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Qian Y, Liu C, Zeng X, Li LC. RNAa: Mechanisms, therapeutic potential, and clinical progress. MOLECULAR THERAPY. NUCLEIC ACIDS 2025; 36:102494. [PMID: 40125270 PMCID: PMC11930103 DOI: 10.1016/j.omtn.2025.102494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 03/25/2025]
Abstract
RNA activation (RNAa), a gene regulatory mechanism mediated by small activating RNAs (saRNAs) and microRNAs (miRNAs), has significant implications for therapeutic applications. Unlike small interfering RNA (siRNA), which is known for gene silencing in RNA interference (RNAi), synthetic saRNAs can stably upregulate target gene expression at the transcriptional level through the assembly of the RNA-induced transcriptional activation (RITA) complex. Moreover, the dual functionality of endogenous miRNAs in RNAa (hereafter referred to as mi-RNAa) reveals their complex role in cellular processes and disease pathology. Emerging studies suggest saRNAs' potential as a novel therapeutic modality for diseases such as metabolic disorders, hearing loss, tumors, and Alzheimer's. Notably, MTL-CEBPA, the first saRNA drug candidate, shows promise in hepatocellular carcinoma treatment, while RAG-01 is being explored for non-muscle-invasive bladder cancer, highlighting clinical advancements in RNAa. This review synthesizes our current understanding of the mechanisms of RNAa and highlights recent advancements in the study of mi-RNAa and the therapeutic development of saRNAs.
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Affiliation(s)
- Yukang Qian
- Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong, Jiangsu 226019, China
| | - Cody Liu
- Univeristy of California, Davis, Davis, CA 95616, USA
| | - Xuhui Zeng
- Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong, Jiangsu 226019, China
| | - Long-Cheng Li
- Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong, Jiangsu 226019, China
- Ractigen Therapeutics, Nantong, Jiangsu 226400, China
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2
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Sarkar N, Kumar A. Paradigm shift: microRNAs interact with target gene promoters to cause transcriptional gene activation or silencing. Exp Cell Res 2025; 444:114372. [PMID: 39662662 DOI: 10.1016/j.yexcr.2024.114372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Revised: 11/29/2024] [Accepted: 12/08/2024] [Indexed: 12/13/2024]
Abstract
MicroRNAs (miRNAs/miRs) are small (18-25 nucleotides in length), endogenous, non-coding RNAs that typically repress gene expression by interacting with the 3'untranslated regions (3'UTRs) of target mRNAs in the cytoplasm. While most of the scientific community still views miRNAs as repressors of gene expression, this review highlights their non-canonical novel role in the nucleus as activators or silencers of target gene transcription through miRNA-promoter interaction. The mechanistic details of the transcriptional role of miRNAs are yet to be elucidated, however, they can be explained by prospective models. In this review, we aim to discuss the different examples of transcriptional regulation by miRNAs and their possible mechanism of action, thereby offering a comprehensive perspective on the role of miRNAs in gene regulation and their importance in health and diseases.
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Affiliation(s)
- Neelanjana Sarkar
- Department of Developmental Biology and Genetics, Indian Institute of Science, Bangalore, 560012, India.
| | - Arun Kumar
- Department of Developmental Biology and Genetics, Indian Institute of Science, Bangalore, 560012, India.
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3
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Asberger J, Berner K, Bicker A, Metz M, Jäger M, Weiß D, Kreutz C, Juhasz-Böss I, Mayer S, Ge I, Erbes T. In Vitro microRNA Expression Profile Alterations under CDK4/6 Therapy in Breast Cancer. Biomedicines 2023; 11:2705. [PMID: 37893081 PMCID: PMC10604872 DOI: 10.3390/biomedicines11102705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 09/16/2023] [Accepted: 09/27/2023] [Indexed: 10/29/2023] Open
Abstract
BACKGROUND Breast cancer is the most common type of cancer worldwide. Cyclin-dependent kinase inhibition is one of the backbones of metastatic breast cancer therapy. However, there are a significant number of therapy failures. This study evaluates the biomarker potential of microRNAs for the prediction of a therapy response under cyclin-dependent kinase inhibition. METHODS This study comprises the analysis of intracellular and extracellular microRNA-expression-level alterations of 56 microRNAs under palbociclib mono as well as combination therapy with letrozole. Breast cancer cell lines BT-474, MCF-7 and HS-578T were analyzed using qPCR. RESULTS A palbociclib-induced microRNA signature could be detected intracellularly as well as extracellularly. Intracellular miR-10a, miR-15b, miR-21, miR-23a and miR-23c were constantly regulated in all three cell lines, whereas let-7b, let-7d, miR-15a, miR-17, miR-18a, miR-20a, miR-191 and miR301a_3p were regulated only in hormone-receptor-positive cells. Extracellular miR-100, miR-10b and miR-182 were constantly regulated across all cell lines, whereas miR-17 was regulated only in hormone-receptor-positive cells. CONCLUSIONS Because they are secreted and significantly upregulated in the microenvironment of tumor cells, miRs-100, -10b and -182 are promising circulating biomarkers that can be used to predict or detect therapy responses under CDK inhibition. MiR-10a, miR-15b, miR-21, miR-23a and miR-23c are potential tissue-based biomarkers.
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Affiliation(s)
- Jasmin Asberger
- Department of Obstetrics and Gynecology, Medical Center—University Hospital Freiburg, 79106 Freiburg, Germany
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Kai Berner
- Department of Obstetrics and Gynecology, Medical Center—University Hospital Freiburg, 79106 Freiburg, Germany
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Anna Bicker
- Department of Obstetrics and Gynecology, Medical Center—University Hospital Freiburg, 79106 Freiburg, Germany
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Department of Obstetrics and Gynecology, St. Josefs-Hospital Wiesbaden, 65189 Wiesbaden, Germany
| | - Marius Metz
- Department of Obstetrics and Gynecology, Medical Center—University Hospital Freiburg, 79106 Freiburg, Germany
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Markus Jäger
- Department of Obstetrics and Gynecology, Medical Center—University Hospital Freiburg, 79106 Freiburg, Germany
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Daniela Weiß
- Department of Obstetrics and Gynecology, Medical Center—University Hospital Freiburg, 79106 Freiburg, Germany
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Clemens Kreutz
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Institute of Medical Biometry and Statistics, Medical Center – University of Freiburg, 79104 Freiburg, Germany
| | - Ingolf Juhasz-Böss
- Department of Obstetrics and Gynecology, Medical Center—University Hospital Freiburg, 79106 Freiburg, Germany
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Sebastian Mayer
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Department of Gynaecology and Obstetrics, Hospital Krumbach, 86381 Krumbach, Germany
| | - Isabell Ge
- Department of Obstetrics and Gynecology, Medical Center—University Hospital Freiburg, 79106 Freiburg, Germany
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Department of Obstetrics and Gynaecology, University Hospital of Basel, 4056 Basel, Switzerland
| | - Thalia Erbes
- Department of Obstetrics and Gynecology, Medical Center—University Hospital Freiburg, 79106 Freiburg, Germany
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Department of Gynaecology and Obstetrics, Diako Mannheim, 68135 Mannheim, Germany
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4
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Babaei Z, Keyvanloo Shahrestanaki M, Aghaei M. MiR-1236: Key controller of tumor development and progression: Focus on the biological functions and molecular mechanisms. Pathol Res Pract 2023; 248:154671. [PMID: 37418995 DOI: 10.1016/j.prp.2023.154671] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 07/02/2023] [Indexed: 07/09/2023]
Abstract
Combating with the cancer, as one of the leading causes of morbidity and mortality worldwide, scientific community extensively evidenced microRNA 1236 (miR-1236) roles in the pathogenesis of malignant tumors. It has been mentioned that miR-1236 target genes and signal pathways that are key controller of tumor development and progression. Consistently, increasing evidence reports that miR-1236 participates in cancer cell growth, migration, invasion, apoptosis, and drug resistance, as well as tumor diagnosis, and prognosis. MiR-1236 is also implicated in epithelial-mesenchymal transition (EMT), which is a significant indicator of the metastatic process. Moreover, miR-1236 itself is regulated by several newly discovered long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs). Current review aimed to summarize and discuss different dimensions of miR-1236 involvement in the fundamental cellular and molecular mechanisms of tumor progressions. We believe that miR-1236 may serve as a non-invasive diagnostic marker and potential therapeutic target for cancer.
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Affiliation(s)
- Zeinab Babaei
- Department of Clinical Biochemistry and Biophysics, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | | | - Mahmoud Aghaei
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
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Babaei Z, Panjehpour M, Ghorbanhosseini SS, Parsian H, Khademi M, Aghaei M. VEGFR3 suppression through miR-1236 inhibits proliferation and induces apoptosis in ovarian cancer via ERK1/2 and AKT signaling pathways. J Cell Biochem 2023; 124:674-686. [PMID: 36922713 DOI: 10.1002/jcb.30395] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Revised: 12/24/2022] [Accepted: 02/24/2023] [Indexed: 03/17/2023]
Abstract
Vascular endothelial growth factor receptor 3 (VEGFR3) is expressed in cancer cell lines and exerts a critical role in cancer progression. However, the signaling pathways of VEGFR3 in ovarian cancer cell proliferation remain unclear. This study aimed to demonstrate the signaling pathways of VEGFR3 through the upregulated expression of miR-1236 in ovarian cancer cells. We found that the messenger RNA and protein of VEGFR3 were expressed in the ovarian cancer cell lines, but downregulated after microRNA-1236 (miR-1236) transfection. The inhibition of VEGFR3, using miR-1236, significantly reduced cell proliferation, clonogenic survival, migration, and invasion ability in SKOV3 and OVCAR3 cells (p < 0.01). The flow cytometry results indicated that the rate of apoptotic cells in SKOV3 (38.65%) and OVCAR3 (41.95%) cells increased following VEGFR3 inhibition. Moreover, VEGFR3 stimulation (using a specific ligand, VEGF-CS) significantly increased extracellular signal-regulated kinase 1/2 (ERK1/2) and protein kinase B (AKT) phosphorylation (p < 0.01), whereas VEGFR3 suppression reduced p-ERK1/2 (67.94% in SKOV3 and 93.52% in OVCAR3) and p-AKT (59.56% in SKOV3 and 78.73% in OVCAR3) compared to the VEGF-CS treated group. This finding demonstrated that miR-1236 may act as an endogenous regulator of ERK1/2 and AKT signaling by blocking the upstream regulator of VEGFR3. Overall, we demonstrated the important role of the miR-1236/VEGFR3 axis in ovarian cancer cell proliferation by regulating the ERK1/2 and AKT signaling that might be an effective strategy against ovarian cancer.
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Affiliation(s)
- Zeinab Babaei
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mojtaba Panjehpour
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Seyedeh Sara Ghorbanhosseini
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Hadi Parsian
- Department of Biochemistry, Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Mahsa Khademi
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mahmoud Aghaei
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
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6
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Khademi M, Babaei Z, Ghorbanhosseini SS, Emami Razavi A, Aghaei M. Molecular mechanisms of miR-1236 in the assessment of tumor lymphangiogenesis in human ovarian cancer patients. J Gene Med 2023; 25:e3480. [PMID: 36750632 DOI: 10.1002/jgm.3480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 01/03/2023] [Accepted: 02/04/2023] [Indexed: 02/09/2023] Open
Abstract
BACKGROUND Tumor lymphangiogenesis is a critical component in the progression of cancers and specific microRNAs have been reported to be implicated in this process. Recent studies revealed the involvement of miR-1236 in lymphangiogenic signaling by targeting vascular endothelial growth factor receptor 3 (VEGFR3). However, the prognostic importance of miR-1236 and its clinical relevance for lymphangiogenesis in ovarian cancer (OC) remains unclear. METHODS The study included 52 ovarian tumors and 28 normal ovarian tissues. Quantitative real-time PCR was utilized to analyze the VEGFR3, VEGF-C, LYVE-1 and PROX1 mRNA expression as well as miR-1236. VEGFR3 protein expression was measured by immunohistochemistry staining. Immunohistochemistry for the podoplanin marker (D2-40) was performed to measure lymphatic vessel density (LVD). In addition, diagnostic evaluation based on the receiver-operating characteristic (ROC) curve was performed. The influence of miR-1236 on overall survival was evaluated by Kaplan-Meier method. RESULTS Here, we show that miR-1236 expression was significantly decreased in ovarian tumors compared with control tissues (p < 0.001) and correlated with advanced clinical stage, lymph node metastasis, distant metastasis and patient survival (All P < 0.05). Moreover, in ovarian tumors, LVD as well as the gene expression of VEGFR3, VEGF-C and LYVE-1, but not PROX1, were found to be remarkably higher compared with control tissues. We also detected a more robust positive staining for VEGFR3 in OC tissues than in control tissues. Furthermore, our results demonstrated an inverse association of miR-1236 expression with LVD, VEGFR3, LYVE-1 and PROX1 expression in OC tissues. The ROC curve analysis indicated that miR-1236 expression has the potential to be used as a diagnostic and prognostic biomarker in OC. Survival analysis further verified a lowered overall survival rate in patients with low miR-1236 expression than in those with high expression. CONCLUSIONS Our results provide evidence for the translational involvement of miR-1236 in the lymphangiogenesis of OC by regulating lymphangiogenesis-related factors and support the clinical importance of miR-1236 as a new diagnostic and prognostic biomarker for OC.
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Affiliation(s)
- Mahsa Khademi
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Zeinab Babaei
- Department of Clinical Biochemistry and Biophysics, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Seyedeh Sara Ghorbanhosseini
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Amirnader Emami Razavi
- Iran National Tumor Bank, Cancer Biology Research Center, Cancer Institute of Iran. Tehran University of Medical Sciences, Tehran, Iran
| | - Mahmoud Aghaei
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
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Zhao J, Lin Z, Ying P, Zhao Z, Yang H, Qian J, Gong Y, Zhou Y, Dai Y, Jiao Y, Zhu W, Wang H, Tang L. circSMAD4 promotes experimental colitis and impairs intestinal barrier functions by targeting JAK2 through sponging miR-135a-5p. J Crohns Colitis 2022; 17:593-613. [PMID: 36239525 DOI: 10.1093/ecco-jcc/jjac154] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND Numerous studies have explored the association between circular RNAs (circRNAs) and Crohn's disease (CD). However, the pathological role, biological functions, and molecular mechanisms of circRNAs in CD have not been fully elucidated. METHODS The circRNA microarray analysis was performed to identify deregulated circRNAs in colon tissues. The identified circRNA were verified through quantitative real time-polymerase chain reaction (qRT-PCR). In vivo and in vitro functional studies were performed to verify the role of circSMAD4 in CD and investigate the mechanisms involved. RESULTS We found that circSMAD4 was the most significantly upregulated circRNA. The expression level of circSMAD4 was positively correlated with levels of inflammatory factors. Overexpression of circSMAD4 impaired tight junction (TJ) proteins and enhanced apoptosis of epithelial cells. These effects were reversed by treatment with miR-135a-5p mimic. Mechanistic studies showed that circSMAD4 exerts its effects on CD by "sponging" miR-135a-5p to regulate Janus kinase 2 (JAK2). Si-circSMAD4 delivery through microspheres ameliorated experimental colitis and protected the intestinal barrier function in IL-10 knock-out mice. CONCLUSION This study shows that circSMAD4 regulates the progression of experimental colitis via the miR-135a-5p/JAK2 signaling axis and it may be a potential therapeutic target.
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Affiliation(s)
- Jie Zhao
- Department of Gastrointestinal Surgery and and Central Laboratory, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University
| | - Zhiliang Lin
- Department of Colorectal Disease, Intestinal Microenvironment Treatment Center, Shanghai Tenth People's Hospital, Tenth People's Hospital of Tongji University
| | - Pu Ying
- Department of Orthopedics, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine
| | - Zhibin Zhao
- Department of Gastroenterology, Taizhou People's Hospital Affiliated to Nanjing Medical University
| | - Haojun Yang
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University
| | - Jun Qian
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University
| | - Yu Gong
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University
| | - Yan Zhou
- Department of Gastrointestinal Surgery and and Central Laboratory, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University
| | - Yi Dai
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University
| | - Yuwen Jiao
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University
| | - Weiming Zhu
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University
| | - Honggang Wang
- Department of General Surgery, Taizhou People's Hospital Affiliated to Nanjing Medical University
| | - Liming Tang
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University
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Zhao J, Sun Y, Yang H, Qian J, Zhou Y, Gong Y, Dai Y, Jiao Y, Zhu W, Wang H, Lin Z, Tang L. PLGA-microspheres-carried circGMCL1 protects against Crohn's colitis through alleviating NLRP3 inflammasome-induced pyroptosis by promoting autophagy. Cell Death Dis 2022; 13:782. [PMID: 36088391 PMCID: PMC9464224 DOI: 10.1038/s41419-022-05226-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 08/25/2022] [Accepted: 08/31/2022] [Indexed: 01/21/2023]
Abstract
This study aimed to at explore exploring the biological functions of dysregulated circRNA in Crohn's disease (CD) pathogenesis, with the overarching goal of and providing potential novel therapeutic targets. CircRNA microarray and quantitative real time-polymerase chain reaction (qRT-PCR) analyses were performed to investigate and verify the candidate dysregulated circRNA. The Next, clinical, in vivo, and in vitro studies were performed to investigate explore the biological function and mechanisms of the candidate circRNA in CD. The therapeutic effect of poly (lactic-co-glycolic acid)-microspheres (PLGA MSs)-carried oe-circGMCL1 in experimental colitis models of IL-10 knock-out mice was assessed. CircGMCL1 was identified as the candidate circRNA by microarray and qRT-PCR analyses. Results showed that circGMCL1 expression was negatively correlated with CD-associated inflammatory indices, suggesting that it is a CD-associated circRNA. Microarray and bioinformatics analyses identified miR-124-3p and Annexin 7 (ANXA7) as its downstream mechanisms. The in vitro studies revealed that circGMCL1 mediates its effects on autophagy and NLRP3 inflammasome-mediated pyroptosis in epithelial cells through the ceRNA network. Moreover, the in vivo studies identified the therapeutic effect of PLGA MSs-carried oe-circGMCL1 in experimental colitis models. This study suggests that circGMCL1 protects intestinal barrier function against Crohn's colitis through alleviating NLRP3 inflammasome-mediated epithelial pyroptosis by promoting autophagy through regulating ANXA7 via sponging miR-124-3p. Therefore, circGMCL1 can serve as a potential biological therapeutic target for Crohn's colitis.
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Affiliation(s)
- Jie Zhao
- grid.89957.3a0000 0000 9255 8984Department of Gastrointestinal Surgery and Central Laboratory, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, China
| | - Ye Sun
- grid.412676.00000 0004 1799 0784Department of Orthopaedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Haojun Yang
- grid.89957.3a0000 0000 9255 8984Department of Gastrointestinal Surgery, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, China
| | - Jun Qian
- grid.89957.3a0000 0000 9255 8984Department of Gastrointestinal Surgery, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, China
| | - Yan Zhou
- grid.89957.3a0000 0000 9255 8984Department of Gastrointestinal Surgery and Central Laboratory, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, China
| | - Yu Gong
- grid.89957.3a0000 0000 9255 8984Department of Gastrointestinal Surgery, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, China
| | - Yi Dai
- grid.89957.3a0000 0000 9255 8984Department of Gastrointestinal Surgery, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, China
| | - Yuwen Jiao
- grid.89957.3a0000 0000 9255 8984Department of Gastrointestinal Surgery, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, China
| | - Weiming Zhu
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Honggang Wang
- grid.89957.3a0000 0000 9255 8984Department of General Surgery, Taizhou People’s Hospital, Taizhou Clinical Medical School of Nanjing Medical University, Nanjing, China
| | - Zhiliang Lin
- grid.412538.90000 0004 0527 0050Department of Colorectal Disease, Intestinal Microenvironment Treatment Center, Shanghai Tenth People’s Hospital, Tenth People’s Hospital of Tongji University, Shanghai, China
| | - Liming Tang
- grid.89957.3a0000 0000 9255 8984Department of Gastrointestinal Surgery, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, China
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Splice and Dice: Intronic microRNAs, Splicing and Cancer. Biomedicines 2021; 9:biomedicines9091268. [PMID: 34572454 PMCID: PMC8465124 DOI: 10.3390/biomedicines9091268] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 09/13/2021] [Accepted: 09/16/2021] [Indexed: 12/17/2022] Open
Abstract
Introns span only a quarter of the human genome, yet they host around 60% of all known microRNAs. Emerging evidence indicates the adaptive advantage of microRNAs residing within introns is attributed to their complex co-regulation with transcription and alternative splicing of their host genes. Intronic microRNAs are often co-expressed with their host genes, thereby providing functional synergism or antagonism that is exploited or decoupled in cancer. Additionally, intronic microRNA biogenesis and the alternative splicing of host transcript are co-regulated and intertwined. The importance of intronic microRNAs is under-recognized in relation to the pathogenesis of cancer.
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10
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Zhao Y, Zhou H, Shen J, Yang S, Deng K, Li Q, Cui W. MiR-1236-3p Inhibits the Proliferation, Invasion, and Migration of Colon Cancer Cells and Hinders Epithelial-Mesenchymal Transition by Targeting DCLK3. Front Oncol 2021; 11:688882. [PMID: 34540665 PMCID: PMC8446622 DOI: 10.3389/fonc.2021.688882] [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: 04/06/2021] [Accepted: 08/09/2021] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Dysregulated microRNAs (miRNAs) are common in human cancer and are involved in the proliferation, promotion, and metastasis of tumor cells. Therefore, this study aimed to evaluate the expression and biological function of miR-1236-3p in colon cancer. METHODS This study screened the miRNA in normal and colon cancer tissues through array analysis. In addition, quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) analysis was performed to validate the expression of miR-1236-3p in normal and tumor tissues from colon cancer patients and cancer cell lines. Online predicting algorithms and luciferase reporter assays were also employed to confirm Doublecortin Like Kinase 3 (DCLK3) was the target for miR-1236-3p. Moreover, the impact of miR-1236-3p on the progression of colon cancer was evaluated in vitro and in vivo. Western blotting and qRT-PCR were also performed to investigate the interactions between miR-1236-3p and DCLK3. RESULTS MiR-1236-3p was significantly downregulated in colon cancer tissues and its expression was associated with the TNM stage and metastasis of colon. In addition, the in vitro and in vivo experiments showed that miR-1236-3p significantly promoted cancer cell apoptosis and inhibited the proliferation, invasion, and migration of cancer cells. The results also showed that miR-1236-3p hindered Epithelial-mesenchymal Transition (EMT) by targeting DCLK3. Moreover, the expression of DCLK3 mediated the effects of miR-1236-3p on the progression of cancer. CONCLUSIONS MiR-1236-3p functions as a tumor suppressor in colon cancer by targeting DCLK3 and is therefore a promising therapeutic target for colon cancer.
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Affiliation(s)
| | | | | | | | | | | | - Wei Cui
- Department of Colorectal Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo City, China
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11
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Petitprez F, Ayadi M, de Reyniès A, Fridman WH, Sautès-Fridman C, Job S. Review of Prognostic Expression Markers for Clear Cell Renal Cell Carcinoma. Front Oncol 2021; 11:643065. [PMID: 33996558 PMCID: PMC8113694 DOI: 10.3389/fonc.2021.643065] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 02/17/2021] [Indexed: 12/12/2022] Open
Abstract
Context: The number of prognostic markers for clear cell renal cell carcinoma (ccRCC) has been increasing regularly over the last 15 years, without being integrated and compared. Objective: Our goal was to perform a review of prognostic markers for ccRCC to lay the ground for their use in the clinics. Evidence Acquisition: PubMed database was searched to identify RNA and protein markers whose expression level was reported as associated with survival of ccRCC patients. Relevant studies were selected through cross-reading by two readers. Evidence Synthesis: We selected 249 studies reporting an association with prognostic of either single markers or multiple-marker models. Altogether, these studies were based on a total of 341 distinct markers and 13 multiple-marker models. Twenty percent of these markers were involved in four biological pathways altered in ccRCC: cell cycle, angiogenesis, hypoxia, and immune response. The main genes (VHL, PBRM1, BAP1, and SETD2) involved in ccRCC carcinogenesis are not the most relevant for assessing survival. Conclusion: Among single markers, the most validated markers were KI67, BIRC5, TP53, CXCR4, and CA9. Of the multiple-marker models, the most famous model, ClearCode34, has been highly validated on several independent datasets, but its clinical utility has not yet been investigated. Patient Summary: Over the years, the prognosis studies have evolved from single markers to multiple-marker models. Our review highlights the highly validated prognostic markers and multiple-marker models and discusses their clinical utility for better therapeutic care.
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Affiliation(s)
- Florent Petitprez
- Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre le Cancer, Paris, France
| | - Mira Ayadi
- Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre le Cancer, Paris, France
| | - Aurélien de Reyniès
- Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre le Cancer, Paris, France
| | - Wolf H. Fridman
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Equipe Inflammation, Complément et Cancer, Paris, France
| | - Catherine Sautès-Fridman
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Equipe Inflammation, Complément et Cancer, Paris, France
| | - Sylvie Job
- Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre le Cancer, Paris, France
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12
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Shin E, Jin H, Suh D, Luo Y, Ha H, Kim TH, Hahn Y, Hyun S, Lee K, Bae J. An alternative miRISC targets a cancer-associated coding sequence mutation in FOXL2. EMBO J 2020; 39:e104719. [PMID: 33215742 PMCID: PMC7737606 DOI: 10.15252/embj.2020104719] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Revised: 08/28/2020] [Accepted: 09/06/2020] [Indexed: 12/16/2022] Open
Abstract
Recent evidence suggests that animal microRNAs (miRNAs) can target coding sequences (CDSs); however, the pathophysiological importance of such targeting remains unknown. Here, we show that a somatic heterozygous missense mutation (c.402C>G; p.C134W) in FOXL2, a feature shared by virtually all adult-type granulosa cell tumors (AGCTs), introduces a target site for miR-1236, which causes haploinsufficiency of the tumor-suppressor FOXL2. This miR-1236-mediated selective degradation of the variant FOXL2 mRNA is preferentially conducted by a distinct miRNA-loaded RNA-induced silencing complex (miRISC) directed by the Argonaute3 (AGO3) and DHX9 proteins. In both patients and a mouse model of AGCT, abundance of the inversely regulated variant FOXL2 with miR-1236 levels is highly correlated with malignant features of AGCT. Our study provides a molecular basis for understanding the conserved FOXL2 CDS mutation-mediated etiology of AGCT, revealing the existence of a previously unidentified mechanism of miRNA-targeting disease-associated mutations in the CDS by forming a non-canonical miRISC.
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Affiliation(s)
| | - Hanyong Jin
- Department of Life ScienceChung‐Ang UniversitySeoulKorea
| | - Dae‐Shik Suh
- Department of Obstetrics and GynecologyAsan Medical CenterUniversity of Ulsan College of MedicineSeoulKorea
| | - Yongyang Luo
- School of PharmacyChung‐Ang UniversitySeoulKorea
| | - Hye‐Jeong Ha
- School of PharmacyChung‐Ang UniversitySeoulKorea
| | - Tae Heon Kim
- Department of PathologyBundang CHA HospitalCHA UniversitySeongnamKorea
| | - Yoonsoo Hahn
- Department of Life ScienceChung‐Ang UniversitySeoulKorea
| | - Seogang Hyun
- Department of Life ScienceChung‐Ang UniversitySeoulKorea
| | - Kangseok Lee
- Department of Life ScienceChung‐Ang UniversitySeoulKorea
| | - Jeehyeon Bae
- School of PharmacyChung‐Ang UniversitySeoulKorea
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13
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Li J, Chen J, Hu Z, Xu W. MicroRNA-1236-3p inhibits human osteosarcoma growth. Oncol Lett 2020; 20:367. [PMID: 33133267 PMCID: PMC7590435 DOI: 10.3892/ol.2020.12229] [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] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Accepted: 09/18/2020] [Indexed: 12/16/2022] Open
Abstract
Osteosarcoma (OS) is a common bone tumor with high mortality worldwide. The long-term survival rate of patients with metastatic or recurrent disease is <20%. The present study explored the biological role of microRNA (miRNA/miR)-1236-3p in OS. miRNA and mRNA expression levels were measured via reverse transcription-quantitative PCR. Fluorescence in situ hybridization was performed to determine miR-1236-3p expression levels in clinical specimens. Protein expression was measured via western blotting. Immunohistochemical analysis was used to detect Wnt target gene expression in tumor tissues. The interaction between the Wnt3a 3′untranslated region and miR-1236-3p was assessed via dual-luciferase reporter assays. Cell cycle, Transwell, Cell Counting Kit-8 and wound healing assays were conducted to evaluate the function of the miR-1236-3p/Wnt3a axis. Human OS (HOS) cells stably transfected with vector or miR-1236-3p sponge were injected subcutaneously into nude mice to assess the role of miR-1236-3p in vivo. miR-1236-3p expression was downregulated in OS tissues compared with chondroma tissues, and miR-1236-3p overexpression inhibited OS cell migration and proliferation compared with the negative control group. Furthermore, in vivo xenograft assays displayed enhanced tumour growth rates in the miR-1236-3p sponge group compared with the vector control group. In the present study, the results indicated that miR-1236-3p inhibited OS progression and Wnt3a was identified as a target of miR-1236-3p.
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Affiliation(s)
- Jiarui Li
- Department of Urology Surgery, The First Affiliated Hospital of Nanchang University, Medical College of Nanchang University, Nanchang, Jiangxi 330000, P.R. China
| | - Junxin Chen
- Department of Orthopedic Surgery, Sir Run Run Shaw Hospital, Medical College of Zhejiang University & Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, Zhejiang 310016, P.R. China
| | - Zhijun Hu
- Department of Orthopedic Surgery, Sir Run Run Shaw Hospital, Medical College of Zhejiang University & Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, Zhejiang 310016, P.R. China
| | - Wenbin Xu
- Department of Orthopedic Surgery, Sir Run Run Shaw Hospital, Medical College of Zhejiang University & Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, Zhejiang 310016, P.R. China
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14
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microRNA-93-5p promotes hepatocellular carcinoma progression via a microRNA-93-5p/MAP3K2/c-Jun positive feedback circuit. Oncogene 2020; 39:5768-5781. [PMID: 32719439 DOI: 10.1038/s41388-020-01401-0] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 07/03/2020] [Accepted: 07/20/2020] [Indexed: 12/19/2022]
Abstract
Cumulative evidence suggests that microRNAs (miRNAs) promote gene expression in cancers. However, the pathophysiologic relevance of miRNA-mediated RNA activation in hepatocellular carcinoma (HCC) remains to be established. Our previous miRNA expression profiling in seven-paired HCC specimens revealed miR-93-5p as an HCC-related miRNA. In this study, miR-93-5p expression was assessed in HCC tissues and cell lines by quantitative real-time PCR and fluorescence in situ hybridization. The correlation of miR-93-5p expression with survival and clinicopathological features of HCC was determined by statistical analysis. The function and potential mechanism of miR-93-5p in HCC were further investigated by a series of gain- or loss-of-function experiments in vitro and in vivo. We identified that miR-93-5p, overexpressed in HCC specimens and cell lines, leads to poor outcomes in HCC cases and promotes proliferation, migration, and invasion in HCC cell lines. Mechanistically, rather than decreasing target mRNA levels as expected, miR-93-5p binds to the 3'-untranslated region (UTR) of mitogen-activated protein kinase kinase kinase 2 (MAP3K2) to directly upregulate its expression and downstream p38 and c-Jun N-terminal kinase (JNK) pathway, thereby leading to cell cycle progression in HCC. Notably, we also demonstrated that c-Jun, a downstream effector of the JNK pathway, enhances miR-93-5p transcription by targeting its promoter region. Besides, downregulation of miR-93-5p significantly retarded tumor growth, while overexpression of miR-93-5p accelerated tumor growth in the HCC xenograft mouse model. Altogether, we revealed a miR-93-5p/MAP3K2/c-Jun positive feedback loop to promote HCC progression in vivo and in vitro, representing an RNA-activating role of miR-93-5p in HCC development.
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15
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Xiao BD, Zhao YJ, Jia XY, Wu J, Wang YG, Huang F. Multifaceted p21 in carcinogenesis, stemness of tumor and tumor therapy. World J Stem Cells 2020; 12:481-487. [PMID: 32742565 PMCID: PMC7360995 DOI: 10.4252/wjsc.v12.i6.481] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 04/17/2020] [Accepted: 05/05/2020] [Indexed: 02/06/2023] Open
Abstract
Cancer cells possess metabolic properties that are different from those of benign cells. p21, encoded by CDKN1A gene, also named p21Cip1/WAF1, was first identified as a cyclin-dependent kinase regulator that suppresses cell cycle G1/S phase and retinoblastoma protein phosphorylation. CDKN1A (p21) acts as the downstream target gene of TP53 (p53), and its expression is induced by wild-type p53 and it is not associated with mutant p53. p21 has been characterized as a vital regulator that involves multiple cell functions, including G1/S cell cycle progression, cell growth, DNA damage, and cell stemness. In 1994, p21 was found as a tumor suppressor in brain, lung and colon cancer by targeting p53 and was associated with tumorigenesis and metastasis. Notably, p21 plays a significant role in tumor development through p53-dependent and p53-independent pathways. In addition, expression of p21 is closely related to the resting state or terminal differentiation of cells. p21 is also associated with cancer stem cells and acts as a biomarker for such cells. In cancer therapy, given the importance of p21 in regulating the G1/S and G2 check points, it is not surprising that p21 is implicated in response to many cancer treatments and p21 promotes the effect of oncolytic virotherapy.
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Affiliation(s)
- Bo-Duan Xiao
- Department of Pathology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
- Xinyuan Institute of Medicine and Biotechnology, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang Province, China
| | - Yu-Jia Zhao
- Xinyuan Institute of Medicine and Biotechnology, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang Province, China
| | - Xiao-Yuan Jia
- Xinyuan Institute of Medicine and Biotechnology, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang Province, China
| | - Jiong Wu
- Xinyuan Institute of Medicine and Biotechnology, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang Province, China
| | - Yi-Gang Wang
- Xinyuan Institute of Medicine and Biotechnology, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang Province, China
| | - Fang Huang
- Department of Pathology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
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16
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Li J, Jiang D, Zhang Q, Peng S, Liao G, Yang X, Tang J, Xiong H, Pang J. MiR-301a Promotes Cell Proliferation by Repressing PTEN in Renal Cell Carcinoma. Cancer Manag Res 2020; 12:4309-4320. [PMID: 32606927 PMCID: PMC7294045 DOI: 10.2147/cmar.s253533] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 05/30/2020] [Indexed: 12/15/2022] Open
Abstract
Objective Renal cell carcinoma (RCC) displays an increasing incidence and mortality rate worldwide in recent years. More and more evidence demonstrated microRNAs function as positive or negative regulatory factors in many cancers, while the role of miR-301a in RCC is still unclear. Material and Methods The expression and clinical significance of miR-301a were assessed via bioinformatic software on open microarray datasets of the Cancer Genome Atlas (TCGA) and then confirmed by quantitative real-time PCR (qRT-PCR) in RCC cell lines. Loss of function assays were performed in RCC cell lines both in vitro and in vivo. Cell Counting Kit-8 (CCK-8), flow cytometry, luciferase reporter assays, Western blotting, and immunohistochemistry were employed to explore the mechanisms of the effect of miR-301a on RCC. Results By analyzing RCC clinical specimens and cell lines, we found a uniform increased miR-301a in expression in comparison with normal renal tissue or normal human proximal tubule epithelial cell line (HK-2). In addition, miR-301a upregulation correlated advanced stage and poor prognosis of clear cell RCC (ccRCC). Anti-miR-301a could inhibit growth and cell cycle G1/S transition in RCC cell lines. Moreover, we found that PTEN was identified as a direct target of miR-301a that might partially interrupt miR-301a-induced G1/S transition. Importantly, nude-mouse models revealed that knockdown of miR-301a delayed tumor growth. Conclusion These results indicate that miR-301a functions as a tumor-promoting miRNA through regulating PTEN expression, representing a novel therapeutic target for RCC.
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Affiliation(s)
- Jun Li
- Department of Urology, Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, People's Republic of China
| | - Donggen Jiang
- Department of Urology, Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, People's Republic of China
| | - Qian Zhang
- Department of Rehabilitation Medicine, Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, People's Republic of China
| | - Shubin Peng
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China
| | - Guolong Liao
- Department of Urology, Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, People's Republic of China
| | - Xiangwei Yang
- Department of Urology, Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, People's Republic of China
| | - Jiani Tang
- Department of Urology, Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, People's Republic of China
| | - Haiyun Xiong
- Department of Urology, Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, People's Republic of China
| | - Jun Pang
- Department of Urology, Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, People's Republic of China
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An JX, Ma ZS, Ma MH, Shao S, Cao FL, Dai DQ. MiR-1236-3p serves as a new diagnostic and prognostic biomarker for gastric cancer. Cancer Biomark 2019; 25:127-132. [PMID: 31045511 DOI: 10.3233/cbm-171026] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND The microRNA plays an important role in tumor progression. MiR-1236-3p acts as a tumor suppressor in various malignancies. OBJECTIVE The aim of present study was to explore the expression of miR-1236-3p in gastric cancer (GC) and its correlation with clinicopathological features, and evaluate the feasibility of using it as a prognostic biomarker in GC. METHODS Seventy-six pairs of tissue specimens were collected from GC patients. MiR-1236-3p expression level was detected by using qRT-PCR. The diagnostic value of miR-1236-3p was evaluated by receiver operating characteristic curve, and Kaplan-Meier method was used to analyze the overall survival. Prognosis analysis was performed using multivariate cox proportional hazards regression analysis. RESULTS The expression of miR-1236-3p was significantly reduced in tumor tissues (P< 0.001). In addition, miR-1236-3p expression was correlated with TNM stage (P= 0.001), lymph node metastasis (P= 0.005) and differentiated degree (P= 0.001). The area under the curve was 0.7016, and its specificity and sensitivity were 60.53% and 73.68%. Kaplan-Meier survival curves showed that patients with high miR-1236-3p expression had better overall survival than those with low expression (P= 0.0190). Multivariate Cox regression analysis showed that the miR-1236-3p expression (P= 0.033) was an independent prognostic factor for overall survival of GC prognosis. CONCLUSIONS The study showed that miR-1236-3p is downregulated in GC tissues, and low expression of miR-1236-3p is associated with a poor prognosis in GC. It may be a new diagnostic and prognostic biomarker for GC.
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Affiliation(s)
- Jia-Xiang An
- Department of Surgical Oncology, Taizhou Hospital, Wenzhou Medical University, Linhai, Zhejiang, China.,Department of Gastroenterological Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Zhao-Sheng Ma
- Department of Surgical Oncology, Taizhou Hospital, Wenzhou Medical University, Linhai, Zhejiang, China
| | - Ming-Hui Ma
- Department of Gastroenterological Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Shuai Shao
- Department of Gastroenterological Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Fei-Lin Cao
- Department of Surgical Oncology, Taizhou Hospital, Wenzhou Medical University, Linhai, Zhejiang, China
| | - Dong-Qiu Dai
- Department of Gastroenterological Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
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Zhou D, Lai M, Luo A, Yu CY. An RNA Metabolism and Surveillance Quartet in the Major Histocompatibility Complex. Cells 2019; 8:E1008. [PMID: 31480283 PMCID: PMC6769589 DOI: 10.3390/cells8091008] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 08/27/2019] [Accepted: 08/29/2019] [Indexed: 02/07/2023] Open
Abstract
At the central region of the mammalian major histocompatibility complex (MHC) is a complement gene cluster that codes for constituents of complement C3 convertases (C2, factor B and C4). Complement activation drives the humoral effector functions for immune response. Sandwiched between the genes for serine proteinase factor B and anchor protein C4 are four less known but critically important genes coding for essential functions related to metabolism and surveillance of RNA during the transcriptional and translational processes of gene expression. These four genes are NELF-E (RD), SKIV2L (SKI2W), DXO (DOM3Z) and STK19 (RP1 or G11) and dubbed as NSDK. NELF-E is the subunit E of negative elongation factor responsible for promoter proximal pause of transcription. SKIV2L is the RNA helicase for cytoplasmic exosomes responsible for degradation of de-polyadenylated mRNA and viral RNA. DXO is a powerful enzyme with pyro-phosphohydrolase activity towards 5' triphosphorylated RNA, decapping and exoribonuclease activities of faulty nuclear RNA molecules. STK19 is a nuclear kinase that phosphorylates RNA-binding proteins during transcription. STK19 is also involved in DNA repair during active transcription and in nuclear signal transduction. The genetic, biochemical and functional properties for NSDK in the MHC largely stay as a secret for many immunologists. Here we briefly review the roles of (a) NELF-E on transcriptional pausing; (b) SKIV2L on turnover of deadenylated or expired RNA 3'→5' through the Ski-exosome complex, and modulation of inflammatory response initiated by retinoic acid-inducible gene 1-like receptor (RLR) sensing of viral infections; (c) DXO on quality control of RNA integrity through recognition of 5' caps and destruction of faulty adducts in 5'→3' fashion; and (d) STK19 on nuclear protein phosphorylations. There is compelling evidence that a dysregulation or a deficiency of a NSDK gene would cause a malignant, immunologic or digestive disease.
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Affiliation(s)
- Danlei Zhou
- The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
- School of Life Science, Beijing Institute of Technology, Beijing 100081, China.
- Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA.
| | - Michalea Lai
- The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA
- Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA
| | - Aiqin Luo
- School of Life Science, Beijing Institute of Technology, Beijing 100081, China.
| | - Chack-Yung Yu
- The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
- Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA.
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Abstract
The phenomenon of RNA activation (RNAa) was initially discovered by Li and colleagues about a decade ago. Subsequently, gene activation by exogenously expressed small activating RNA has been demonstrated in different cellular contexts by a number of laboratories. Conceivably, endogenously expressed microRNAs may also utilize RNA activation as a cellular mechanism for gene regulation, which may be dysregulated in disease states such as cancer. RNA activation can be applied to gain-of-function studies and holds great promise for disease intervention. This chapter will discuss examples of promoter-targeting microRNAs discovered in recent years and their pathophysiological relevance. I will also briefly touch upon other novel classes of microRNAs with positive gene regulatory roles, including TATA-box-activating microRNAs and enhancer-associated microRNAs.
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Affiliation(s)
- Vera Huang
- Molecular Stethoscope, Inc., 10835 Road to the Cure, Suite 100, San Diego, CA, 92121, USA.
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20
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Lin C, Li Z, Chen P, Quan J, Pan X, Zhao L, Zhou L, Lai Y, He T, Xu W, Xu J, Guan X, Li H, Yang S, Hu Y, Lai Y. Oncogene miR-154-5p regulates cellular function and acts as a molecular marker with poor prognosis in renal cell carcinoma. Life Sci 2018; 209:481-489. [PMID: 30138594 DOI: 10.1016/j.lfs.2018.08.044] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Revised: 08/11/2018] [Accepted: 08/19/2018] [Indexed: 02/05/2023]
Abstract
AIMS In adult population, the renal cell carcinoma (RCC) is one of the most common urological malignancies. It is meaningful to research for the molecular markers which are involved in the occurrence and development of RCC. Therefore, we concentrate on illuminating the role of microRNA-154-5p in progression of RCC and explore its prognostic values. MAIN METHODS The real-time quantitative polymerase chain reaction (RT-qPCR) was applied to determine expression level of miR-154-5p in tissues. Afterwards, the transfected cell lines ACHN and 786-O were used for the CCK-8 assay, MTT assay, wound healing assay, transwell assay and flow cytometric assay to explore the role of miR-154-5p in regulating cellular function. In addition, formalin-fixed paraffin-embedded (FFPE) renal cancer samples were used for detecting the relationship between expression level of miR-154-5p and clinical information. Furthermore, univariate and multivariate Cox proportional-hazards regression analyses, and the Kaplan-Meier survival curves were performed to evaluate the prognostic value of miR-154-5p in RCC. KEY FINDINGS The RT-qPCR indicated that miR-154-5p is up-regulated in RCC pathologic specimens and cell lines. Results of study also demonstrated that upregulation of miR-154-5p reduced cell apoptosis and promoted cell proliferation, viability, migration as well as invasion in RCC cells. The prognosis analyses indicated that the expression level of miR-154-5p is associated with the prognosis of renal cancer, and the overall survival of patients with low expression is longer. SIGNIFICANCE The present study revealed that the oncogene miR-154-5p regulates cellular function and acts as a molecular marker with poor prognosis in renal cell carcinoma.
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Affiliation(s)
- Canbin Lin
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, PR China; Department of Urology, Shantou University Medical College, Shantou, Guangdong 515041, PR China; Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, Guangdong 518036, P.R. China
| | - Zuwei Li
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, PR China; Department of Urology, Shantou University Medical College, Shantou, Guangdong 515041, PR China; Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, Guangdong 518036, P.R. China
| | - Peijie Chen
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, PR China; Department of Urology, Shantou University Medical College, Shantou, Guangdong 515041, PR China; Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, Guangdong 518036, P.R. China
| | - Jing Quan
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, PR China; Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, Guangdong 518036, P.R. China
| | - Xiang Pan
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, PR China; Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, Guangdong 518036, P.R. China
| | - Liwen Zhao
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, PR China; Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, Guangdong 518036, P.R. China
| | - Liang Zhou
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, PR China; Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, Guangdong 518036, P.R. China
| | - Yulin Lai
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, PR China; Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, Guangdong 518036, P.R. China
| | - Tao He
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, PR China; Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, Guangdong 518036, P.R. China
| | - Weijie Xu
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, PR China
| | - Jinling Xu
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, PR China
| | - Xin Guan
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, PR China
| | - Hang Li
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, PR China
| | - Shangqi Yang
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, PR China
| | - Yimin Hu
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, PR China.
| | - Yongqing Lai
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, PR China; Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, Guangdong 518036, P.R. China.
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Piegols HJ, Takada M, Parys M, Dexheimer T, Yuzbasiyan-Gurkan V. Investigation of novel chemotherapeutics for feline oral squamous cell carcinoma. Oncotarget 2018; 9:33098-33109. [PMID: 30237854 PMCID: PMC6145701 DOI: 10.18632/oncotarget.26006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Accepted: 08/03/2018] [Indexed: 01/03/2023] Open
Abstract
Feline oral squamous cell carcinomas (FOSCC) are highly aggressive neoplasms with short survival times despite multimodal treatment. FOSCC are similar to squamous cell carcinomas of the head and neck (SCCHN) in humans, which also present therapeutic challenges. The current study was undertaken to identify novel chemotherapeutics using FOSCC cell lines. A high throughput drug screen using 1,952 drugs was performed to identify chemotherapeutics for further investigation. Two of the drugs identified in the drug screen, actinomycin D and methotrexate, and two drugs with similar molecular targets to drugs found to be efficacious in the screening, dinaciclib and flavopiridol, were selected for further investigation. Drug inhibition profiles were generated for each drug and cell line using an MTS assay. In addition, the effects of the drugs of interest on cell cycle progression were analyzed via a propidium iodide DNA labeling assay. Changes in caspase-3/7 activity after treatment with each drug were also determined. The findings demonstrated effectiveness of the drugs at nanomolar concentrations with sensitivity varying across cell lines. With all of the drugs except for actinomycin D, evidence for G1 arrest was found. Dinaciclib and flavopiridol were demonstrated to induce apoptosis. The results of the study suggest that the selected drugs are potential candidates for developing novel chemotherapeutic approaches to FOSCC. Through these studies, novel therapeutic strategies for the treatment of FOSCC can be developed to provide better care for affected cats which can also serve as proof of concept studies to inform translational studies in SCCHN in humans.
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Affiliation(s)
- Hunter John Piegols
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA
| | - Marilia Takada
- Comparative Medicine and Integrative Biology Program, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA
| | - Maciej Parys
- Comparative Medicine and Integrative Biology Program, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA
- Current Affiliation: The Royal (Dick) School of Veterinary Studies and the Roslin Institute, Roslin, Midlothian, United Kingdom
| | - Thomas Dexheimer
- Department of Pharmacology and Toxicology, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA
| | - Vilma Yuzbasiyan-Gurkan
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA
- Comparative Medicine and Integrative Biology Program, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA
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Atef A, Bedeer AE, Elmonem GA. Evaluation of P21 and peroxisome proliferator-activated receptor gamma as prognostic markers for renal cell carcinoma. EGYPTIAN JOURNAL OF PATHOLOGY 2018; 38:68-77. [DOI: 10.1097/01.xej.0000542227.68517.54] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
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An JX, Ma MH, Zhang CD, Shao S, Zhou NM, Dai DQ. miR-1236-3p inhibits invasion and metastasis in gastric cancer by targeting MTA2. Cancer Cell Int 2018; 18:66. [PMID: 29743816 PMCID: PMC5930941 DOI: 10.1186/s12935-018-0560-9] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2018] [Accepted: 04/19/2018] [Indexed: 01/06/2023] Open
Abstract
Background MicroRNAs deregulation are common in human tumor progression. miR-1236-3p has been reported to function as tumor suppressor microRNA in various malignancies. The aim of this study was to demonstrate the downregulated expression of miR-1236-3p in gastric cancer (GC) tissues and cell lines, and clarify its biological function in GC. Methods Real-time polymerase chain reaction was used to measure the mRNA level of miR-1236-3p in GC. Dual luciferase assay was used to demonstrate that MTA2 was one of the candidate target genes of miR-1236-3p. Western blots were utilized to detect the protein levels. Cell function assays were also performed to determine the function of miR-1236-3p in GC. Results miR-1236-3p expression, which was associated with lymph node metastasis, differentiation and clinical stage, was significantly reduced in GC tissues and cell lines. miR-1236-3p over-expression could inhibit GC cell proliferation, migration and invasion, and inhibition of miR-1236-3p expression had opposite effects. Furthermore, we demonstrated that MTA2 was a candidate target of miR-1236-3p, and miR-1236-3p over-expression significantly inhibited the process of epithelial-mesenchymal transition. We also found that miR-1236-3p could suppress the PI3K/Akt signaling pathway in GC cells. Conclusions Our results suggest that miR-1236-3p functions as a tumor suppressor in GC and could be a promising therapeutic target for GC.
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Affiliation(s)
- Jia-Xiang An
- Department of Gastroenterological Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032 China
| | - Ming-Hui Ma
- Department of Gastroenterological Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032 China
| | - Chun-Dong Zhang
- Department of Gastroenterological Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032 China
| | - Shuai Shao
- Department of Gastroenterological Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032 China
| | - Nuo-Ming Zhou
- Department of Gastroenterological Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032 China
| | - Dong-Qiu Dai
- Department of Gastroenterological Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032 China
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An J, Xu J, Li J, Jia S, Li X, Lu Y, Yang Y, Lin Z, Xin X, Wu M, Zheng Q, Pu H, Gui X, Li T, Lu D. HistoneH3 demethylase JMJD2A promotes growth of liver cancer cells through up-regulating miR372. Oncotarget 2018; 8:49093-49109. [PMID: 28467776 PMCID: PMC5564752 DOI: 10.18632/oncotarget.17095] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Accepted: 04/01/2017] [Indexed: 11/25/2022] Open
Abstract
Changes in histone lysine methylation status have been observed during cancer formation. JMJD2A protein is a demethylase that is overexpressed in several tumors. Herein, our results demonstrate that JMJD2A accelerates malignant progression of liver cancer cells in vitro and in vivo. Mechanistically, JMJD2A promoted the expression and mature of pre-miR372 epigenetically. Notably, miR372 blocks the editing of 13th exon-introns-14th exon and forms a novel transcript(JMJD2AΔ) of JMJD2A. In particular, JMJD2A inhibited P21(WAF1/Cip1) expression by decreasing H3K9me3 dependent on JMJD2AΔ. Thereby, JMJD2A could enhance Pim1 transcription by suppressing P21(WAF1/Cip1). Furthermore, through increasing the expression of Pim1, JMJD2A could facilitate the interaction among pRB, CDK2 and CyclinE which prompts the transcription and translation of oncogenic C-myc. Strikingly, JMJD2A may trigger the demethylation of Pim1. On the other hand, Pim1 knockdown and P21(WAF1/Cip1) overexpression fully abrogated the oncogenic function of JMJD2A. Our observations suggest that JMJD2A promotes liver cancer cell cycle progress through JMJD2A-miR372-JMJD2AΔ-P21WAF1/Cip1-Pim1-pRB-CDK2-CyclinE-C-myc axis. This study elucidates a novel mechanism for JMJD2A in liver cancer cells and suggests that JMJD2A can be used as a novel therapeutic targets of liver cancer.
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Affiliation(s)
- Jiahui An
- School of Life Science and Technology, Tongji University, Shanghai, 20092, China
| | - Jie Xu
- School of Life Science and Technology, Tongji University, Shanghai, 20092, China
| | - Jiao Li
- School of Medicine, Tongji University, Shanghai, 200092, China
| | - Song Jia
- School of Medicine, Tongji University, Shanghai, 200092, China
| | - Xiaonan Li
- School of Life Science and Technology, Tongji University, Shanghai, 20092, China
| | - Yanan Lu
- School of Life Science and Technology, Tongji University, Shanghai, 20092, China
| | - Yuxin Yang
- School of Life Science and Technology, Tongji University, Shanghai, 20092, China
| | - Zhuojia Lin
- School of Life Science and Technology, Tongji University, Shanghai, 20092, China
| | - Xiaoru Xin
- School of Life Science and Technology, Tongji University, Shanghai, 20092, China
| | - Mengying Wu
- School of Life Science and Technology, Tongji University, Shanghai, 20092, China
| | - Qidi Zheng
- School of Life Science and Technology, Tongji University, Shanghai, 20092, China
| | - Hu Pu
- School of Life Science and Technology, Tongji University, Shanghai, 20092, China
| | - Xin Gui
- School of Life Science and Technology, Tongji University, Shanghai, 20092, China
| | - Tianming Li
- School of Life Science and Technology, Tongji University, Shanghai, 20092, China
| | - Dongdong Lu
- School of Life Science and Technology, Tongji University, Shanghai, 20092, China
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25
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Lin Z, Lu Y, Meng Q, Wang C, Li X, Yang Y, Xin X, Zheng Q, Xu J, Gui X, Li T, Pu H, Xiong W, Li J, Jia S, Lu D. miR372 Promotes Progression of Liver Cancer Cells by Upregulating erbB-2 through Enhancement of YB-1. MOLECULAR THERAPY. NUCLEIC ACIDS 2018; 11:494-507. [PMID: 29858084 PMCID: PMC5992473 DOI: 10.1016/j.omtn.2018.04.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/11/2017] [Revised: 03/30/2018] [Accepted: 04/04/2018] [Indexed: 12/16/2022]
Abstract
MicroRNAs are known to be involved in carcinogenesis. Recently, microRNA-372 (miR372) has been proven to play a substantial role in several human cancers, but its functions in liver cancer remain unclear. Herein, our results demonstrate that miR372 accelerates growth of liver cancer cells in vitro and in vivo. Mechanistically, miR372 enhances expression of Y-box-binding protein 1 (YB-1) by targeting for phosphatase and tensin homolog (PTEN) directly and consequently promotes phosphorylation of YB-1 via HULC looping dependent on ERK1/2 and PTEN. In particular, HULC knockdown or PTEN overexpression abrogated this miR372 action. Moreover, miR372 inhibits the degradation of β-catenin dependent on phosphorylation of YB-1 and then enhances the expression and activity of pyruvate kinase M2 isoform (PKM2) by β-catenin-LEF/TCF4 pathway. Furthermore, the loading of LEF/TCF4 on PKM2 promoter region was significantly increased in miR372 overexpressing Hep3B, and thus, glycolytic proton efflux rate (glycoPER) was significantly increased in rLV-miR372 group compared to the rLV group. Moreover, β-catenin knockdown abrogates this function of miR372. Ultimately, miR372 promotes the expression of erbB-2 through PKM2-pH3T11-acetylation on histone H3 lysine 9 (H3K9Ac) pathway. Of significance, both YB-1 knockdown and erbB-2 knockdown abrogate oncogenic action of miR372. Our observations suggest that miR372 promotes liver cancer cell cycle progress by activating cyclin-dependent kinase 2 (CDK2)-cyclin E-P21/Cip1 complex through miR372-YB-1-β-catenin-LEF/TCF4-PKM2-erbB-2 axis. This study elucidates a novel mechanism for miR372 in liver cancer cells and suggests that miR372 can be used as a novel therapeutic target of liver cancer.
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Affiliation(s)
- Zhuojia Lin
- Research Center for Translational Medicine at Shanghai East Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Yanan Lu
- Research Center for Translational Medicine at Shanghai East Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Qiuyu Meng
- Research Center for Translational Medicine at Shanghai East Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Chen Wang
- Research Center for Translational Medicine at Shanghai East Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Xiaonan Li
- Research Center for Translational Medicine at Shanghai East Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Yuxin Yang
- Research Center for Translational Medicine at Shanghai East Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Xiaoru Xin
- Research Center for Translational Medicine at Shanghai East Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Qidi Zheng
- Research Center for Translational Medicine at Shanghai East Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Jie Xu
- Research Center for Translational Medicine at Shanghai East Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Xin Gui
- Research Center for Translational Medicine at Shanghai East Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Tianming Li
- Research Center for Translational Medicine at Shanghai East Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Hu Pu
- Research Center for Translational Medicine at Shanghai East Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Wujun Xiong
- Department of Hepatology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Jiao Li
- School of Medicine, Tongji University, Shanghai 200092, China
| | - Song Jia
- School of Medicine, Tongji University, Shanghai 200092, China
| | - Dongdong Lu
- Research Center for Translational Medicine at Shanghai East Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China.
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Vaschetto LM. miRNA activation is an endogenous gene expression pathway. RNA Biol 2018; 15:826-828. [PMID: 29537927 PMCID: PMC6152443 DOI: 10.1080/15476286.2018.1451722] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Accepted: 03/07/2018] [Indexed: 12/27/2022] Open
Abstract
Transfection of small non-coding RNAs (sncRNAs) molecules has become a routine technique widely used for silencing gene expression by triggering post-transcriptional and transcriptional RNA interference (RNAi) pathways. Moreover, in the past decade, small activating (saRNA) sequences targeting promoter regions were also reported, thereby a RNA-based gene activation (RNAa) mechanism has been proposed. In this regard, Turner and colleagues recently discovered an endogenous microRNA (miRNA) which binds its promoter in order to upregulate its own expression. Interestingly, several miRNA-induced RNA activation (miRNAa) phenomena have since then been identified. My objective here is to introduce the reader into the emergent miRNAa research field, as well as bring together important discoveries about this unexplored transcriptional activation pathway.
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Affiliation(s)
- Luis M. Vaschetto
- Instituto de Diversidad y Ecología Animal, Consejo Nacional de Investigaciones Científicas y Técnicas (IDEA, CONICET), Av. Vélez Sarsfield 299, X5000JJC Córdoba, Argentina
- Cátedra de Diversidad Animal I, Facultad de Ciencias Exactas, Físicas y Naturales, Universidad Nacional de Córdoba, (FCEFyN, UNC), Av. Vélez Sarsfield 299, X5000JJC Córdoba, Argentina
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27
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Zheng R, Liu Y, Zhang X, Zhao P, Deng Q. miRNA-200c enhances radiosensitivity of esophageal cancer by cell cycle arrest and targeting P21. Biomed Pharmacother 2017; 90:517-523. [PMID: 28402920 DOI: 10.1016/j.biopha.2017.04.006] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Revised: 03/14/2017] [Accepted: 04/02/2017] [Indexed: 12/15/2022] Open
Abstract
Esophageal squamous cancer is one of the most fatal malignancies and often suffer recurrence after radiotherapy. Downregulation of miRNA-200c is associated with radiotolerance. We aim to investigate the role of miRNA-200c in radiosensitivity and develop a systemic treatment strategy for esophageal squamous cancer. Overexpression of miRNA-200c by transfection was determined by RT-PCR. Radiosensitizing effect of miRNA-200c on esophageal squamous cancer cells was determined by clonogenic assay and xenograft model. Cell cycle was analyzed by flow cytometry. The levels of Cyclin B1, cyclin D1, cyclin E1, CDK2, CDK4, Cdc2 and P21 protein expressions were detected by western blotting. The results of our study revealed that miRNA-200c enhanced the radiosensitivity significantly in esophageal squamous cancer cell line in vitro and in vivo. miRNA-200c induced G2/M and sub-G1 phase arrest and reduced S phase rate of the irradiated Eca-109 cells and downregulated expression levels of Cyclin B1, cdc2 and upregulated P21 expression level. Present results demonstrate that downregulation of miRNA-200c is associated with radiotolerance. miRNA-200c increases radiosensitivity by G2/M and sub-G1 phase arrest through modulating Cyclin B1, cdc2 and P21 expression levels.
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Affiliation(s)
- Ruzhen Zheng
- Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang 310002, PR China
| | - Yuehua Liu
- Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang 310002, PR China
| | - Xiaoling Zhang
- Department of Surgery, Haining People's Hospital, Haining, Zhejiang 314400, PR China
| | - Pengjun Zhao
- Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang 310002, PR China.
| | - Qinghua Deng
- Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang 310002, PR China
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28
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Kang MR, Park KH, Yang JO, Lee CW, Oh SJ, Yun J, Lee MY, Han SB, Kang JS. miR-6734 Up-Regulates p21 Gene Expression and Induces Cell Cycle Arrest and Apoptosis in Colon Cancer Cells. PLoS One 2016; 11:e0160961. [PMID: 27509128 PMCID: PMC4979902 DOI: 10.1371/journal.pone.0160961] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Accepted: 07/27/2016] [Indexed: 01/20/2023] Open
Abstract
Recently, microRNAs have been implicated in the regulation of gene expression in terms of both gene silencing and gene activation. Here, we investigated the effects of miR-6734, which has a sequence homology with a specific region of p21WAF1/CIP1 (p21) promoter, on cancer cell growth and the mechanisms involved in this effect. miR-6734 up-regulated p21 expression at both mRNA and protein levels and chromatin immunoprecipitation analysis using biotin-labeled miR-6734 confirmed the association of miR-6734 with p21 promoter. Moreover, miR-6734 inhibited cancer cell growth and induced cell cycle arrest and apoptosis in HCT-116 cells, which was abolished by knockdown of p21. The phosphorylation of Rb and the cleavage of caspase 3 and PARP were suppressed by miR-6734 transfection in HCT-116 cells and these effects were also reversed by p21 knockdown. In addition, miR-6734 transfection caused prolonged induction of p21 gene and modification of histones in p21 promoter, which are typical aspects of a phenomenon referred to as RNA activation (RNAa). Collectively, our results demonstrated that miR-6734 inhibits the growth of colon cancer cells by up-regulating p21 gene expression and subsequent induction of cell cycle arrest and apoptosis, suggesting its role as an important endogenous regulator of cancer cell proliferation and survival.
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Affiliation(s)
- Moo Rim Kang
- Bio-Evaluation Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea
| | - Ki Hwan Park
- Bio-Evaluation Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea
| | - Jeong-Ook Yang
- Bio-Evaluation Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea
| | - Chang Woo Lee
- Bio-Evaluation Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea
| | - Soo Jin Oh
- Bio-Evaluation Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea
| | - Jieun Yun
- Bio-Evaluation Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea
| | - Myeong Youl Lee
- Bio-Evaluation Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea
| | - Sang-Bae Han
- College of Pharmacy, Chungbuk National University, Cheongju, Republic of Korea
| | - Jong Soon Kang
- Bio-Evaluation Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea
- * E-mail:
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Chen SY, Teng SC, Cheng TH, Wu KJ. miR-1236 regulates hypoxia-induced epithelial-mesenchymal transition and cell migration/invasion through repressing SENP1 and HDAC3. Cancer Lett 2016; 378:59-67. [PMID: 27177472 DOI: 10.1016/j.canlet.2016.05.006] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Revised: 05/03/2016] [Accepted: 05/05/2016] [Indexed: 01/08/2023]
Abstract
Intratumoral hypoxia induces epithelial-mesenchymal transition and promotes cancer metastasis. MicroRNAs (miRNAs) are endogenous, single-strand RNA molecules that regulate gene expression. MiRNAs control cell growth, proliferation, differentiation and cell death and may function as oncogenes or tumor suppressors. HDAC3 and SENP1 are two molecules involved in hypoxia-induced EMT and HIF-1α stability, respectively. In this report, we show that miR-1236 plays a critical role in hypoxia-induced EMT and metastasis. MiRNA prediction programs TargetScan and miRanda show that miR-1236 may target HDAC3 and SENP1. MiR-1236 represses the luciferase activity of reporter constructs containing 3'UTR of HDAC3 and SENP1 as well as the expression levels of HDAC3 and SENP1. MiR-1236 abolishes hypoxia-induced EMT and inhibits migration and invasion activity of tumor cells. Hypoxia represses miR-1236 expression. The promoter region of miR-1236 is identified as the NELFE promoter. Twist1, an EMT regulator activated by hypoxia/HIF-1α, is shown to repress the reporter construct driven by the NELFE promoter. The binding site of Twist1 in the NELFE promoter is identified and chromatin immunoprecipitation assays show the direct binding of Twist1 to this site. Overexpression or knockdown of Twist1 in stable cell lines shows the inverse correlation between Twist1 and miR-1236 expression. These results identify a miRNA that regulates hypoxia-induced EMT and metastasis through repressing HDAC3 and SENP1 expression and present a regulatory network that involves many key players in hypoxia-induced EMT.
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Affiliation(s)
- Sung-Yuan Chen
- Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 112, Taiwan
| | - Shu-Chun Teng
- Department of Microbiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan
| | - Tzu-Hao Cheng
- Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 112, Taiwan.
| | - Kou-Juey Wu
- Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 112, Taiwan; Research Center for Tumor Medical Science, Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan.
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Thoma C. Kidney cancer: RNA activation in RCC: p21 and miR-1236 are a promising pair. Nat Rev Urol 2015; 12:598. [PMID: 26481573 DOI: 10.1038/nrurol.2015.259] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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