angiogenesis, and metastasis. Furthermore, miRNAs regulate major molecular pathways affecting PC such as the androgen receptor (AR) pathway, p53 pathway, PTEN/PI3K/AKT pathway, and Wnt/β-catenin pathway. Furthermore, miRNAs alter PC therapeutic response towards the androgen deprivation therapy (ADT), chemotherapy and radiation therapy (RT). Thus, the understanding and profiling of the altered miRNAs expression in PC could be utilized as a non-invasive biomarker for the early diagnosis as well as for patient sub-grouping with different prognoses for individualized treatment. Accordingly, in the current review, we summarized in updated form the roles of various oncogenic and tumor suppressor (TS) miRNAs in PC, revealing their underlying molecular mechanisms in PC initiation and progression.
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Affiliation(s)
- Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231 Cairo, Egypt.
| | - Ahmed Ismail
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231 Cairo, Egypt
| | - Hesham A El-Mahdy
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231 Cairo, Egypt
| | - Mohamed A Elkady
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231 Cairo, Egypt
| | - Mahmoud A Elrebehy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Al-Aliaa M Sallam
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt; Biochemistry Department, Faculty of Pharmacy, Ain-Shams University, Abassia, Cairo 11566, Egypt
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9
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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: 25] [Impact Index Per Article: 8.3] [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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Park JR, Ahn JH, Jung MH, Kim JH, Kang MG, Kim KH, Jang JY, Park HW, Koh JS, Hwang SJ, Park Y, Jeong YH, Kwak CH, Hwang JY. Serum microRNA-185 Levels and Myocardial Injury in Patients with Acute ST-segment Elevation Myocardial Infarction. Intern Med 2022; 61:151-158. [PMID: 34248121 PMCID: PMC8851187 DOI: 10.2169/internalmedicine.7594-21] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Objective Human microRNA-185 (miR-185) has been reported to act as a regulator of fibrosis and angiogenesis in cancer. However, miR-185 has not been investigated in patients with ST-segment elevation myocardial infarction (STEMI). We hypothesized that the changes in miR-185 levels in STEMI patients are related to the processes of myocardial healing and remodeling. Methods Between January 2011 and December 2013, 145 patients with STEMI (65.9±11.6 years old; 41 women) were enrolled. Initial and discharge serum samples collected from 20 patients with STEMI and mixed sera from 8 healthy controls were analyzed by a microarray. A quantitative reverse transcription polymerase chain reaction (RT-qPCR) analysis of miR-185 was performed in all 145 patients. The correlation between the miR-185 levels and the clinical, laboratory, angiographic, and echocardiographic parameters was analyzed. Results The microarray analysis revealed a biphasic pattern in miR-185 levels, with an initial decrease followed by an increase at discharge. The miR-185 levels at discharge were significantly correlated with the troponin-I, CK-MB, and area under the curve of CK-MB levels. There was a positive correlation between the transforming growth factor-β and miR-185 levels at discharge (ρ=0.242, p=0.026). A high wall motion score index and a low ejection fraction, as measured by echocardiography, and high B-type natriuretic peptide level at one month after STEMI were related to high miR-185 levels. Conclusion Our results showed that elevated miR-185 levels at the late stage of STEMI were related to a large amount of myocardial injury and adverse remodeling.
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Affiliation(s)
- Jeong Rang Park
- Division of Cardiology, Department of Internal Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Republic of Korea
- Institute of Health Sciences, Gyeongsang National University School of Medicine, Republic of Korea
| | - Jong Hwa Ahn
- Institute of Health Sciences, Gyeongsang National University School of Medicine, Republic of Korea
- Division of Cardiology, Department of Internal Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Changwon Hospital, Republic of Korea
| | - Myeong Hee Jung
- Institute of Health Sciences, Gyeongsang National University School of Medicine, Republic of Korea
- Biomedical Research Institute, Gyeongsang National University Hospital, Republic of Korea
| | - Jin Hyun Kim
- Institute of Health Sciences, Gyeongsang National University School of Medicine, Republic of Korea
- Biomedical Research Institute, Gyeongsang National University Hospital, Republic of Korea
| | - Min Gyu Kang
- Division of Cardiology, Department of Internal Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Republic of Korea
- Institute of Health Sciences, Gyeongsang National University School of Medicine, Republic of Korea
| | - Kye Hwan Kim
- Division of Cardiology, Department of Internal Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Republic of Korea
- Institute of Health Sciences, Gyeongsang National University School of Medicine, Republic of Korea
| | - Jeong Yoon Jang
- Institute of Health Sciences, Gyeongsang National University School of Medicine, Republic of Korea
- Division of Cardiology, Department of Internal Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Changwon Hospital, Republic of Korea
| | - Hyun Woong Park
- Division of Cardiology, Department of Internal Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Republic of Korea
- Institute of Health Sciences, Gyeongsang National University School of Medicine, Republic of Korea
| | - Jin-Sin Koh
- Division of Cardiology, Department of Internal Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Republic of Korea
- Institute of Health Sciences, Gyeongsang National University School of Medicine, Republic of Korea
| | - Seok-Jae Hwang
- Division of Cardiology, Department of Internal Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Republic of Korea
- Institute of Health Sciences, Gyeongsang National University School of Medicine, Republic of Korea
| | - Yongwhi Park
- Institute of Health Sciences, Gyeongsang National University School of Medicine, Republic of Korea
- Division of Cardiology, Department of Internal Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Changwon Hospital, Republic of Korea
| | - Young-Hoon Jeong
- Institute of Health Sciences, Gyeongsang National University School of Medicine, Republic of Korea
- Division of Cardiology, Department of Internal Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Changwon Hospital, Republic of Korea
| | - Choong Hwan Kwak
- Institute of Health Sciences, Gyeongsang National University School of Medicine, Republic of Korea
- Division of Cardiology, Department of Internal Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Changwon Hospital, Republic of Korea
| | - Jin-Yong Hwang
- Division of Cardiology, Department of Internal Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Republic of Korea
- Institute of Health Sciences, Gyeongsang National University School of Medicine, Republic of Korea
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11
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Yadav P, Bandyopadhayaya S, Ford BM, Mandal C. Interplay between DNA Methyltransferase 1 and microRNAs During Tumorigenesis. Curr Drug Targets 2021; 22:1129-1148. [PMID: 33494674 DOI: 10.2174/1389450122666210120141546] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 09/16/2020] [Accepted: 10/18/2020] [Indexed: 01/18/2023]
Abstract
Cancer is a genetic disease resulting from genomic changes; however, epigenetic alterations act synergistically with these changes during tumorigenesis and cancer progression. Epigenetic variations are gaining more attention as an important regulator in tumor progression, metastasis and therapy resistance. Aberrant DNA methylation at CpG islands is a central event in epigeneticmediated gene silencing of various tumor suppressor genes. DNA methyltransferase 1 (DNMT1) predominately methylates at CpG islands on hemimethylated DNA substrates in proliferation of cells. DNMT1 has been shown to be overexpressed in various cancer types and exhibits tumor-promoting potential. The major drawbacks to DNMT1-targeted cancer therapy are the adverse effects arising from nucleoside and non-nucleoside based DNMT1 inhibitors. This paper focuses on the regulation of DNMT1 by various microRNAs (miRNAs), which may be assigned as future DNMT1 modulators, and highlights how DNMT1 regulates various miRNAs involved in tumor suppression. Importantly, the role of reciprocal inhibition between DNMT1 and certain miRNAs in tumorigenic potential is approached in this review. Hence, this review seeks to project an efficient and strategic approach using certain miRNAs in conjunction with conventional DNMT1 inhibitors as a novel cancer therapy. It has also been pinpointed to select miRNA candidates associated with DNMT1 regulation that may not only serve as potential biomarkers for cancer diagnosis and prognosis, but may also predict the existence of aberrant methylation activity in cancer cells.
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Affiliation(s)
- Pooja Yadav
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, NH-8, Bandarsindri, Kishangarh- 305817, Ajmer, Rajasthan, India
| | - Shreetama Bandyopadhayaya
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, NH-8, Bandarsindri, Kishangarh- 305817, Ajmer, Rajasthan, India
| | - Bridget M Ford
- Department of Biology, University of the Incarnate Word, San Antonio, TX 78209, United States
| | - Chandi Mandal
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, NH-8, Bandarsindri, Kishangarh- 305817, Ajmer, Rajasthan, India
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12
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Doldi V, El Bezawy R, Zaffaroni N. MicroRNAs as Epigenetic Determinants of Treatment Response and Potential Therapeutic Targets in Prostate Cancer. Cancers (Basel) 2021; 13:2380. [PMID: 34069147 PMCID: PMC8156532 DOI: 10.3390/cancers13102380] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 05/07/2021] [Accepted: 05/13/2021] [Indexed: 12/15/2022] Open
Abstract
Prostate cancer (PCa) is the second most common tumor in men worldwide, and the fifth leading cause of male cancer-related deaths in western countries. PC is a very heterogeneous disease, meaning that optimal clinical management of individual patients is challenging. Depending on disease grade and stage, patients can be followed in active surveillance protocols or undergo surgery, radiotherapy, hormonal therapy, and chemotherapy. Although therapeutic advancements exist in both radiatiotherapy and chemotherapy, in a considerable proportion of patients, the treatment remains unsuccessful, mainly due to tumor poor responsiveness and/or recurrence and metastasis. microRNAs (miRNAs), small noncoding RNAs that epigenetically regulate gene expression, are essential actors in multiple tumor-related processes, including apoptosis, cell growth and proliferation, autophagy, epithelial-to-mesenchymal transition, invasion, and metastasis. Given that these processes are deeply involved in cell response to anti-cancer treatments, miRNAs have been considered as key determinants of tumor treatment response. In this review, we provide an overview on main PCa-related miRNAs and describe the biological mechanisms by which specific miRNAs concur to determine PCa response to radiation and drug therapy. Additionally, we illustrate whether miRNAs can be considered novel therapeutic targets or tools on the basis of the consequences of their expression modulation in PCa experimental models.
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Affiliation(s)
| | | | - Nadia Zaffaroni
- Molecular Pharmacology Unit, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy; (V.D.); (R.E.B.)
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13
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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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14
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Yang J, Deng P, Qi Y, Feng X, Wen H, Chen F. MicroRNA-185 inhibits the proliferation and migration of HaCaT keratinocytes by targeting peroxisome proliferator-activated receptor β. Exp Ther Med 2021; 21:366. [PMID: 33732339 PMCID: PMC7903386 DOI: 10.3892/etm.2021.9797] [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: 08/05/2019] [Accepted: 12/12/2020] [Indexed: 11/06/2022] Open
Abstract
Proliferation and migration of keratinocytes are major processes of skin wound repair after injury. It has been indicated that microRNAs (miRNAs/miRs) are associated with the proliferation and migration of keratinocytes. However, the mechanism by which miR-185 affects these processes in keratinocytes remains unclear. In the present study, the expression level of miR-185 and peroxisome proliferator-activated receptor β (PPARβ) was examined by reverse transcription-quantitative PCR in HaCaT keratinocytes. Cell proliferation was evaluated using Cell Counting Kit-8 and colony formation assays. Western blot analysis was used to detect the levels of cell proliferation, migration and PI3K/AKT signaling pathway-associated proteins. In addition, the migratory capacity of the cells was determined using Transwell assay. The target gene of miR-185 was verified using dual-luciferase reporter assay. The results indicated that overexpression of miR-185 inhibited proliferation, migration and activation of the PI3K/AKT signaling pathway in HaCaT keratinocytes. PPARβ was indicated to be a target of miR-185 and its overexpression promoted the proliferation and migration of HaCaT keratinocytes, while its knockdown exhibited the adverse effects. Furthermore, PI3K inhibitor LY294002 inhibited activation of the PI3K/AKT signaling pathway and decreased the proliferation and migration of HaCaT keratinocytes. In addition, overexpressed PPARβ reversed the suppressive effects of miR-185 overexpression on proliferation, migration and activation of the PI3K/AKT signaling pathway. In conclusion, the results of the present study demonstrated that miR-185 suppressed activation of the PI3K/AKT signaling pathway via targeting PPARβ, thereby regulating proliferation and migration in HaCaT keratinocytes. The present study provided a novel theoretical basis for the use of miR-185 as a target in wound repair.
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Affiliation(s)
- Jingzhe Yang
- Department of Burn and Plastic Surgery, Affiliated Hospital of Chengde Medical University, South Wing Hospital of Chengde Medical College, Chengde, Hebei 067000, P.R. China
| | - Pingyang Deng
- Department of Burn and Plastic Surgery, Bayingol Mongolia Autonomous Prefecture People's Hospital, Urumqi, Xinjiang Uyghur Autonomous Region 841000, P.R. China
| | - Yonggang Qi
- Department of General Surgery, Bayingol Mongolia Autonomous Prefecture People's Hospital, Urumqi, Xinjiang Uyghur Autonomous Region 841000, P.R. China
| | - Xinshu Feng
- Department of Burn and Plastic Surgery, Affiliated Hospital of Chengde Medical University, South Wing Hospital of Chengde Medical College, Chengde, Hebei 067000, P.R. China
| | - Hailing Wen
- Department of Burn and Plastic Surgery, Affiliated Hospital of Chengde Medical University, South Wing Hospital of Chengde Medical College, Chengde, Hebei 067000, P.R. China
| | - Fengping Chen
- Department of Burn and Plastic Surgery, Affiliated Hospital of Chengde Medical University, South Wing Hospital of Chengde Medical College, Chengde, Hebei 067000, P.R. China
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15
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Dai J, Yuan G, Li Y, Zhou H. MicroRNA-596 is epigenetically inactivated and suppresses prostatic cancer cell growth and migration via regulating Wnt/β-catenin signaling. Clin Transl Oncol 2021; 23:1394-1404. [PMID: 33387246 DOI: 10.1007/s12094-020-02536-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 11/24/2020] [Indexed: 11/25/2022]
Abstract
OBJECTIVES Although studies have reported that miR-596 extensively participates in multiple cancer progression, the biological mechanisms and effects of miR-596 in prostatic cancer remain unclear. The literature is aimed to reveal the function and possible molecular mechanisms of miR-596 in prostatic cancer carcinogenesis. MATERIALS AND METHODS qRT-PCR was applied to examine miR-596 expression in prostatic cancer cell lines and samples, also methylation-specific PCR was used to detect the methylation status of the promoter CpG islands in prostatic cancer samples. Meanwhile, the tumor-related effects of miR-596 were detected via cell viability, clone formation assay, migration assay, flow cytometric and AO/EB assay. qRT-PCR and Western blots were applied to investigate the function of miR-596 on malignant behavior in prostatic cancer cells. RESULTS We found that miR-596 mRNA was decreased in prostatic cancer samples and cell lines. miR-596 mRNA level was also correlated to cancer stage, Gleason scores, while miR-596 promoter methylation was related to cancer tumor stage, Gleason score and preoperative PSA levels. miR-596 inhibited the cell growth and activity by causing cell apoptosis, and also suppressed the migration of prostatic cancer cells by revealing the epithelial-mesenchymal transition process. In addition, Western blot indicates that miR-596 overexpression deregulated Wnt/β-catenin signaling, by restraining phosphorylation levels of β-catenin and expression levels of downstream targets. CONCLUSIONS In summary, this research indicates that miR-596 overexpression could be potentially useful in the cell growth and migration of prostatic cancer and serves as a potential molecular marker in prostatic cancer.
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Affiliation(s)
- J Dai
- Chongqing University Cancer Hospital, Chongqing, China
| | - G Yuan
- Chongqing University Cancer Hospital, Chongqing, China
| | - Y Li
- Chongqing University Cancer Hospital, Chongqing, China
| | - H Zhou
- Chongqing University Cancer Hospital, Chongqing, China.
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16
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Liu J, Han Y, Liu X, Wei S. Serum miR-185 Is a Diagnostic and Prognostic Biomarker for Non-Small Cell Lung Cancer. Technol Cancer Res Treat 2020; 19:1533033820973276. [PMID: 33251978 PMCID: PMC7705799 DOI: 10.1177/1533033820973276] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE MicroRNAs (miRNAs) have been found to play important roles in the development of non-small cell lung carcinoma (NSCLC). The aim of this study was to analyze the expression and clinical value of serum miR-185 in NSCLC. METHODS Serum miR-185 levels were detected in 146 NSCLC patients, 50 patients with carcinoma in situ, 25 patients with non-malignant lung diseases (NMLD), and 80 healthy controls using quantitative reverse transcription PCR. The correlation between serum miR-185 level and clinical status of NSCLC was explored. RESULTS The results revealed that serum miR-185 expression was progressively decreased in healthy controls, patients with NMLD, patients with carcinoma in situ and NSCLC patients. In addition, compared to carcinoembryonic antigen (CEA), serum miR-185 demonstrated better diagnostic accuracy for discriminating patients with carcinoma from healthy controls, NSCLC patients from healthy controls and NSCLC patients from patients with carcinoma in situ. In addition, serum miR-185 levels were significantly elevated in post-treated samples compared to the pre-treated samples. Moreover, reduced serum miR-185 was closely associated with unfavorable clinicopathological parameters and worse survival. Univariate and multivariate cox regression analysis confirmed that serum miR-185 was an independent prognostic indicator for NSCLC. CONCLUSIONS Collectively, our findings have demonstrated that serum miR-185 might serve as a promising and robust biomarker for the early detection and prognosis prediction of NSCLC.
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Affiliation(s)
- Jinghao Liu
- Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin City, China
| | - Yueting Han
- Department of Clinical Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin City, China
| | - Xingyu Liu
- Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin City, China
| | - Sen Wei
- Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin City, China
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17
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Comparison of miRNA Expression Profiles between HIV-1 and HIV-2 Infected Monocyte-Derived Macrophages (MDMs) and Peripheral Blood Mononuclear Cells (PBMCs). Int J Mol Sci 2020; 21:ijms21186970. [PMID: 32971935 PMCID: PMC7556008 DOI: 10.3390/ijms21186970] [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: 08/16/2020] [Revised: 09/17/2020] [Accepted: 09/17/2020] [Indexed: 12/13/2022] Open
Abstract
During the progression of HIV-1 infection, macrophage tropic HIV-1 that use the CCR5 co-receptor undergoes a change in co-receptor use to CXCR4 that is predominately T cell tropic. This change in co-receptor preference makes the virus able to infect T cells. HIV-2 is known to infect MDMs and T cells and is dual tropic. The aim of this study was to elucidate the differential expression profiles of host miRNAs and their role in cells infected with HIV-1/HIV-2. To achieve this goal, a comparative global miRNA expression profile was determined in human PBMCs and MDMs infected with HIV-1/HIV-2. Differentially expressed miRNAs were identified in HIV-1/HIV-2 infected PBMCs and MDMs using the next-generation sequencing (NGS) technique. A comparative global miRNA expression profile in infected MDMs and PBMCs with HIV-1 and HIV-2 identified differential expression of several host miRNAs. These differentially expressed miRNAs are likely to be involved in many signaling pathways, like the p53 signaling pathway, PI3K-Akt signaling pathways, MAPK signaling pathways, FoxO signaling pathway, and viral carcinogenesis. Thus, a comparative study of the differential expression of host miRNAs in MDMs and T cell in response to HIV-1 and HIV-2 infection will help us to identify unique biomarkers that can differentiate HIV-1 and HIV-2 infection.
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18
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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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19
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Li Y, Zhong W, Zhu M, Li M, Yang Z. miR-185 inhibits prostate cancer angiogenesis induced by the nodal/ALK4 pathway. BMC Urol 2020; 20:49. [PMID: 32366240 PMCID: PMC7197131 DOI: 10.1186/s12894-020-00617-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 04/21/2020] [Indexed: 12/12/2022] Open
Abstract
Background Inhibition of angiogenesis in prostatic cancer could be a brand-new method to suppress tumour progression. Nodal/ALK4 has been associated with vascularization in many cancers. However, the relationship between and role of Nodal/ALK4 and miR-185 in human prostatic cancer is still unknown. Methods Prostatic cancer DU145 cells and LNCaP cells were used to investigate the angiogenic effect induced by Nodal and the anti-angiogenic roles of miR-185. Colony formation assay, MTT assay, transwell assay and tube formation assay were used to explore cell proliferation, migration and tube-forming ability, respectively. A luciferase reporter assay confirmed the binding relationship between miR-185 and ALK4. The expression levels of miR-185, ALK4 and VEGF were detected by qRT-PCR and Western blotting. The effects of miR-185 and Nodal in prostate cancer were also investigated in animal experiments. Results VEGF expression was increased in DU145 cells and LNCaP cells after Nodal incubation, and Nodal activated the proliferation ability of prostatic cancer cells and the migration and tube-forming ability of human umbilical vein endothelial cells (HUVECs), which were all inhibited by treatment with the Nodal inhibitor SB431524. Bioinformatics analysis and luciferase assay were used to verify miR-185 as a target of ALK4. Prostatic cancer cell proliferation was inhibited by overexpression of miR-185, which was shown to regulate the migration and angiogenesis of HUVECs by targeting ALK4 for suppression. miR-185 also showed a significant inverse correlation with Nodal treatment and reversed the angiogenic effects induced by Nodal. More importantly, for the first time, xenograft experiments indicated that overexpression of miR-185 suppressed tumour development. Conclusion The Nodal/ALK4 pathway is important in the angiogenesis of prostate cancer and can be inhibited by targeting miR-185 to downregulate ALK4. These findings provide a new perspective on the mechanism of prostate cancer formation.
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Affiliation(s)
- Youkong Li
- Department of Urology, Jingzhou Central Hospital and The Second Clinical Medical College, Yangtze University, No.60 Jingzhong Road, Jingzhou District, Jingzhou, 434020, Hubei Province, People's Republic of China.
| | - Wen Zhong
- Department of Endocrine, Jingzhou Central Hospital and The Second Clinical Medical College, Yangtze University, Jingzhou, 434020, Hubei Province, People's Republic of China
| | - Min Zhu
- Department of Urology, Jingzhou Central Hospital and The Second Clinical Medical College, Yangtze University, No.60 Jingzhong Road, Jingzhou District, Jingzhou, 434020, Hubei Province, People's Republic of China
| | - Mengbo Li
- Department of Urology, Jingzhou Central Hospital and The Second Clinical Medical College, Yangtze University, No.60 Jingzhong Road, Jingzhou District, Jingzhou, 434020, Hubei Province, People's Republic of China
| | - Zhenwei Yang
- Department of Urology, Jingzhou Central Hospital and The Second Clinical Medical College, Yangtze University, No.60 Jingzhong Road, Jingzhou District, Jingzhou, 434020, Hubei Province, People's Republic of China
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20
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Dart DA, Ashelford K, Jiang WG. AR mRNA stability is increased with AR-antagonist resistance via 3'UTR variants. Endocr Connect 2020; 9:9-19. [PMID: 31778359 PMCID: PMC6933836 DOI: 10.1530/ec-19-0340] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 11/28/2019] [Indexed: 12/13/2022]
Abstract
Advanced prostate cancer is often treated with AR antagonists which target the androgen receptor (AR) on which the growth of the tumour depends. Prostate cancer often develops AR-antagonist resistance via a plethora of mechanisms, many of which are as yet unknown, but it is thought that AR upregulation or AR ligand-binding site mutations, may be responsible. Here we describe the production of cell lines based on LNCaP and VCaP, with acquired resistance to the clinically relevant AR antagonists, bicalutamide and enzalutamide. In these resistant cells, we observed, via RNA-seq, that new variants in the 3'UTR of the AR mRNA were detectable and that the levels were increased both with AR-antagonist treatment and with hormonal starvation. Around 20% of AR transcripts showed a 3 kb deletion within the 6.7 kb 3'UTR sequence. Actinomycin D and luciferase fusion studies indicated that this shorter mRNA variant was inherently more stable in anti-androgen-resistant cell lines. Of additional interest was that the AR UTR variant could be detected in the sera of prostate cancer patients in a cohort of serum samples collected from patients of Gleason grades 6-10, with an increasing level correlated to increasing grade. We hypothesise that the shorter AR UTR variant is a survival adaptation to low hormone levels and/or AR-antagonist treatment in these cells, where a more stable mRNA may allow higher levels of AR expression under these conditions.
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Affiliation(s)
- D A Dart
- Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff, Wales, UK
- Imperial College London, London, UK
| | - K Ashelford
- Division of Cancer and Genetics, Wales Gene Park, School of Medicine, Cardiff University, Cardiff, Wales, UK
| | - W G Jiang
- Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff, Wales, UK
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21
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Razdan A, de Souza P, Roberts TL. Role of MicroRNAs in Treatment Response in Prostate Cancer. Curr Cancer Drug Targets 2019; 18:929-944. [PMID: 29644941 PMCID: PMC6463399 DOI: 10.2174/1568009618666180315160125] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Revised: 06/14/2017] [Accepted: 06/15/2017] [Indexed: 12/16/2022]
Abstract
Prostate cancer (PCa) is the most common non-skin cancer in men worldwide, resulting in significant mortality and morbidity. Depending on the grade and stage of the cancer, patients may be given radiation therapy, hormonal therapy, or chemotherapy. However, more than half of these patients develop resistance to treatment, leading to disease progression and metastases, often with lethal consequences. MicroRNAs (miRNAs) are short, non-coding RNAs, which regulate numerous physiological as well as pathological processes, including cancer. miRNAs mediate their regulatory effect predominately by binding to the 3'-untranslated region (UTR) of their target mRNAs. In this review, we will describe the mechanisms by which miRNAs mediate resistance to radiation and drug therapy (i.e. hormone therapy and chemotherapy) in PCa, including control of apoptosis, cell growth and proliferation, autophagy, epithelial-to-mesenchymal transition (EMT), invasion and metastasis, and cancer stem cells (CSCs). Furthermore, we will discuss the utility of circulating miRNAs isolated from different body fluids of prostate cancer patients as non-invasive biomarkers of cancer detection, disease progression, and therapy response. Finally, we will shortlist the candidate miRNAs, which may have a role in drug and radioresistance, that could potentially be used as predictive biomarkers of treatment response.
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Affiliation(s)
- Anshuli Razdan
- Medical Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia.,School of Medicine, Western Sydney University, Sydney, New South Wales, Australia.,Centre for Oncology Education and Research Translation (CONCERT), Liverpool, New South Wales, Australia
| | - Paul de Souza
- Medical Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia.,School of Medicine, Western Sydney University, Sydney, New South Wales, Australia.,Centre for Oncology Education and Research Translation (CONCERT), Liverpool, New South Wales, Australia.,School of Medicine, The University of New South Wales, Sydney, New South Wales, Australia.,Department of Medical Oncology, Liverpool Hospital, Liverpool, New South Wales, Australia
| | - Tara Laurine Roberts
- Medical Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia.,School of Medicine, Western Sydney University, Sydney, New South Wales, Australia.,Centre for Oncology Education and Research Translation (CONCERT), Liverpool, New South Wales, Australia.,School of Medicine, The University of New South Wales, Sydney, New South Wales, Australia.,The University of Queensland Centre for Clinical Research, Brisbane, Queensland, Australia
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22
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Rezaei S, Mahjoubin Tehran M, Sahebkar A, Jalili A, Aghaee‐Bakhtiari SH. Androgen receptor‐related micro RNAs in prostate cancer and their role in antiandrogen drug resistance. J Cell Physiol 2019; 235:3222-3234. [DOI: 10.1002/jcp.29275] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Accepted: 09/27/2019] [Indexed: 12/24/2022]
Affiliation(s)
- Samaneh Rezaei
- Department of Medical Biotechnology, Faculty of Medicine Mashhad University of Medical Sciences Mashhad Iran
| | - Maryam Mahjoubin Tehran
- Department of Medical Biotechnology, Faculty of Medicine Mashhad University of Medical Sciences Mashhad Iran
| | - Amirhossein Sahebkar
- Department of Medical Biotechnology, Faculty of Medicine Mashhad University of Medical Sciences Mashhad Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute Mashhad University of Medical Sciences Mashhad Iran
- Neurogenic Inflammation Research Center Mashhad University of Medical Sciences Mashhad Iran
| | - Amin Jalili
- Department of Medical Biotechnology, Faculty of Medicine Mashhad University of Medical Sciences Mashhad Iran
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23
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Fletcher CE, Sulpice E, Combe S, Shibakawa A, Leach DA, Hamilton MP, Chrysostomou SL, Sharp A, Welti J, Yuan W, Dart DA, Knight E, Ning J, Francis JC, Kounatidou EE, Gaughan L, Swain A, Lupold SE, de Bono JS, McGuire SE, Gidrol X, Bevan CL. Androgen receptor-modulatory microRNAs provide insight into therapy resistance and therapeutic targets in advanced prostate cancer. Oncogene 2019; 38:5700-5724. [PMID: 31043708 PMCID: PMC6755970 DOI: 10.1038/s41388-019-0823-5] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 02/05/2019] [Accepted: 02/05/2019] [Indexed: 02/07/2023]
Abstract
Androgen receptor (AR) signalling is a key prostate cancer (PC) driver, even in advanced 'castrate-resistant' disease (CRPC). To systematically identify microRNAs (miRs) modulating AR activity in lethal disease, hormone-responsive and -resistant PC cells expressing a luciferase-based AR reporter were transfected with a miR inhibitor library; 78 inhibitors significantly altered AR activity. Upon validation, miR-346, miR-361-3p and miR-197 inhibitors markedly reduced AR transcriptional activity, mRNA and protein levels, increased apoptosis, reduced proliferation, repressed EMT, and inhibited PC migration and invasion, demonstrating additive effects with AR inhibition. Corresponding miRs increased AR activity through a novel and anti-dogmatic mechanism of direct association with AR 6.9 kb 3'UTR and transcript stabilisation. In addition, miR-346 and miR-361-3p modulation altered levels of constitutively active AR variants, and inhibited variant-driven PC cell proliferation, so may contribute to persistent AR signalling in CRPC in the absence of circulating androgens. Pathway analysis of AGO-PAR-CLIP-identified miR targets revealed roles in DNA replication and repair, cell cycle, signal transduction and immune function. Silencing these targets, including tumour suppressors ARHGDIA and TAGLN2, phenocopied miR effects, demonstrating physiological relevance. MiR-346 additionally upregulated the oncogene, YWHAZ, which correlated with grade, biochemical relapse and metastasis in patients. These AR-modulatory miRs and targets correlated with AR activity in patient biopsies, and were elevated in response to long-term enzalutamide treatment of patient-derived CRPC xenografts. In summary, we identified miRs that modulate AR activity in PC and CRPC, via novel mechanisms, and may represent novel PC therapeutic targets.
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Affiliation(s)
- Claire E Fletcher
- Imperial Centre for Translational and Experimental Medicine, Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
| | - Eric Sulpice
- Université Grenoble Alpes, CEA, INSERM, BIG, BGE, 17 Avenue des Martyrs, 38054, Grenoble, France
| | - Stephanie Combe
- Université Grenoble Alpes, CEA, INSERM, BIG, BGE, 17 Avenue des Martyrs, 38054, Grenoble, France
| | - Akifumi Shibakawa
- Imperial Centre for Translational and Experimental Medicine, Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
| | - Damien A Leach
- Imperial Centre for Translational and Experimental Medicine, Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
| | - Mark P Hamilton
- Department of Molecular and Cellular Biology, Baylor College of Medicine, 1 Baylor Plaza Houston M822, Houston, TX, 77030, USA
| | - Stelios L Chrysostomou
- Imperial Centre for Translational and Experimental Medicine, Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
| | - Adam Sharp
- Prostate Cancer Target Therapy Group, Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, UK
| | - Jon Welti
- Prostate Cancer Target Therapy Group, Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, UK
| | - Wei Yuan
- Prostate Cancer Target Therapy Group, Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, UK
| | - Dafydd A Dart
- Imperial Centre for Translational and Experimental Medicine, Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
| | - Eleanor Knight
- Tumour Profiling Unit, Institute of Cancer Research, London, SW3 6JB, UK
| | - Jian Ning
- Tumour Profiling Unit, Institute of Cancer Research, London, SW3 6JB, UK
| | - Jeffrey C Francis
- Tumour Profiling Unit, Institute of Cancer Research, London, SW3 6JB, UK
| | - Evangelia E Kounatidou
- Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
| | - Luke Gaughan
- Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
| | - Amanda Swain
- Tumour Profiling Unit, Institute of Cancer Research, London, SW3 6JB, UK
| | - Shawn E Lupold
- The James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Johann S de Bono
- Prostate Cancer Target Therapy Group, Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, UK
| | - Sean E McGuire
- Department of Molecular and Cell Biology, Baylor College of Medicine Hospital, Houston, TX, USA
- Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xavier Gidrol
- Université Grenoble Alpes, CEA, INSERM, BIG, BGE, 17 Avenue des Martyrs, 38054, Grenoble, France
| | - Charlotte L Bevan
- Imperial Centre for Translational and Experimental Medicine, Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
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24
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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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25
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Li CC, Qiu XT, Sun Q, Zhou JP, Yang HJ, Wu WZ, He LF, Tang CE, Zhang GG, Bai YP. Endogenous reduction of miR-185 accelerates cardiac function recovery in mice following myocardial infarction via targeting of cathepsin K. J Cell Mol Med 2018; 23:1164-1173. [PMID: 30450725 PMCID: PMC6349160 DOI: 10.1111/jcmm.14016] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Revised: 08/27/2018] [Accepted: 09/14/2018] [Indexed: 12/15/2022] Open
Abstract
Angiogenesis is critical for re‐establishing the blood supply to the surviving myocardium after myocardial infarction (MI) in patients with acute coronary syndrome (ACS). MicroRNAs are recognised as important epigenetic regulators of endothelial function. The aim of this study was to determine the roles of microRNAs in angiogenesis. Eighteen circulating microRNAs including miR‐185‐5p were differently expressed in plasma from patients with ACS by high‐throughput RNA sequencing. The expressional levels of miR‐185‐5p were dramatically reduced in hearts isolated from mice following MI and cultured human umbilical vein endothelial cells (HUVECs) under hypoxia, as determined by fluorescence in situ hybridisation and quantitative RT‐PCR. Evidence from computational prediction and luciferase reporter gene activity indicated that cathepsin K (CatK) mRNA is a target of miR‐185‐5p. In HUVECs, miR‐185‐5p mimics inhibited cell proliferations, migrations and tube formations under hypoxia, while miR‐185‐5p inhibitors performed the opposites. Further, the inhibitory effects of miR‐185‐5p up‐regulation on cellular functions of HUVECs were abolished by CatK gene overexpression, and adenovirus‐mediated CatK gene silencing ablated these enhancive effects in HUVECs under hypoxia. In vivo studies indicated that gain‐function of miR‐185‐5p by agomir infusion down‐regulated CatK gene expression, impaired angiogenesis and delayed the recovery of cardiac functions in mice following MI. These actions of miR‐185‐5p agonists were mirrored by in vivo knockdown of CatK in mice with MI. Endogenous reductions of miR‐185‐5p in endothelial cells induced by hypoxia increase CatK gene expression to promote angiogenesis and to accelerate the recovery of cardiac function in mice following MI.
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Affiliation(s)
- Chuan-Chang Li
- Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorder, Xiangya Hospital, Central South University, Changsha, China
| | - Xue-Ting Qiu
- Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, China
| | - Quan Sun
- Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China
| | - Ji-Peng Zhou
- National Clinical Research Center for Geriatric Disorder, Xiangya Hospital, Central South University, Changsha, China
| | - Hui-Jun Yang
- Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China
| | - Wan-Zhou Wu
- Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, China
| | - Ling-Fang He
- Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, China
| | - Can-E Tang
- Institute of Medical Science Research, Xiangya Hospital, Central South University, Changsha, China
| | - Guo-Gang Zhang
- National Clinical Research Center for Geriatric Disorder, Xiangya Hospital, Central South University, Changsha, China.,Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China
| | - Yong-Ping Bai
- Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorder, Xiangya Hospital, Central South University, Changsha, China
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26
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Yu DP, Zhou Y. Astrocyte Elevated Gene 1 (AEG-1) Acts as a Promoter Gene in Clear Cell Renal Cell Carcinoma Cell Growth and Metastasis. Med Sci Monit 2018; 24:8213-8223. [PMID: 30431025 PMCID: PMC6253984 DOI: 10.12659/msm.911010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Background Clear cell renal cell carcinoma (ccRCC) is usually incurable once it progresses to metastatic stage. Hence, in-depth investigations to reveal the precise molecular mechanisms behind the metastasis of ccRCC are required to improve the therapeutic outcome of ccRCC. Material/Methods The level of astrocyte elevated gene 1 (AEG-1) in ccRCC tissues and cell lines was determined by quantitative real-time PCR (qRT-PCR) assay. The MTS, colony formation, wound-healing, and Transwell invasion assays were used to assess the role of AEG-1 in ccRCC cells growth, migration, and invasion in vitro, respectively. Xenograft model and lung metastasis models were constructed to analyze the functions of AEG-1 in ccRCC cells growth and metastasis in vivo. Result We found that AEG-1 was overexpressed in ccRCC and was associated with the progression of ccRCC. Knocked-down AEG-1 impaired the migration and invasion of ccRCC cells in vitro. Furthermore, under-expression of AEG-1 caused complete inhibition of ccRCC cells growth and metastasis in vivo. In contrast, overexpression of AEG-1 significantly increased the migration and invasion ability of ccRCC cells in vitro. Finally, we revealed that AEG-1 boosted the metastatic ability of ccRCC cells via regulating Notch homolog 1 (Notch1). Conclusions The AEG-1/Notch1 signaling axis plays a vital role in ccRCC cell growth and metastasis.
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Affiliation(s)
- Da Peng Yu
- Department of Surgical Urology, The First People's Hospital of Jining City, Jining, Shandong, China (mainland)
| | - Yan Zhou
- Department of Surgical Urology, Wenshang County's First People's Hospital, Wenshang, Shandong, China (mainland)
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27
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Tan B, Li Y, Zhao Q, Fan L, Wang D. ZNF139 increases multidrug resistance in gastric cancer cells by inhibiting miR-185. Biosci Rep 2018; 38:BSR20181023. [PMID: 30126848 PMCID: PMC6123064 DOI: 10.1042/bsr20181023] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 08/05/2018] [Accepted: 08/13/2018] [Indexed: 12/12/2022] Open
Abstract
It has been reported that the expression of zinc finger protein 139 (ZNF139) and microRNA-185 (miR-185) were associated with proliferation, drug resistance of gastric cancer (GC) cells. However, the detailed mechanisms have not been fully investigated. The expression of ZNF139 in both GC tissues and cell lines was tested, then SGC7901/ADR or SGC7901 cells were transfected with ZNF139-siRNA, miR-185 analog, or pcDNA-ZNF139. Cell activity was determined by MTT assay. Real-time PCR and Western blot were utilized to detect ZNF139, miR-185, and multidrug resistance (MDR) related genes including MDR1/P-gp, GST-π, MRP-1, Bcl-2, TS and Bax. ChIP and dual luciferase activity assay were used to investigate regulation between ZNF139 and miR-185 Increased ZNF139 and decreased miR-185 expression were detected in GC tissues and cell lines. Transfection with ZNF139-siRNA into SGC7901/ADR cells markedly increased expression of miR-185, and treating with chemotherapeutic drugs ADR, 5-FU, L-OHP, the survival rate of SGC7901/ADR cells obviously decreased after ZNF139-siRNA transfection. On the other hand, transfection with pcDNA-ZNF139 in GC cell line SGC7901 resulted in an increased expression level of ZNF139 and a decline in the expression level of miR-185, meanwhile drug resistance of GC cells was clearly enhanced to ADR, 5-FU, L-OHP. Dual luciferase activity assay demonstrated that ZNF139 inhibited transcriptional activities of miR-185's promoter in cells transfected with the reporter plasmid encompassing the upstream promoter region of miR-185 along with pcDNA-ZNF139. Our data reveal that ZNF139 might promote MDR gene MDR1/P-gp, MRP-1 and Bcl-2 by prohibiting miR-185.
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Affiliation(s)
- Bibo Tan
- Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province 050011, China
| | - Yong Li
- Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province 050011, China
| | - Qun Zhao
- Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province 050011, China
| | - Liqiao Fan
- Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province 050011, China
| | - Dong Wang
- Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province 050011, China
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28
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Li C, Yang B, Pan P, Ma Q, Wu Y, Zhang Z, Guo X, Ye J, Gui Y. MicroRNA-130a inhibits spermatogenesis by directly targeting androgen receptor in mouse Sertoli cells. Mol Reprod Dev 2018; 85:768-777. [PMID: 30191667 DOI: 10.1002/mrd.23058] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Accepted: 09/04/2018] [Indexed: 12/18/2022]
Abstract
MicroRNAs (miRNAs) have been shown to play a key role in spermatogenesis. However, whether the miRNAs influence androgen/androgen receptor (AR) signaling during spermatogenesis remains unclear. Using a bioinformatic approach, a potential miRNA, miR-130a, which could bind to Ar-3'untranslated region directly was identified. The expression pattern of miR-130a was further characterized by quantitative real-time polymerase chain reaction. It was found that miR-130a was abundant in testis and its expression level was negatively correlated with age. Overexpression of miR-130a could inhibit AR expression both in vitro and in vivo. Moreover, the mice with an intratesticular injection of miR-130a showed defects in spermatogenesis and increased germ cell apoptosis. Taken together, these results suggest that miR-130a could negatively regulate AR expression in mouse Sertoli cell, which further cause defects in spermatogenesis.
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Affiliation(s)
- Cailing Li
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, China
| | - Bo Yang
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, China
| | - Peng Pan
- Reproductive Medicine Center, Jinling Hospital affiliated of Nanjing University, Nanjing, China
| | - Qian Ma
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, China
| | - Yong Wu
- Reproductive Center, Jingzhou Central Hospital affiliated of The Second Clinical Medical College, Yangze University, Jingzhou, China
| | - Zeng Zhang
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, China
| | - Xin Guo
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, China
| | - Jing Ye
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, China
| | - Yaoting Gui
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, China
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29
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Zhang C, Xiong J, Yang Q, Wang Y, Shi H, Tian Q, Huang H, Kong D, Lv J, Liu D, Gao X, Zi X, Sun Y. Profiling and bioinformatics analyses of differential circular RNA expression in prostate cancer cells. Future Sci OA 2018; 4:FSOA340. [PMID: 30416748 PMCID: PMC6222276 DOI: 10.4155/fsoa-2018-0046] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Accepted: 07/30/2018] [Indexed: 12/13/2022] Open
Abstract
AIM There is little knowledge about the expression profile and function of circular RNAs (circRNAs) in prostate cancer (PCa). METHODS The expression profiles of circRNAs in RWPE-1, 22RV1 and PC3 cells were explored via high-throughput circRNAs sequencing and validated by real-time qPCR. The roles of differentially expressed circRNAs were evaluated by bioinformatics analyses. RESULTS Altogether 9545 circRNAs were identified and hundreds of differentially expressed circRNAs were recognized. CircRNA-miRNA networks analysis showed that many circRNAs, including circSLC7A6, circGUCY1A2 and circZFP57 could cross-talk with tumor-related miRNAs such as miR-21, miR-143 and miR-200 family. CONCLUSION The results of our bioinformatics analyses suggested that circRNAs should play critical roles in the development and progression of PCa.
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Affiliation(s)
- Chunlei Zhang
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, PR China
- Department of Urology, Lanzhou General Hospital of PLA, Lanzhou, PR China
| | - Jun Xiong
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, PR China
- Department of Histological Embryology, Second Military Medical University, Shanghai, PR China
| | - Qi Yang
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, PR China
- Department of Urology, Lanzhou General Hospital of PLA, Lanzhou, PR China
| | - Ye Wang
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, PR China
| | - Haoqing Shi
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, PR China
| | - Qinqin Tian
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, PR China
| | - Hai Huang
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, PR China
| | - Depei Kong
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, PR China
| | - Jianmin Lv
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, PR China
| | - Dan Liu
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, PR China
| | - Xu Gao
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, PR China
| | - Xiaoyuan Zi
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, PR China
- Department of Cell Biology, Second Military Medical University, Shanghai, PR China
| | - Yinghao Sun
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, PR China
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30
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Ostadrahimi S, Abedi Valugerdi M, Hassan M, Haddad G, Fayaz S, Parvizhamidi M, Mahdian R, Fard Esfahani P. miR-1266-5p and miR-185-5p Promote Cell Apoptosis in Human Prostate Cancer Cell Lines. Asian Pac J Cancer Prev 2018; 19:2305-2311. [PMID: 30141307 PMCID: PMC6171381 DOI: 10.22034/apjcp.2018.19.8.2305] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Objective: Small non-coding RNA molecules are dysregulated in prostate cancer (PCa). In our previous study, downregulation of miR-1266 and miR-185 was demonstrated in PCa tissues and cell lines. The aim of the present study was to investigate whether miR-1266 and miR-185 are involved in the regulation of B-cell lymphoma (BCL) 2 and BCL2L1, respectively, and whether transfection of PCa cell lines with miR-1266 and miR-185 mimics can alter tumorigenic phenotypes. Methods: In order to investigate the regulation of BCL2 and BCL2L1 mRNA levels by miR-1266 and miR-185, respectively, a luciferase reporter assay was used. Real-time PCR was also used to analyze changes in the levels of BCL2 and BCL2L1 mRNAs in PCa cell lines following transfection with synthetic miR-1266 and miR-185. Cell apoptosis was determined by Annexin V protein expression analysis via flow cytometry. In addition to the MTT assay, a cell proliferation assay was performed. Result: A luciferase assay confirmed that the BCL2 and BCL2L1 genes may be targeted by miR-1266 and miR-185, respectively, through binding to their 3′UTR regions. Transfection of PC3 and DU145 cells with miR-1266 and miR-185 induced apoptosis and reduced proliferation, which also revealed an inverse correlation with BCL2 and BCL2L1 gene expression in the treated cells. Conclusion: Our data suggests that miR-1266 and miR-185 may be novel candidates for further research in PCa treatment through the anti-apoptotic pathway.
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Affiliation(s)
- Shiva Ostadrahimi
- Department of Biochemistry, Pasteur Institute of Iran, Tehran, Iran.,Department of Laboratory Medicine, Department of Experimental Cancer Medicine, Karolinska Institutet Huddinge, 141 86 Stockholm, Sweden. ,
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31
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MicroRNA-155, -185 and -193b as biomarkers in human papillomavirus positive and negative tonsillar and base of tongue squamous cell carcinoma. Oral Oncol 2018; 82:8-16. [PMID: 29909906 DOI: 10.1016/j.oraloncology.2018.04.021] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 03/23/2018] [Accepted: 04/26/2018] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Three-year disease-free survival (DFS) is 80% for human papillomavirus (HPV) positive tonsillar and base of tongue cancer (TSCC/BOTSCC) treated with radiotherapy alone, and today's intensified therapy does not improve prognosis. More markers are therefore needed to more accurately identify patients with good prognosis or in need of alternative therapy. Here, microRNAs (miRs) 155, 185 and 193b were examined as potential prognostic markers in TSCC/BOTSCC. MATERIAL AND METHODS 168 TSCC/BOTSCC patients diagnosed 2000-2013, with known data on HPV-status, CD8+ tumour infiltrating lymphocytes, tumour staging and survival were examined for expression of miR-155, -185 and -193b using Real-Time PCR. Associations between miR expression and patient and tumour characteristics were analysed using univariate testing and multivariate regression. RESULTS Tumours compared to normal tonsils showed decreased miR-155 and increased miR-193b expression. miR-155 expression was associated with HPV-positivity, low T-stage, high CD8+ TIL counts and improved survival. miR-185 expression was associated with HPV-negativity and a tendency towards decreased survival, while miR-193b expression was associated with higher T-stage, male gender and lower CD8+ TIL counts, but not with outcome. Upon Cox regression, miR-185 was the only miR significantly associated with survival. Combining miR-155 and miR-185 to predict outcome in HPV+ patients yielded an area under curve (AUC) of 71%. CONCLUSION Increased miR-155 expression was found as a positive predictor of survival, with the effect mainly due to its association with high CD8+ TIL numbers, while miR-185 independently associated with decreased survival. Addition of these miRs to previously validated prognostic biomarkers could improve patient stratification accuracy.
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32
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Kristensen H, Thomsen AR, Haldrup C, Dyrskjøt L, Høyer S, Borre M, Mouritzen P, Ørntoft TF, Sørensen KD. Novel diagnostic and prognostic classifiers for prostate cancer identified by genome-wide microRNA profiling. Oncotarget 2017; 7:30760-71. [PMID: 27120795 PMCID: PMC5058715 DOI: 10.18632/oncotarget.8953] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Accepted: 04/02/2016] [Indexed: 02/07/2023] Open
Abstract
Purpose This study investigates the diagnostic and prognostic biomarker potential of miRNAs in prostate cancer (PC). Results We identified several new deregulated miRNAs between non-malignant (NM) and PC tissue samples and between more/less aggressive PC subgroups. We also developed and validated a novel 13-miRNA diagnostic classifier with high sensitivity and specificity for PC. Finally, we trained a new 3-miRNA prognostic classifier (miR-185-5p+miR-221-3p+miR-326) that predicted time to biochemical recurrence (BCR) independently of routine clinicopathological variables in a training radical prostatectomy (RP) cohort (n = 126) as well as in two independent validation cohorts (n = 110 and n = 99). Experimental Design After RT-qPCR-based profiling of 752 miRNAs in 13 NM and 134 PC tissue samples (cohort 1), we selected 93 top candidate diagnostic/prognostic miRNAs for validation in two independent patient sets (cohort 2: 19 NM and 138 PC; cohort 3: 28 NM and 113 PC samples). Diagnostic potential was assessed by ROC curve analysis and prognostic potential by Kaplan-Meier, uni- and multivariate Cox regression analyses. BCR after RP was used as endpoint. Conclusions This is the first report of a miRNA signature with significant independent prognostic value demonstrated in three PC patient cohorts.
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Affiliation(s)
- Helle Kristensen
- Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.,Exiqon A/S, Skelstedet, Vedbaek, Denmark
| | | | - Christa Haldrup
- Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Lars Dyrskjøt
- Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Søren Høyer
- Institute of Pathology, Aarhus University Hospital, Aarhus, Denmark
| | - Michael Borre
- Department of Urology, Aarhus University Hospital, Aarhus, Denmark
| | | | - Torben F Ørntoft
- Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark
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Upregulation of miR‑185 promotes apoptosis of the human gastric cancer cell line MGC803. Mol Med Rep 2017; 17:3115-3122. [PMID: 29257260 DOI: 10.3892/mmr.2017.8206] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Accepted: 05/05/2017] [Indexed: 11/05/2022] Open
Abstract
MicroRNA (miR)-185, which has been reported to be abnormally expressed in some types of cancer, exerts significant effects on the proliferation, apoptosis, drug resistance and metastasis of cancer cells. The present study aimed to explore the effects and underlying molecular mechanisms of miR‑185 upregulation on the apoptosis of gastric cancer (GC) cells. Quantitative polymerase chain reaction (qPCR) and western blotting were used to detect the expression levels of miR‑185 in GC and adjacent normal tissues. In addition, miR‑185 expression was detected in the following GC cell lines: MKN74, SGC7901, BGC823, MGC803, as well as in the gastric epithelial cell line GES‑1. Subsequently, miR‑185 mimics were transfected into MGC803 cells. Post‑transfection, the following experiments were conducted: MTT assay was applied to test cell viability; flow cytometry (FCM) was used to determine the apoptotic rate of the cells; and qPCR and western blotting were conducted to detect the expression levels of the following apoptosis‑associated factors: B‑cell lymphoma 2 (Bcl‑2), Bcl‑2‑associated X protein (Bax), survivin, X‑linked inhibitor of apoptosis protein (XIAP), livin, caspase‑3 and caspase‑8. The results demonstrated that miR‑185 was downregulated in GC tissues compared with the adjacent tissues. In cell lines, miR‑185 expression was higher in GES‑1 cells compared with in the GC cell lines; in the 4 GC cell lines, the strongest miR‑185 expression was in MKN74 cells, followed by SGC7901 and BGC823 cells, and the weakest was in MGC803 cells (P<0.05). Expression of miR‑185 was associated with tumor size, differentiation and lymphatic metastasis. Post-transfection with miR‑185 mimics, miR‑185 expression was significantly increased in a time‑ and concentration‑dependent manner. MGC803 cell viability was significantly decreased following miR‑185 mimics transfection. The results of FCM demonstrated that post‑transfection with miR‑185 mimics, the apoptotic rate of MGC803 cells was significantly increased. Post‑transfection with miR‑185 mimics, the expression levels of Bcl‑2, survivin and XIAP were significantly decreased in MGC803 cells, whereas the expression levels of Bax and livin were not altered, and caspase‑3 and caspase‑8 expression was significantly increased. Spectrophotometry indicated that caspase‑3 and caspase‑8 activity was significantly increased in MGC803 cells following transfection with miR‑185 mimics. In conclusion, the present study suggested that miR‑185 upregulation in GC cells may promote apoptosis of tumor cells via gene expression regulation.
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Hosnedlova B, Kepinska M, Skalickova S, Fernandez C, Ruttkay-Nedecky B, Malevu TD, Sochor J, Baron M, Melcova M, Zidkova J, Kizek R. A Summary of New Findings on the Biological Effects of Selenium in Selected Animal Species-A Critical Review. Int J Mol Sci 2017; 18:E2209. [PMID: 29065468 PMCID: PMC5666889 DOI: 10.3390/ijms18102209] [Citation(s) in RCA: 128] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Revised: 10/10/2017] [Accepted: 10/11/2017] [Indexed: 12/18/2022] Open
Abstract
Selenium is an essential trace element important for many physiological processes, especially for the functions of immune and reproductive systems, metabolism of thyroid hormones, as well as antioxidant defense. Selenium deficiency is usually manifested by an increased incidence of retention of placenta, metritis, mastitis, aborts, lowering fertility and increased susceptibility to infections. In calves, lambs and kids, the selenium deficiency demonstrates by WMD (white muscle disease), in foals and donkey foals, it is associated with incidence of WMD and yellow fat disease, and in pigs it causes VESD (vitamin E/selenium deficiency) syndrome. The prevention of these health disorders can be achieved by an adequate selenium supplementation to the diet. The review summarizes the survey of knowledge on selenium, its biological significance in the organism, the impact of its deficiency in mammalian livestock (comparison of ruminants vs. non-ruminants, herbivore vs. omnivore) and possibilities of its peroral administration. The databases employed were as follows: Web of Science, PubMed, MEDLINE and Google Scholar.
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Affiliation(s)
- Bozena Hosnedlova
- Department of Viticulture and Enology, Faculty of Horticulture, Mendel University in Brno, Valtická 337, CZ-691 44 Lednice, Czech Republic.
| | - Marta Kepinska
- Department of Biomedical and Environmental Analyses, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211, 50-556 Wroclaw, Poland.
| | - Sylvie Skalickova
- Central Laboratory, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Palackeho 1946/1, 612 42 Brno, Czech Republic.
| | - Carlos Fernandez
- School of Pharmacy and Life Sciences, Robert Gordon University, Garthdee Road, Aberdeen AB107GJ, UK.
| | - Branislav Ruttkay-Nedecky
- Central Laboratory, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Palackeho 1946/1, 612 42 Brno, Czech Republic.
| | | | - Jiri Sochor
- Department of Viticulture and Enology, Faculty of Horticulture, Mendel University in Brno, Valtická 337, CZ-691 44 Lednice, Czech Republic.
| | - Mojmir Baron
- Department of Viticulture and Enology, Faculty of Horticulture, Mendel University in Brno, Valtická 337, CZ-691 44 Lednice, Czech Republic.
| | - Magdalena Melcova
- Department of Biochemistry and Microbiology, University of Chemistry and Technology, Technicka 3, 166 28 Prague, Czech Republic.
| | - Jarmila Zidkova
- Department of Biochemistry and Microbiology, University of Chemistry and Technology, Technicka 3, 166 28 Prague, Czech Republic.
| | - Rene Kizek
- Department of Biomedical and Environmental Analyses, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211, 50-556 Wroclaw, Poland.
- Central Laboratory, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Palackeho 1946/1, 612 42 Brno, Czech Republic.
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Massillo C, Dalton GN, Farré PL, De Luca P, De Siervi A. Implications of microRNA dysregulation in the development of prostate cancer. Reproduction 2017; 154:R81-R97. [DOI: 10.1530/rep-17-0322] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Revised: 06/25/2017] [Accepted: 07/10/2017] [Indexed: 12/21/2022]
Abstract
MicroRNAs (miRNAs) are non-coding small RNAs that target mRNA to reduce protein expression. They play fundamental roles in several diseases, including prostate cancer (PCa). A single miRNA can target hundreds of mRNAs and coordinately regulate them, which implicates them in nearly every biological pathway. Hence, miRNAs modulate proliferation, cell cycle, apoptosis, adhesion, migration, invasion and metastasis, most of them constituting crucial hallmarks of cancer. Due to these properties, miRNAs emerged as promising tools for diagnostic, prognosis and management of cancer patients. Moreover, they come out as potential targets for cancer treatment, and several efforts are being made to progress in the field of miRNA-based cancer therapy. In this review, we will summarize the recent information about miRNAs in PCa. We will recapitulate all the miRNAs involved in the androgen pathway and the biology of PCa, focusing in PCa initiation and progression. In particular, we will describe the miRNAs associated with cell proliferation, cell cycle and apoptosis in PCa, as well as invasion, adhesion and metastatic miRNAs. We will revise the recent progress made understanding the role of circulating miRNAs identified in PCa that might be useful for PCa patient stratification. Another key aspect to be discussed in this review is miRNAs’ role in PCa therapy, including the miRNAs delivery.
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36
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Kumar A, Rimando AM, Levenson AS. Resveratrol and pterostilbene as a microRNA-mediated chemopreventive and therapeutic strategy in prostate cancer. Ann N Y Acad Sci 2017; 1403:15-26. [PMID: 28662290 DOI: 10.1111/nyas.13372] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Revised: 04/07/2017] [Accepted: 04/10/2017] [Indexed: 12/23/2022]
Abstract
Growing evidence indicates that deregulation of the epigenetic machinery comprising the microRNA (miRNA) network is a critical factor in the progression of various diseases, including cancer. Concurrently, dietary phytochemicals are being intensively studied for their miRNA-mediated health-beneficial properties, such as anti-inflammatory, cardioprotective, antioxidative, and anticancer properties. Available experimental data have suggested that dietary polyphenols may be effective miRNA-modulating chemopreventive and therapeutic agents. Moreover, noninvasive detection of changes in miRNA expression in liquid biopsies opens enormous possibilities for their clinical utilization as novel prognostic and predictive biomarkers. In our published studies, we identified resveratrol-regulated miRNA profiles in prostate cancer. Resveratrol downregulated the phosphatase and tensin homolog (PTEN)-targeting members of the oncogenic miR-17 family of miRNAs, which are overexpressed in prostate cancer. We have functionally validated the miRNA-mediated ability of resveratrol and its potent analog pterostilbene to rescue the tumor suppressor activity of PTEN in vitro and in vivo. Taken together, our findings implicate the use of resveratrol and its analogs as an attractive miRNA-mediated chemopreventive and therapeutic strategy in prostate cancer and the use of circulating miRNAs as potential predictive biomarkers for clinical development.
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Affiliation(s)
- Avinash Kumar
- Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, New York
| | - Agnes M Rimando
- United States Department of Agriculture, Agricultural Research Service, Natural Products Utilization Research Unit, Oxford, Mississippi
| | - Anait S Levenson
- Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, New York
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37
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Construction and analyses of the microRNA-target gene differential regulatory network in thyroid carcinoma. PLoS One 2017; 12:e0178331. [PMID: 28570571 PMCID: PMC5453480 DOI: 10.1371/journal.pone.0178331] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Accepted: 05/11/2017] [Indexed: 12/13/2022] Open
Abstract
Thyroid-carcinoma (THCA) is the most common malignancy with an increasing incidence. Recent evidence has emphasized the role of microRNA (miRNA) in THCA. However, knowledge concerning the roles of miRNAs in THCA is still limited. We therefore use a miRNA-target gene differential regulatory network (MGDRN) to identify key miRNAs and characterize their synergistic regulation in THCA. Both miRNA-target gene interactions from multiple databases and negative expression correlations between miRNA-target genes were used to characterize the interactions. Then, two regulatory networks involving normal and tumor conditions were constructed, respectively. The MGDRN was finally constructed using different interactions between the above two regulatory networks. By analyzing topological features of the MGDRN, four miRNAs (hsa-mir-152-3p, hsa-mir-148a, hsa-mir-130b and hsa-mir-15b) are identified as key miRNAs in THCA. Over-expression of mir-152-3p inhibited proliferation and colony formation of TPC-1 cells. Furthermore, mir-152-3p negatively regulated ERBB3 by binding to the 3'-UTR of ERBB3, and down-regulation of ERBB3 by small interfering (si)RNAs inhibited proliferation and colony formation of TPC-1 cells, indicating that mir-152-3p acted as an anti-tumor miRNA by negatively regulating ERBB3. Finally, two synergistically dysregulated modules were identified which may contribute to the initiation and progression of THCA. Overall, the results provided a better understanding of the molecular basis of THCA, and suggested novel treatment strategies for this cancer.
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38
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Zhao Y, Yan M, Yun Y, Zhang J, Zhang R, Li Y, Wu X, Liu Q, Miao W, Jiang H. MicroRNA-455-3p functions as a tumor suppressor by targeting eIF4E in prostate cancer. Oncol Rep 2017; 37:2449-2458. [PMID: 28350134 DOI: 10.3892/or.2017.5502] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 01/23/2017] [Indexed: 11/06/2022] Open
Abstract
MicroRNAs (miRNAs) are strongly implicated in various cancers, including prostate cancer. Recently, microRNA-455-3p (miR-455-3p) has been shown to be aberrantly expressed in many tumor tissues, but its functions in tumorigenesis remain unknown. In this study, we investigated the role of miR-455-3p in prostate cancer. We found that miR-455-3p is markedly downregulated in prostate cancer cell lines and clinical tumor specimens. Gain-of-function and loss-of-function studies showed that miR-455-3p promotes prostate cancer cell growth both in vitro and in vivo. Bioinformatics analysis and Luciferase reporter assays demonstrated that miR-455-3p directly targets and suppresses eIF4E, the rate-limiting factor for cap-dependent translation, which plays important roles in the initiation and progression of prostate cancers. Further studies demonstrated that miR-455-3p inhibits cap-dependent translation and the proliferation of prostate cancer cells through targeting eIF4E. Taken together, our findings suggest that miR-455-3p functions as a tumor suppressor by directly targeting eIF4E in prostate carcinogenesis and may be used as a potential target for therapeutic intervention in prostate cancer.
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Affiliation(s)
- Yongxiang Zhao
- Department of Urinary Surgery of The Fourth Hospital of Baotou, Baotou, Inner Mongolia, P.R. China
| | - Mingyu Yan
- The Third Affiliated Hospital, Inner Mongolia Medical University, Baotou, Inner Mongolia, P.R. China
| | - Ye Yun
- Department of Urinary Surgery of The Fourth Hospital of Baotou, Baotou, Inner Mongolia, P.R. China
| | - Jianguo Zhang
- Department of Urinary Surgery of The Fourth Hospital of Baotou, Baotou, Inner Mongolia, P.R. China
| | - Ruimin Zhang
- Department of Urinary Surgery of The Fourth Hospital of Baotou, Baotou, Inner Mongolia, P.R. China
| | - Yan Li
- Baotou Center for Disease Control and Prevention, Baotou, Inner Mongolia, P.R. China
| | - Xiangming Wu
- Department of Urinary Surgery of The Fourth Hospital of Baotou, Baotou, Inner Mongolia, P.R. China
| | - Qiang Liu
- Department of Urinary Surgery of The Fourth Hospital of Baotou, Baotou, Inner Mongolia, P.R. China
| | - Wei Miao
- Department of Urinary Surgery of The Fourth Hospital of Baotou, Baotou, Inner Mongolia, P.R. China
| | - Haishan Jiang
- Department of Urinary Surgery of The Fourth Hospital of Baotou, Baotou, Inner Mongolia, P.R. China
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39
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Zhou L, Liu S, Han M, Feng S, Liang J, Li Z, Li Y, Lu H, Liu T, Ma Y, Cheng J. MicroRNA-185 induces potent autophagy via AKT signaling in hepatocellular carcinoma. Tumour Biol 2017; 39:1010428317694313. [PMID: 28240051 DOI: 10.1177/1010428317694313] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Studies have demonstrated that microRNA 185 may be a promising therapeutic target in liver cancer. However, its role in hepatocellular carcinoma is largely unknown. In this study, the proliferation of human HepG2 cells was inhibited by transfection of microRNA 185 mimics. Cell-cycle analysis revealed arrest at the G0/G1 phase. Transfection of HepG2 cells with microRNA 185 mimics significantly induced apoptosis. These data confirmed microRNA 185 as a potent cancer suppressor. We demonstrated that microRNA 185 was a compelling inducer of autophagy, for the first time. When cell autophagy was inhibited by chloroquine or 3-methyladenine, microRNA 185 induced more cell apoptosis. MicroRNA 185 acted as a cancer suppressor by regulating AKT1 expression and phosphorylation. Dual-luciferase reporter assays indicated that microRNA 185 suppressed the expression of target genes including RHEB, RICTOR, and AKT1 by directly interacting with their 3'-untranslated regions. Binding site mutations eliminated microRNA 185 responsiveness. Our findings demonstrate a new role of microRNA 185 as a key regulator of hepatocellular carcinoma via autophagy by dysregulation of AKT1 pathway.
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Affiliation(s)
- Li Zhou
- 1 Beijing Ditan Hospital, Peking University Teaching Hospital, Beijing, China.,2 Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China
| | - Shunai Liu
- 2 Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China.,3 Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ming Han
- 1 Beijing Ditan Hospital, Peking University Teaching Hospital, Beijing, China.,2 Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China
| | - Shenghu Feng
- 1 Beijing Ditan Hospital, Peking University Teaching Hospital, Beijing, China.,2 Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China
| | - Jinqiu Liang
- 4 Division of Infectious Disease, Civil Aviation General Hospital, Beijing, China
| | - Zhongshu Li
- 2 Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China.,3 Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yaru Li
- 2 Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China.,3 Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Hongping Lu
- 2 Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China.,3 Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ting Liu
- 1 Beijing Ditan Hospital, Peking University Teaching Hospital, Beijing, China.,2 Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China
| | - Yanhua Ma
- 1 Beijing Ditan Hospital, Peking University Teaching Hospital, Beijing, China.,2 Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China
| | - Jun Cheng
- 1 Beijing Ditan Hospital, Peking University Teaching Hospital, Beijing, China.,2 Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China.,3 Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
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40
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He J, Tian N, Yang Y, Jin L, Feng X, Hua J, Lin S, Wang B, Li H, Wang J. miR-185 enhances the inhibition of proliferation and migration induced by ionizing radiation in melanoma. Oncol Lett 2017; 13:2442-2448. [PMID: 28454417 DOI: 10.3892/ol.2017.5699] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Accepted: 12/02/2016] [Indexed: 12/14/2022] Open
Abstract
Melanoma is an aggressive malignancy that is increasingly common and exhibits a poor patient survival rate. Radiotherapy is the primary option for patients with melanoma, particularly those who are not candidates for surgery; however, the therapeutic effect is limited due to the relative radioresistance of melanoma to ionizing radiation (IR). It has been reported that microRNAs (miRNAs) serve a vital role in determining the radiosensitivity of tumors; however, little is known concerning the radiosensitization of melanoma using miRNA. In the present study, the radiosensitization effect of miRNA 185 (miR-185), which has been demonstrated to reduce renal cancer radioresistance, was investigated in B16 cells, a skin melanoma cell line derived from C57/BL mice, was investigated. Cell proliferation and scratch wound healing assays were used to determine the proliferative and migratory abilities of B16 cells. Annexin V/propidium iodide double staining was used to determine the apoptosis induced by IR. A tumor formation assay was performed to determine the radiosensitization effect of miR-185 on melanoma cells in vivo. Proliferation marker protein Ki-67, and hematoxylin and eosin staining were used to assess the proliferative activity and histological changes, respectively. The results of the present study demonstrated that miR-185 suppresses cellular proliferation and migration, and enhances IR-induced apoptosis, and the inhibition of proliferation and migration, in vitro and in vivo, which provides an insight into understanding the radiosensitization of melanoma using miRNA.
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Affiliation(s)
- Jinpeng He
- Gansu Key Laboratory of Space Radiobiology, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, Gansu 730000, P.R. China.,Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, Gansu 730000, P.R. China
| | - Ning Tian
- Gansu Key Laboratory of Space Radiobiology, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, Gansu 730000, P.R. China.,School of Pharmacy, Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Yanli Yang
- Department of Pathology, Lanzhou General Hospital, Lanzhou Command of the Chinese People's Liberation Army, Lanzhou, Gansu 730050, P.R. China
| | - Liangliang Jin
- Department of Pathology, Lanzhou General Hospital, Lanzhou Command of the Chinese People's Liberation Army, Lanzhou, Gansu 730050, P.R. China
| | - Xiu Feng
- Gansu Key Laboratory of Space Radiobiology, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, Gansu 730000, P.R. China.,School of Pharmacy, Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Junrui Hua
- Gansu Key Laboratory of Space Radiobiology, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, Gansu 730000, P.R. China.,Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, Gansu 730000, P.R. China
| | - Sulan Lin
- Gansu Key Laboratory of Space Radiobiology, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, Gansu 730000, P.R. China.,University of Chinese Academy of Sciences, Beijing 100049, P.R. China
| | - Bing Wang
- Gansu Key Laboratory of Space Radiobiology, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, Gansu 730000, P.R. China.,University of Chinese Academy of Sciences, Beijing 100049, P.R. China
| | - He Li
- Gansu Key Laboratory of Space Radiobiology, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, Gansu 730000, P.R. China.,University of Chinese Academy of Sciences, Beijing 100049, P.R. China
| | - Jufang Wang
- Gansu Key Laboratory of Space Radiobiology, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, Gansu 730000, P.R. China.,Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, Gansu 730000, P.R. China
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41
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Kumar B, Khaleghzadegan S, Mears B, Hatano K, Kudrolli TA, Chowdhury WH, Yeater DB, Ewing CM, Luo J, Isaacs WB, Marchionni L, Lupold SE. Identification of miR-30b-3p and miR-30d-5p as direct regulators of androgen receptor signaling in prostate cancer by complementary functional microRNA library screening. Oncotarget 2016; 7:72593-72607. [PMID: 27683042 PMCID: PMC5341930 DOI: 10.18632/oncotarget.12241] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2016] [Accepted: 09/17/2016] [Indexed: 02/06/2023] Open
Abstract
The Androgen Receptor (AR) plays a key role in prostate biology and in the progression of prostate cancer (PCa) to castration resistance. The role of microRNAs (miRNAs) in aberrant AR signaling have not been fully characterized. Here we screened a library of 810 miRNA mimics to identify miRNAs that alter AR activity in complementary functional assays including protein lysate microarray (LMA) quantification of AR and PSA protein levels, AR transcriptional reporter activity, and AR-positive PCa cell viability. Candidate AR-regulating miRNAs were verified through AR transcriptional reporter and cell viability assays. MiRNA binding sites were found within the AR 3'-untranslated region (UTR) and within the AR and AR-V7 coding regions. MiRNA activity was characterized by western blotting, 3'-UTR reporter assay, and AR-GFP and AR-V7-GFP reporter assays. Results uncovered miR-30 family members as direct AR inhibitors. Inhibition of endogenous miR-30b-3p and miR-30d-5p enhanced AR expression and androgen-independent cell growth. Droplet digital RT-PCR quantification of miR-30c-5p and miR-30d-5p revealed significantly reduced levels in metastatic castration resistant PCa (CRPC), when compared to healthy prostate tissues. MiR-30d-5p levels were inversely correlated with AR activity, as measured by PSA mRNA, in metastatic CRPC. Collectively, these studies provide a comprehensive evaluation of AR-regulating miRNAs in PCa.
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Affiliation(s)
- Binod Kumar
- The James Buchanan Brady Urologic Institute and Department of Urology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Salar Khaleghzadegan
- The James Buchanan Brady Urologic Institute and Department of Urology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Brian Mears
- The James Buchanan Brady Urologic Institute and Department of Urology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Koji Hatano
- The James Buchanan Brady Urologic Institute and Department of Urology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Tarana A. Kudrolli
- The James Buchanan Brady Urologic Institute and Department of Urology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Wasim H. Chowdhury
- The James Buchanan Brady Urologic Institute and Department of Urology, Johns Hopkins School of Medicine, Baltimore, MD, USA
- Current Address: University of Texas at San Antonio, San Antonio, Texas, USA
| | - David B. Yeater
- The James Buchanan Brady Urologic Institute and Department of Urology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Charles M. Ewing
- The James Buchanan Brady Urologic Institute and Department of Urology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Jun Luo
- The James Buchanan Brady Urologic Institute and Department of Urology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - William B. Isaacs
- The James Buchanan Brady Urologic Institute and Department of Urology, Johns Hopkins School of Medicine, Baltimore, MD, USA
- The department of Oncology, Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Luigi Marchionni
- The department of Oncology, Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Shawn E. Lupold
- The James Buchanan Brady Urologic Institute and Department of Urology, Johns Hopkins School of Medicine, Baltimore, MD, USA
- The department of Oncology, Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
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42
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Gutierrez-Pajares JL, Ben Hassen C, Chevalier S, Frank PG. SR-BI: Linking Cholesterol and Lipoprotein Metabolism with Breast and Prostate Cancer. Front Pharmacol 2016; 7:338. [PMID: 27774064 PMCID: PMC5054001 DOI: 10.3389/fphar.2016.00338] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Accepted: 09/12/2016] [Indexed: 12/16/2022] Open
Abstract
Studies have demonstrated the significant role of cholesterol and lipoprotein metabolism in the progression of cancer. The SCARB1 gene encodes the scavenger receptor class B type I (SR-BI), which is an 82-kDa glycoprotein with two transmembrane domains separated by a large extracellular loop. SR-BI plays an important role in the regulation of cholesterol exchange between cells and high-density lipoproteins. Accordingly, hepatic SR-BI has been shown to play an essential role in the regulation of the reverse cholesterol transport pathway, which promotes the removal and excretion of excess body cholesterol. In the context of atherosclerosis, SR-BI has been implicated in the regulation of intracellular signaling, lipid accumulation, foam cell formation, and cellular apoptosis. Furthermore, since lipid metabolism is a relevant target for cancer treatment, recent studies have focused on examining the role of SR-BI in this pathology. While signaling pathways have initially been explored in non-tumoral cells, studies with cancer cells have now demonstrated SR-BI's function in tumor progression. In this review, we will discuss the role of SR-BI during tumor development and malignant progression. In addition, we will provide insights into the transcriptional and post-transcriptional regulation of the SCARB1 gene. Overall, studying the role of SR-BI in tumor development and progression should allow us to gain useful information for the development of new therapeutic strategies.
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Affiliation(s)
- Jorge L Gutierrez-Pajares
- Université François Rabelais de Tours, Faculté de Médecine-INSERM UMR1069 "Nutrition, Croissance et Cancer" Tours, France
| | - Céline Ben Hassen
- Université François Rabelais de Tours, Faculté de Médecine-INSERM UMR1069 "Nutrition, Croissance et Cancer" Tours, France
| | - Stéphan Chevalier
- Université François Rabelais de Tours, Faculté de Médecine-INSERM UMR1069 "Nutrition, Croissance et Cancer" Tours, France
| | - Philippe G Frank
- Université François Rabelais de Tours, Faculté de Médecine-INSERM UMR1069 "Nutrition, Croissance et Cancer" Tours, France
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Liu C, Guo H, Cheng X, Shao M, Wu C, Wang S, Li H, Wei L, Gao Y, Tan W, Cheng S, Wu T, Yu D, Lin D. Exposure to airborne PM2.5 suppresses microRNA expression and deregulates target oncogenes that cause neoplastic transformation in NIH3T3 cells. Oncotarget 2016; 6:29428-39. [PMID: 26338969 PMCID: PMC4745737 DOI: 10.18632/oncotarget.5005] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2015] [Accepted: 08/11/2015] [Indexed: 12/15/2022] Open
Abstract
Long-term exposure to airborne PM2.5 is associated with increased lung cancer risk but the underlying mechanism remains unclear. We characterized global microRNA and mRNA expression in human bronchial epithelial cells exposed to PM2.5 organic extract and integrally analyzed microRNA-mRNA interactions. Foci formation and xenograft tumorigenesis in mice with NIH3T3 cells expressing genes targeted by microRNAs were performed to explore the oncogenic potential of these genes. We also detected plasma levels of candidate microRNAs in subjects exposed to different levels of air PM2.5 and examined the aberrant expression of genes targeted by these microRNAs in human lung cancer. Under our experimental conditions, treatment of cells with PM2.5 extract resulted in downregulation of 138 microRNAs and aberrant expression of 13 mRNAs (11 upregulation and 2 downregulation). In silico and biochemical analyses suggested SLC30A1, SERPINB2 and AKR1C1, among the upregulated genes, as target for miR-182 and miR-185, respectively. Ectopic expression of each of these genes significantly enhanced foci formation in NIH3T3 cells. Following subcutaneous injection of these cells into nude mice, fibrosarcoma were formed from SLC30A1- or SERPINB2-expressing cells. Reduced plasma levels of miR-182 were detected in subjects exposed to high level of PM2.5 than in those exposed to low level of PM2.5 (P = 0.043). Similar results were seen for miR-185 although the difference was not statistically significant (P = 0.328). Increased expressions of SLC30A1, SERPINB2 and AKR1C1 were detected in human lung cancer. These results suggest that modulation of miR-182 and miR-185 and their target genes may contribute to lung carcinogenesis attributable to PM2.5 exposure.
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Affiliation(s)
- Chunling Liu
- State Key Laboratory of Molecular Oncology and Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Huan Guo
- Department of Occupational and Environmental Health and Ministry of Education Key Lab for Environment and Health, School of Public Health, Huazhong University of Sciences and Technology, Wuhan, China
| | - Xinxin Cheng
- State Key Laboratory of Molecular Oncology and Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Mingming Shao
- State Key Laboratory of Molecular Oncology and Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Chen Wu
- State Key Laboratory of Molecular Oncology and Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Suhan Wang
- Department of Occupational and Environmental Health and Ministry of Education Key Lab for Environment and Health, School of Public Health, Huazhong University of Sciences and Technology, Wuhan, China
| | - Hongmin Li
- State Key Laboratory of Molecular Oncology and Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Lixuan Wei
- State Key Laboratory of Molecular Oncology and Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Yanning Gao
- State Key Laboratory of Molecular Oncology and Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Wen Tan
- State Key Laboratory of Molecular Oncology and Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Shujun Cheng
- State Key Laboratory of Molecular Oncology and Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Tangchun Wu
- Department of Occupational and Environmental Health and Ministry of Education Key Lab for Environment and Health, School of Public Health, Huazhong University of Sciences and Technology, Wuhan, China
| | - Dianke Yu
- State Key Laboratory of Molecular Oncology and Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Dongxin Lin
- State Key Laboratory of Molecular Oncology and Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
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Kojima S, Goto Y, Naya Y. The roles of microRNAs in the progression of castration-resistant prostate cancer. J Hum Genet 2016; 62:25-31. [PMID: 27278789 DOI: 10.1038/jhg.2016.69] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2016] [Revised: 04/28/2016] [Accepted: 05/10/2016] [Indexed: 02/06/2023]
Abstract
Prostate cancer (PCa) is one of the leading causes of cancer-related death in men. PCa is androgen-dependent, and androgen-deprivation therapy is effective for first-line hormonal treatment, but the androgen-independent phenotype of PCa eventually develops, which is difficult to treat and has no effective cure. Recently, microRNAs have been discovered to have important roles in the initiation and progression of PCa, suggesting their use in diagnosis, predicting prognosis and development of treatment for castration-resistant PCa (CRPC). Understanding the networks of microRNAs and their target genes is necessary to ascertain their roles and importance in the development and progression of PCa. This review summarizes the current knowledge about microRNAs regulating PCa progression and elucidates the mechanism of progression to CRPC.
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Affiliation(s)
- Satoko Kojima
- Department of Urology, Teikyo University Chiba Medical Center, Ichihara, Japan
| | - Yusuke Goto
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Yukio Naya
- Department of Urology, Teikyo University Chiba Medical Center, Ichihara, Japan
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Jiang CY, Ruan Y, Wang XH, Zhao W, Jiang Q, Jing YF, Han BM, Xia SJ, Zhao FJ. MiR-185 attenuates androgen receptor function in prostate cancer indirectly by targeting bromodomain containing 8 isoform 2, an androgen receptor co-activator. Mol Cell Endocrinol 2016; 427:13-20. [PMID: 26940039 DOI: 10.1016/j.mce.2016.02.023] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Revised: 02/27/2016] [Accepted: 02/28/2016] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Aberrant androgen receptor (AR) signaling functions are implicated in prostate cancer (PCa) pathogenesis. Here, we studied interactions between miR-185 and the bromodomain containing 8 isoform 2 (BRD8 ISO2) to investigate indirect mechanisms of miR-185 with respect to AR function through BRD8 ISO2 in PCa. METHODS Putative miRNA response element (MRE) of miR-185 in 3'-untranslated region (3'-UTR) of BRD8 ISO2 mRNA was predicted by software and confirmed using dual-luciferase assays and Ago2 immunoprecipitation. BRD8 and AR expression were determined by qRT-PCR and Western blot in PCa cells and tissues. MMTV-Fluc reporter plasmids and dual-luciferase assays were used to evaluate AR activity. RESULTS MRE prediction, dual-luciferase assays and Ago2 immunoprecipitation confirmed that miR-185 is capable of binding the 3'-UTR of BRD8 ISO2 mRNA. QRT-PCR and Western blot indicated that BRD8 ISO2 expression is decreased by miR-185 mimic transfection while increased by miR-185 inhibitor transfection. MMTV-Fluc reporter assays revealed that miR-185 can attenuate AR function by suppressing BRD8 ISO2. Additionally, Pearson's correlation analyses confirmed that BRD8 ISO2 mRNA expression is inversely correlated with miR-185 expression in clinical specimens. CONCLUSION In addition to suppression of AR expression, miR-185 can attenuate AR function indirectly by suppressing BRD8 ISO2. MiR-185 and BRD8 ISO2 may be possible therapeutic targets for PCa treatment.
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Affiliation(s)
- Chen-Yi Jiang
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Yuan Ruan
- Department of Urology, Shanghai General Hospital Affiliated to Nanjing Medical University, Shanghai 200080, China
| | - Xiao-Hai Wang
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Wei Zhao
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Qi Jiang
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Yi-Feng Jing
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Bang-Min Han
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; Institute of Urology, Shanghai Jiao Tong University, Shanghai 200080, China
| | - Shu-Jie Xia
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; Department of Urology, Shanghai General Hospital Affiliated to Nanjing Medical University, Shanghai 200080, China; Institute of Urology, Shanghai Jiao Tong University, Shanghai 200080, China.
| | - Fu-Jun Zhao
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; Institute of Urology, Shanghai Jiao Tong University, Shanghai 200080, China.
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Jurcevic S, Klinga-Levan K, Olsson B, Ejeskär K. Verification of microRNA expression in human endometrial adenocarcinoma. BMC Cancer 2016; 16:261. [PMID: 27039384 PMCID: PMC5477761 DOI: 10.1186/s12885-016-2296-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Accepted: 03/24/2016] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND MicroRNAs are small non-coding RNAs that have been implicated in tumor initiation and progression. In a previous study we identified 138 miRNAs as differentially expressed in endometrial adenocarcinoma compared to normal tissues. One of these miRNAs was miRNA-34a, which regulates several genes involved in the Notch pathway, which is frequently altered in endometrial cancer. The aims of this study were to verify the differential expression of a subset of miRNAs and to scrutinize the regulatory role of mir-34a on the target genes NOTCH1 and DLL1. METHODS Twenty-five miRNAs that were previously identified as differentially expressed were subjected to further analysis using qPCR. To investigate the regulation of NOTCH1 and DLL1 by mir-34a, we designed gain- and loss-of-function experiments in Ishikawa and HEK293 cell lines by transfection with a synthetic mir-34a mimic and a mir-34a inhibitor. RESULTS Of the 25 validated miRNAs, seven were down-regulated and 18 were up-regulated compared to normal endometrium, which was fully consistent with our previous findings. In addition, the up-regulation of mir-34a led to a significant decrease in mRNA levels of NOTCH1 and DLL1, while down-regulation led to a significant increase in mRNA levels of these two genes. CONCLUSIONS We verified both up-regulated and down-regulated miRNAs in the tumor samples, indicating various roles of microRNAs during tumor development. Mir-34a functions as a regulator by decreasing the expression of NOTCH1 and DLL1. Our study is the first to identify a correlation between mir-34a and its target genes NOTCH1 and DLL1 in endometrial adenocarcinoma.
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Affiliation(s)
- Sanja Jurcevic
- Systems Biology Research Centre - Biomedical genetics, School of Bioscience, University of Skövde, Skövde, Sweden
| | - Karin Klinga-Levan
- Systems Biology Research Centre - Biomedical genetics, School of Bioscience, University of Skövde, Skövde, Sweden
| | - Björn Olsson
- Systems Biology Research Centre - Bioinformatics, School of Bioscience, University of Skövde, Skövde, Sweden
| | - Katarina Ejeskär
- Systems Biology Research Centre - Biomedical genetics, School of Bioscience, University of Skövde, Skövde, Sweden.
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Ceder Y. Non-coding RNAs in Prostate Cancer: From Discovery to Clinical Applications. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 886:155-170. [PMID: 26659491 DOI: 10.1007/978-94-017-7417-8_8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Prostate cancer is a heterogeneous disease for which the molecular mechanisms are still not fully elucidated. Prostate cancer research has traditionally focused on genomic and epigenetic alterations affecting the proteome, but over the last decade non-coding RNAs, especially microRNAs, have been recognized to play a key role in prostate cancer progression. A considerable number of individual microRNAs have been found to be deregulated in prostate cancer and their biological significance elucidated in functional studies. This review will delineate the current advances regarding the involvement of microRNAs and their targets in prostate cancer biology as well as their potential usage in the clinical management of the disease. The main focus will be on microRNAs contributing to initiation and progression of prostate cancer, including androgen signalling, cellular plasticity, stem cells biology and metastatic processes. To conclude, implications on potential future microRNA-based therapeutics based on the recent advances regarding the interplay between microRNAs and their targets are discussed.
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Affiliation(s)
- Yvonne Ceder
- Translational Cancer Research, Lund University, Medicon Village, Building 404:A3, 223 81, Lund, Sweden.
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Perner S, Cronauer MV, Schrader AJ, Klocker H, Culig Z, Baniahmad A. Adaptive responses of androgen receptor signaling in castration-resistant prostate cancer. Oncotarget 2015; 6:35542-55. [PMID: 26325261 PMCID: PMC4742123 DOI: 10.18632/oncotarget.4689] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Accepted: 06/04/2015] [Indexed: 12/20/2022] Open
Abstract
Prostate Cancer (PCa) is an important age-related disease being the most common cancer malignancy and the second leading cause of cancer mortality in men in Western countries. Initially, PCa progression is androgen receptor (AR)- and androgen-dependent. Eventually advanced PCa reaches the stage of Castration-Resistant Prostate Cancer (CRPC), but remains dependent on AR, which indicates the importance of AR activity also for CRPC. Here, we discuss various pathways that influence the AR activity in CRPC, which indicates an adaptation of the AR signaling in PCa to overcome the treatment of PCa. The adaptation pathways include interferences of the normal regulation of the AR protein level, the expression of AR variants, the crosstalk of the AR with cytokine tyrosine kinases, the Src-Akt-, the MAPK-signaling pathways and AR corepressors. Furthermore, we summarize the current treatment options with regard to the underlying molecular basis of the common adaptation processes of AR signaling that may arise after the treatment with AR antagonists, androgen deprivation therapy (ADT) as well as for CRPC, and point towards novel therapeutic strategies. The understanding of individualized adaptation processes in PCa will lead to individualized treatment options in the future.
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Affiliation(s)
- Sven Perner
- Section for Prostate Cancer Research, Institute of Pathology, Center for Integrated Oncology Cologne/Bonn, University Hospital of Bonn, Bonn, Germany
| | | | | | - Helmut Klocker
- Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, Austria
| | - Zoran Culig
- Department of Urology, Medical University of Innsbruck, Austria
| | - Aria Baniahmad
- Institute of Human Genetics, Jena University Hospital, Germany
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Wang T, Song W, Chen Y, Chen R, Liu Z, Wu L, Li M, Yang J, Wang L, Liu J, Ye Z, Wang C, Chen K. Flightless I Homolog Represses Prostate Cancer Progression through Targeting Androgen Receptor Signaling. Clin Cancer Res 2015; 22:1531-44. [PMID: 26527749 DOI: 10.1158/1078-0432.ccr-15-1632] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Accepted: 10/25/2015] [Indexed: 11/16/2022]
Abstract
PURPOSE Flightless I (FLII), member of the gelsolin superfamily of actin-remodeling proteins, functions as a transcriptional coregulator. We aim to evaluate a tumor-suppressive function of FLII in regulating androgen receptor (AR) in prostate cancer progression. EXPERIMENTAL DESIGN We examined FLII protein and mRNA expression in clinical prostate cancer specimens by immunohistochemistry. Kaplan-Meier analysis was conducted to evaluate the difference in disease-overall survival associated with the expression levels of FLII and AR. Prostate cancer cells stably expressing FLII or shRNA knockdown were used for functional analyses. Immunoprecipitation, Luciferase reporter, and immunofluorescence staining assays were performed to examine the functional interaction between FLII and AR. RESULTS Our analysis of the expression levels of FLII in a clinical gene expression array dataset showed that the expression of FLII was positively correlated with the overall survival of prostate cancer patients exhibiting high levels of AR expression. Examination of protein and mRNA levels of FLII showed a significant decrease of FLII expression in human prostate cancers. AR and FLII formed a complex in a ligand-dependent manner through the ligand-binding domain (LBD) of AR. Subsequently, we observed a competitive binding to AR between FLII and the ligand. FLII inhibited AR transactivation and decreased AR nuclear localization. Furthermore, FLII contributed to castration-sensitive and castration-resistant prostate cancer cell growth through AR-dependent signaling, and reintroduction of FLII in prostate cancer cells sensitized the cells to bicalutamide and enzalutamide treatment. CONCLUSIONS FLII plays a tumor-suppressive role and serves as a crucial determinant of resistance of prostate cancer to endocrine therapies.
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Affiliation(s)
- Tao Wang
- Department of Urology, Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Wen Song
- Department of Urology, Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yuan Chen
- Department of Urology, Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ruibao Chen
- Department of Urology, Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhuo Liu
- Department of Urology, Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Licheng Wu
- Department of Urology, Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Mingchao Li
- Department of Urology, Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jun Yang
- Department of Urology, Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Liang Wang
- Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jihong Liu
- Department of Urology, Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhangqun Ye
- Department of Urology, Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Chenguang Wang
- Key Laboratory of Tianjin Radiation and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College & Chinese Academy of Medical Sciences, Tianjin, China
| | - Ke Chen
- Department of Urology, Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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Jing R, Chen W, Wang H, Ju S, Cong H, Sun B, Jin Q, Chu S, Xu L, Cui M. Plasma miR-185 is decreased in patients with esophageal squamous cell carcinoma and might suppress tumor migration and invasion by targeting RAGE. Am J Physiol Gastrointest Liver Physiol 2015; 309:G719-29. [PMID: 26316588 DOI: 10.1152/ajpgi.00078.2015] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2015] [Accepted: 08/13/2015] [Indexed: 01/31/2023]
Abstract
The receptor for advanced-glycation end products (RAGE) is upregulated in various cancers and has been associated with tumor progression, but little is known about its expression and regulation by microRNAs (miRNAs) in esophageal squamous cell carcinoma (ESCC). Here, we describe miR-185, which represses RAGE expression, and investigate the biological role of miR-185 in ESCC. In this study, we found that the high level of RAGE expression in 29 pairs of paraffin-embedded ESCC tissues was correlated positively with the depth of invasion by immunohistochemistry, suggesting that RAGE was involved in ESCC. We used bioinformatics searches and luciferase reporter assays to investigate the prediction that RAGE was regulated directly by miR-185. Besides, overexpression of miR-185 in ESCC cells was accompanied by 27% (TE-11) and 49% (Eca-109) reduced RAGE expression. The effect was further confirmed in RAGE protein by immunofluorescence in both cell lines. The effects were reversed following cotransfection with miR-185 and high-level expression of the RAGE vector. Furthermore, the biological role of miR-185 in ESCC cell lines was investigated using assays of cell viability, Ki-67 staining, and cell migration and invasion, as well as in a xenograft model. We found that overexpression of miR-185 inhibited migration and invasion by ESCC cells in vitro and reduced their capacity to develop distal pulmonary metastases in vivo partly through the RAGE/heat shock protein 27 pathway. Interestingly, in clinical specimens, the level of plasma miR-185 expression was decreased significantly (P = 0.002) in patients with ESCC [0.500; 95% confidence interval (CI) 0.248-1.676] compared with healthy controls (2.410; 95% CI 0.612-5.671). The value of the area under the receiver-operating characteristic curve was 0.73 (95% CI 0.604-0.855). In conclusion, our findings shed novel light on the role of miR-185/RAGE in ESCC metastasis, and plasma miR-185 has potential as a novel diagnostic biomarker in ESCC.
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Affiliation(s)
- Rongrong Jing
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Wen Chen
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Huimin Wang
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Shaoqing Ju
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Hui Cong
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Baolan Sun
- Department of Pediatrics, Affiliated Hospital of Nantong University, Nantong, China
| | - Qin Jin
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, China
| | - Shaopeng Chu
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Lili Xu
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Ming Cui
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China;
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