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Kapadia B, Roychowdhury A, Kayastha F, Lee WS, Nanaji N, Windle J, Gartenhaus R. m6A eraser ALKBH5/treRNA1/DDX46 axis regulates BCR expression. Neoplasia 2025; 62:101144. [PMID: 39987653 PMCID: PMC11905846 DOI: 10.1016/j.neo.2025.101144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 02/10/2025] [Accepted: 02/18/2025] [Indexed: 02/25/2025]
Abstract
Epitranscriptomic modifications, particularly N6-methyladenosine (m6A), have emerged as critical regulators of RNA stability, localization, and translation, shaping immune responses and tumor progression. In B-cell biology, m6A modifications influence germinal center formation and antigen-driven differentiation, underscoring their importance in immune regulation. Among m6A regulators, ALKBH5 (RNA demethylase) is pivotal in removing methylation marks and modulating gene expression in diverse cellular contexts. Despite advancements in understanding m6A dynamics, the mechanistic interplay between m6A demethylation and B-cell receptor (BCR) signaling pathways still needs to be explored. This study reveals a novel regulatory axis involving ALKBH5, treRNA1 (Translation Regulatory Long Non-Coding RNA 1), and DDX46 (RNA helicase). Upon activation signals, ALKBH5 and treRNA1 translocate to the nucleus, forming a functional complex with DDX46 to orchestrate the removal of m6A modifications on key transcripts, including those involved in BCR signaling. This demethylation enhances transcript stability and facilitates cytoplasmic export through interaction with the RNA-binding protein HuR, promoting efficient translation. Disruption of this axis, via loss of ALKBH5, DDX46, or treRNA1, led to impaired transcript processing and diminished BCR-related gene expression, highlighting the critical role of m6A demethylation in maintaining RNA dynamics. These findings uncover a previously unrecognized epitranscriptomic mechanism driven by the ALKBH5-treRNA1-DDX46 complex, with significant implications for B-cell functionality, immune regulation, and oncogenic pathways. Targeting this axis offers a promising avenue for developing therapeutic strategies in cancer and immune-related disorders where m6A dysregulation plays a central role.
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Affiliation(s)
- Bandish Kapadia
- Division of Hematology, Oncology, and Palliative Care, Department of Internal Medicine, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA; Section of Hematology and Oncology, Medicine Service, Richmond VA Cancer Center, Richmond Veteran Affairs Medical Center, Richmond, VA, USA; VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA.
| | - Anirban Roychowdhury
- Division of Hematology, Oncology, and Palliative Care, Department of Internal Medicine, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA; Section of Hematology and Oncology, Medicine Service, Richmond VA Cancer Center, Richmond Veteran Affairs Medical Center, Richmond, VA, USA; VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA
| | - Forum Kayastha
- Division of Hematology, Oncology, and Palliative Care, Department of Internal Medicine, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA; Section of Hematology and Oncology, Medicine Service, Richmond VA Cancer Center, Richmond Veteran Affairs Medical Center, Richmond, VA, USA; VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA
| | - Won Sok Lee
- Department of Pathology, Richmond Veteran Affairs Medical Center, Richmond, VA, USA
| | - Nahid Nanaji
- Department of Veteran Affairs, Maryland Healthcare System, Baltimore, MD, USA
| | - Jolene Windle
- VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA; Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA
| | - Ronald Gartenhaus
- Division of Hematology, Oncology, and Palliative Care, Department of Internal Medicine, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA; Section of Hematology and Oncology, Medicine Service, Richmond VA Cancer Center, Richmond Veteran Affairs Medical Center, Richmond, VA, USA; VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA.
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Kamali MJ, Salehi M, Mostafavi M, Morovatshoar R, Akbari M, Latifi N, Barzegari O, Ghadimi F, Daraei A. Hijacking and rewiring of host CircRNA/miRNA/mRNA competitive endogenous RNA (ceRNA) regulatory networks by oncoviruses during development of viral cancers. Rev Med Virol 2024; 34:e2530. [PMID: 38517354 DOI: 10.1002/rmv.2530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 03/04/2024] [Accepted: 03/11/2024] [Indexed: 03/23/2024]
Abstract
A significant portion of human cancers are caused by oncoviruses (12%-25%). Oncoviruses employ various strategies to promote their replication and induce tumourigenesis in host cells, one of which involves modifying the gene expression patterns of the host cells, leading to the rewiring of genes and resulting in significant changes in cellular processes and signalling pathways. In recent studies, a specific mode of gene regulation known as circular RNA (circRNA)-mediated competing endogenous RNA (ceRNA) networks has emerged as a key player in this context. CircRNAs, a class of non-coding RNA molecules, can interact with other RNA molecules, such as mRNAs and microRNAs (miRNAs), through a process known as ceRNA crosstalk. This interaction occurs when circRNAs, acting as sponges, sequester miRNAs, thereby preventing them from binding to their target mRNAs and modulating their expression. By rewiring the host cell genome, oncoviruses have the ability to manipulate the expression and activity of circRNAs, thereby influencing the ceRNA networks that can profoundly impact cellular processes such as cell proliferation, differentiation, apoptosis, and immune responses. This review focuses on a comprehensive evaluation of the latest findings on the involvement of virus-induced reprogramming of host circRNA-mediated ceRNA networks in the development and pathophysiology of human viral cancers, including cervical cancer, gastric cancer, nasopharyngeal carcinoma, Kaposi's sarcoma, hepatocellular carcinoma, and diffuse large B cell lymphoma. Understanding these mechanisms can improve our knowledge of how oncoviruses contribute to human tumourigenesis and identify potential targets for developing optimised therapies and diagnostic tools for viral cancers.
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Affiliation(s)
- Mohammad Javad Kamali
- Department of Medical Genetics, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Mohammad Salehi
- Department of Medical Genetics, School of Advanced Technologies in Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Mehrnaz Mostafavi
- Department of Physics, Faculty of Allied Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Reza Morovatshoar
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Mitra Akbari
- Eye Department, Eye Research Center, Amiralmomenin Hospital, School of Medicine, Guilan University of Medical Science, Rasht, Iran
| | - Narges Latifi
- Department of Cell and Molecular Biology & Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Omid Barzegari
- Department of Medical Genetics, School of Advanced Technologies in Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Fatemeh Ghadimi
- Department of Medical Genetics, School of Advanced Technologies in Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Abdolreza Daraei
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
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Arslan S, Bakir M, Bayyurt B, Aydemir EI, Kinaci K, Engin A. Long noncoding RNA expression analysis in Crimean Congo hemorrhagic fever patients. J Med Virol 2022; 94:3257-3262. [DOI: 10.1002/jmv.27721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Revised: 12/03/2021] [Accepted: 03/11/2022] [Indexed: 11/07/2022]
Affiliation(s)
- Serdal Arslan
- Department of Medical BiologyFaculty of Medicine, Mersin University33343MersinTurkey
| | - Mehmet Bakir
- Department of Infectious Diseases and Clinical MicrobiologyFaculty of Medicine, Sivas Cumhuriyet University58140SivasTurkey
| | - Burcu Bayyurt
- Department of Medical BiologyFaculty of Medicine, Sivas Cumhuriyet University58140SivasTurkey
| | - Eylem Itir Aydemir
- Department of StatisticFaculty of Science, Sivas Cumhuriyet University58140SivasTurkey
| | - Kenan Kinaci
- SEM Laboratories, Barbaros NeighbourhoodJuly Street, SEM Plaza, No:6Atasehir, IstanbulTurkey
| | - Aynur Engin
- Department of Infectious Diseases and Clinical MicrobiologyFaculty of Medicine, Sivas Cumhuriyet University58140SivasTurkey
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Liu W, Pan Y, Zhu H, Zhou Y, Zhang H, Liu L, Liu Q, Ji G. CircRNA_0008194 functions as a ceRNA to promote invasion of hepatocellular carcinoma via inhibiting miR-190a/AHNAK signaling pathway. J Clin Lab Anal 2022; 36:e24286. [PMID: 35199873 PMCID: PMC8993631 DOI: 10.1002/jcla.24286] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 01/21/2022] [Accepted: 01/23/2022] [Indexed: 12/29/2022] Open
Abstract
Background Hepatitis B virus infection was identified as the main risk factor of hepatocellular carcinoma (HCC) in China, which induced a high morbidity and mortality. In recent years, circRNAs were reported involving in the oncogenesis and development of multiple malignant tumors. Method Bioinformatical analysis has been employed to predict the relevant circRNA with AHNAK. The loss of function and gain of function have been used by knocking‐down circRNA through the shRNA technology while overexpressing through lentivirus infection. Dual‐luciferase reporter assay was used to detect circRNA binding to miRNA and target genes. We further used immunoprecipitation technique to detect the binding ability between non‐coding RNAs. Results In this study, according to the previous report, we mainly focused on AHNAK, which has been confirmed as an oncogene involving in the metastasis of HCC. Bioinformatics analysis showed that circ_0008194 could be spliced by AHNAK. In this study, the abnormal upregulated circ_0008194 in tumor tissues was detected. The positive correlation between circ_0008194 and AHNAK was also confirmed. Through knockdown and overexpression of circ_0008194, we conducted in vitro functional studies. We found circ_0008194 could induce the invasion of cells in vitro. Mechanically, circ_0008194 presented the binding ability with miR‐190a causing the suppression of miR‐190a expression, causing the competitive inhibition of AHNAK, resulting in the promotion of EMT. Conclusion Our results suggested that circ_0008194 may act as a sponge to adsorb miR‐190a, thereby promoting the expression of AHNAK and promoting the metastasis of liver cancer tumors.
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Affiliation(s)
- Wei Liu
- Medical Center for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Medical Center for Digestive Diseases, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ying Pan
- Medical Center for Digestive Diseases, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hengbo Zhu
- Medical Center for Digestive Diseases, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yi Zhou
- Medical Center for Digestive Diseases, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hui Zhang
- Medical Center for Digestive Diseases, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Liu Liu
- Medical Center for Digestive Diseases, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Qing Liu
- Medical Center for Digestive Diseases, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Guozhong Ji
- Medical Center for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Wei L, Sun J, Zhang N, Shen Y, Wang T, Li Z, Yang M. Novel Implications of MicroRNAs, Long Non-coding RNAs and Circular RNAs in Drug Resistance of Esophageal Cancer. Front Cell Dev Biol 2021; 9:764313. [PMID: 34881242 PMCID: PMC8645845 DOI: 10.3389/fcell.2021.764313] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 10/12/2021] [Indexed: 12/24/2022] Open
Abstract
Esophageal cancer is the eighth most common malignancy and the sixth leading cause of cancer-related deaths worldwide. Chemotherapy based on platinum drugs, 5-fluorouracil, adriamycin, paclitaxel, gemcitabine, and vinorelbine, as well as targeted treatment and immunotherapy with immune checkpoint inhibitors improved the prognosis in a portion of patients with advanced esophageal cancer. Unfortunately, a number of esophageal cancer patients develop drug resistance, resulting in poor outcomes. Multiple mechanisms contributing to drug resistance of esophageal cancer have been reported. Notably, non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), have been identified to play crucial roles in modulating esophageal cancer drug resistance. In the present review, we highlight the underlying mechanisms how miRNAs, lncRNAs, and circRNAs impact the drug resistance of esophageal cancer. Several miRNAs, lncRNAs, and circRNAs may have potential clinical implications as novel biomarkers and therapeutic targets for esophageal cancer.
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Affiliation(s)
- Ling Wei
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Jujie Sun
- Department of Pathology, Shandong Cancer Hospital and Institute, Jinan, China
| | - Nasha Zhang
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, China
| | - Yue Shen
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Teng Wang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Zengjun Li
- Department of Endoscopy, Shandong Cancer Hospital and Institute, Jinan, China
| | - Ming Yang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
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Liang D, Hu M, Tang Q, Huang M, Tang L. Nine Pyroptosis-Related lncRNAs are Identified as Biomarkers for Predicting the Prognosis and Immunotherapy of Endometrial Carcinoma. Int J Gen Med 2021; 14:8073-8085. [PMID: 34803394 PMCID: PMC8594792 DOI: 10.2147/ijgm.s338298] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 11/04/2021] [Indexed: 12/28/2022] Open
Abstract
Background Endometrial carcinoma (EC) is one of the most common malignancies. Immunotherapy has shown promising effects in the treatment against specific subtypes of EC. Methods The RNA and clinical information of patients with EC were acquired from The Cancer Gene Atlas (TCGA) database. Firstly, the differentially expressed pyroptosis-related lncRNAs (PRLs) were screened between the tumor and normal control tissue. Secondly, the PRLs closely related to survival were identified by univariate and multivariate regression analysis, based on which, we evaluated the risk score for each EC patient to construct a risk signature. Moreover, we assessed the prognostic value, clinical relevance immunity, and immunotherapy based on this signature. Results We screened out 9 individual PRLs (AC087491.1, AL353622.1, AL035530.2, LINC02036, AL021578.1, AL390195.2, AC009097.2, AC004585.1, and AC244517.7) closely related to the prognosis of EC. Kaplan–Meier analyses showed a poorer prognosis for the patients in the high-risk FRLs signature (P < 0.001). The area under the curve (AUC) for 1 year, 2 years, 3 years was 0.693, 0.694, 0.750, respectively. Our risk model could be considered as an independent prognostic marker for EC (P < 0.001, HR:2.172, 95% CI:1.532–3.079). Moreover, immune functions and checkpoints were generally different in the 2 groups. Simulation analysis by termed immunophenoscores hinted that immunotherapy might bring optimal therapeutic effect in the low-risk group. Conclusion We successfully developed a novel signature with 9 lncRNAs related to pyroptosis, which may be used as biomarkers to evaluate the prognosis and immune treatment of EC.
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Affiliation(s)
- Deku Liang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China.,Department of Obstetrics and Gynecology, Chengdu Women and Children's Central Hospital Affiliated to University of Electronic Science and Technology of China, Chengdu, Sichuan Province, People's Republic of China
| | - Min Hu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Qin Tang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Mao Huang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Liangdan Tang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
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Zou Y, Sun Z, Sun S. LncRNA HCG18 contributes to the progression of hepatocellular carcinoma via miR-214-3p/CENPM axis. J Biochem 2021; 168:535-546. [PMID: 32663252 DOI: 10.1093/jb/mvaa073] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 06/18/2020] [Indexed: 01/04/2023] Open
Abstract
Long non-coding RNA (lnc) HCG18 has been reported to contribute progression of a variety of tumours. However, its roles in hepatocellular carcinoma (HCC) remains unknown. In the current study, we intended to uncover the biological functions of HCG18 in HCC. Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to detect the expression of HCG18, microRNA-214-3p (miR-214-3p) and centromere protein M (CENPM) messenger RNA (mRNA). The role of HCG18 in the growth and migration were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, colony formation assay, wound healing assay and flow cytometry in vitro and animal experiments in vivo. The results showed that HCG18 was highly expressed in HCC tissues. HCG18 silencing inhibited the proliferation and migration while induced the apoptosis of HCC cells. Besides, miR-214-3p was down-regulated in HCC cells. Further experiments revealed that miR-214-3p could directly bind to HCG18 and exerted an anti-tumour role to counteracted siHCG18-1-mediated influence in HCC cells. Moreover, miR-214-3p could directly interact with CENPM mRNA and down-regulating the expression of CENPM. While HCG18 could up-regulate the expression of CENPM through acting as a sponge of miR-214-3p. Therefore, those results suggested HCG18 functioned as an oncogene to promote the proliferation and migration of HCC cells via miR-214-3p/CENPM axis.
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Affiliation(s)
- Yuepei Zou
- Zhengzhou University, No. 100 Science Ave, Gaoxin District, Zhengzhou 450001, China
| | - Zhonghua Sun
- Medical Department, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, No. 16369 Jingshi Road, Jinan 250011, China
| | - Shuangming Sun
- Security and Anti-Terrorism Department, People's Public Security University of China, No. 1 Muxidinanli, Xicheng District, Beijing 100038, China
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Hepigenetics: A Review of Epigenetic Modulators and Potential Therapies in Hepatocellular Carcinoma. BIOMED RESEARCH INTERNATIONAL 2020; 2020:9593254. [PMID: 33299889 PMCID: PMC7707949 DOI: 10.1155/2020/9593254] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 10/13/2020] [Accepted: 11/05/2020] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma is the fifth most common cancer worldwide and the second most lethal, following lung cancer. Currently applied therapeutic practices rely on surgical resection, chemotherapy and radiotherapy, or a combination thereof. These treatment options are associated with extreme adversities, and risk/benefit ratios do not always work in patients' favor. Anomalies of the epigenome lie at the epicenter of aberrant molecular mechanisms by which the disease develops and progresses. Modulation of these anomalous events poses a promising prospect for alternative treatment options, with an abundance of felicitous results reported in recent years. Herein, the most recent epigenetic modulators in hepatocellular carcinoma are recapitulated on.
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Wang R, Zheng B, Liu H, Wan X. Long non-coding RNA PCAT1 drives clear cell renal cell carcinoma by upregulating YAP via sponging miR-656 and miR-539. Cell Cycle 2020; 19:1122-1131. [PMID: 32286142 PMCID: PMC7217353 DOI: 10.1080/15384101.2020.1748949] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Revised: 12/08/2019] [Accepted: 12/29/2019] [Indexed: 01/13/2023] Open
Abstract
Clear cell renal cell carcinoma (ccRCC) is the most common RCC subtype with high metastasis, poor prognosis and conventional chemotherapy resistance. Prostate cancer associated transcript 1 (PCAT1) is an important lncRNA that was reported to be involved in cell proliferation, migration and invasion of several types of cancer cells. However, its role in ccRCC is still undetermined. This study found that PCAT1 levels were elevated in ccRCC tumors as well as several ccRCC cells, and knockdown of PCAT1 with siRNA (si-PCAT1) alleviated cell proliferation, migration and invasion of Caki-2 and ACHN cells. With bioinformatics analysis, dual-luciferase reported assay, RNA pull-down assay and Spearman's correlation analysis, we demonstrated that PCAT1 acted as a sponge for miR-656 and miR-539. Moreover, we found dual competitive interaction of miR-656/539 with PCAT1 and yes-associated protein (YAP), resulting in the identification of PCAT1-miR-656/539-YAP axis in Caki-2 and ACHN cells. With CCK-8 assay and transwell assay, miR-656/539 inhibitor or YAP overexpression could alleviate the effects of si-PCAT1 on the proliferation, migration and invasion of Caki-2 and ACHN cells. Our data indicated that PCAT1 promotes proliferation, migration and invasion of ccRCC cells by upregulating YAP via sponging miR-656 and miR-539. Taken together, this study provided a novel therapeutic target for ccRCC treatment.
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Affiliation(s)
- Rui Wang
- Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Bin Zheng
- Department of Nephrology, The Affiliated Lianyungang Oriental Hospital of Xuzhou Medical University, Lianyungang, Jiangsu, China
| | - Hongyan Liu
- Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xiuxian Wan
- Department of Nephrology, The Affiliated Lianyungang Oriental Hospital of Xuzhou Medical University, Lianyungang, Jiangsu, China
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Abstract
miRNAs, a major class of small noncoding RNAs approximately 18-25 nucleotides in length, function by repressing the expression of target genes through binding to complementary sequences in the 3'-UTRs of target genes. Emerging evidence has highlighted their important roles in numerous diseases, including human cancers. Recently, miR-190 has been shown to be dysregulated in various types of human cancers that participates in cancer-related biological processes, including proliferation, apoptosis, metastasis, drug resistance, by regulating associated target genes, and to predict cancer diagnosis and prognosis. In this review, we summarized the roles of miR-190-5p in human diseases, especially in human cancers. Then we classified its target genes in tumorigenesis and progression, which might provide evidence for cancer diagnosis and prognosis, promising tools for cancer treatment, or leads for further investigation.
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Affiliation(s)
- Yue Yu
- 1The First Department of Breast Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Huan-Hu-Xi Road, Hexi District, Tianjin, 300060 China.,2Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060 China.,Tianjin's Clinical Research Center for Cancer, Tianjin, 300060 China.,4Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060 China
| | - Xu-Chen Cao
- 1The First Department of Breast Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Huan-Hu-Xi Road, Hexi District, Tianjin, 300060 China.,2Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060 China.,Tianjin's Clinical Research Center for Cancer, Tianjin, 300060 China.,4Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060 China
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11
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Zhou Q, Zhang W, Wang Z, Liu S. Long non-coding RNA PTTG3P functions as an oncogene by sponging miR-383 and up-regulating CCND1 and PARP2 in hepatocellular carcinoma. BMC Cancer 2019; 19:731. [PMID: 31340767 PMCID: PMC6657059 DOI: 10.1186/s12885-019-5936-2] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Accepted: 07/12/2019] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Emerging evidence indicates that Long non-coding RNAs (LncRNAs) and microRNAs (miRNAs) play crucial roles in tumor progression, including hepatocellular carcinoma (HCC). However, whether there is a crosstalk between LncRNA pituitary tumor-transforming 3 (PTTG3P) and miR-383 in HCC remains unknown. This study is designed to explore the underlying mechanism by which LncRNA PTTG3P sponges miR-383 during HCC progression. METHODS qPCR and Western blot were used to analyze LncRNA PTTG3P, miR-383 and other target genes' expression. CCK-8 assay was performed to examine cell proliferation. Annexin V-PE/PI and PI staining were used to analyze cell apoptosis and cell cycle distribution by flow cytometry, respectively. Transwell migration and invasion assays were used to examine cell migration and invasion abilities. An in vivo xenograft study was performed to detect tumor growth. Luciferase reporter assay and RNA pull-down assay were carried out to detect the interaction between miR-383 and LncRNA PTTG3P. RIP was carried out to detect whether PTTG3P and miR-383 were enriched in Ago2-immunoprecipitated complex. RESULTS In this study, we found that PTTG3P was up-regulated in HCC tissues and cells. Functional experiments demonstrated that knockdown of PTTG3P inhibited cell proliferation, migration and invasion, and promoted cell apoptosis, acting as an oncogene. Mechanistically, PTTG3P upregulated the expression of miR-383 targets Cyclin D1 (CCND1) and poly ADP-ribose polymerase 2 (PARP2) by sponging miR-383, acting as a competing endogenous RNA (ceRNA). The PTTG3P-miR-383-CCND1/PARP2 axis modulated HCC phenotypes. Moreover, PTTG3P also affected the PI3K/Akt signaling pathway. CONCLUSION The data indicate a novel PTTG3P-miR-383-CCND1/PARP2 axis in HCC tumorigenesis, suggesting that PTTG3P may be used as a potential therapeutic target in HCC.
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Affiliation(s)
- Qiang Zhou
- Department of Hepatology, the First Hospital of Jilin University, Changchun, 130021, Jilin, China
| | - Wei Zhang
- Department of Hepatobiliary and Pancreatic Surgery, the First Hospital of Jilin University, Changchun, 130021, Jilin, China
| | - Zhongfeng Wang
- Department of Hepatology, the First Hospital of Jilin University, Changchun, 130021, Jilin, China
| | - Songyang Liu
- Department of Hepatobiliary and Pancreatic Surgery, the First Hospital of Jilin University, Changchun, 130021, Jilin, China.
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12
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Sun G, Liu M, Han H. Overexpression of microRNA‐190 inhibits migration, invasion, epithelial‐mesenchymal transition, and angiogenesis through suppression of protein kinase B‐extracellular signal‐regulated kinase signaling pathway via binding to stanniocalicin 2 in breast cancer. J Cell Physiol 2019; 234:17824-17838. [PMID: 30993707 DOI: 10.1002/jcp.28409] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Accepted: 01/30/2019] [Indexed: 12/11/2022]
Affiliation(s)
- Guiming Sun
- Department of Oncology Liaocheng People's Hospital Liaocheng P.R. China
| | - Meirong Liu
- Department of Oncology Liaocheng People's Hospital Liaocheng P.R. China
| | - Hui Han
- Department of Oncology Liaocheng People's Hospital Liaocheng P.R. China
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13
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Yu Y, Yin W, Yu ZH, Zhou YJ, Chi JR, Ge J, Cao XC. miR-190 enhances endocrine therapy sensitivity by regulating SOX9 expression in breast cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:22. [PMID: 30658681 PMCID: PMC6339391 DOI: 10.1186/s13046-019-1039-9] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/28/2018] [Accepted: 01/13/2019] [Indexed: 12/22/2022]
Abstract
Background Breast cancer is the most common cancer among women worldwide, and approximately 70% of breast cancers are hormone receptor-positive and express estrogen receptor-α (ERα) or/and progesterone receptor. Therapies targeting ERα have been successfully used in patients with ERα+ breast cancer. However, intrinsic or acquired resistance to anti-estrogen therapy presents a major challenge. The Wnt/β-catenin signaling pathway regulates various processes that are important for cancer progression, and emerging evidences have shown a close interaction between Wnt/β-catenin and ERα signaling. miR-190 is also involved in ER signaling and our previous study indicated that miR-190 suppresses breast cancer metastasis. Methods The effect of miR-190 on breast cancer anti-estrogen sensitivity was investigated both in vitro and in vivo. The protein expression levels and localization were analyzed by western blotting and immunofluorescence, respectively. Chromatin immunoprecipitation and dual-luciferase reporter assays were used to validate the regulation of the zinc-finger E-box binding homeobox 1/ ERα-miR-190-SRY-related high mobility group box 9 (ZEB1/ERα-miR-190-SOX9) axis. Results miR-190 increased the anti-estrogen sensitivity of breast cancer cells both in vitro and in vivo. miR-190 inhibited Wnt/β-catenin signaling by targeting SOX9, and its expression inversely correlated with that of SOX9 in breast cancer samples. Furthermore, ERα and ZEB1 competitively regulated miR-190 expression. Conclusions Our data uncover the ZEB1/ERα-miR-190-SOX9 axis and suggest a mechanism by which the Wnt/β-catenin signaling pathway is involved in breast cancer anti-estrogen therapy. Electronic supplementary material The online version of this article (10.1186/s13046-019-1039-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yue Yu
- The First Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huan-Hu-Xi Road, Hexi District, Tianjin, 300060, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.,Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, China
| | - Wen Yin
- The First Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huan-Hu-Xi Road, Hexi District, Tianjin, 300060, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.,Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, China
| | - Zhi-Hao Yu
- The First Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huan-Hu-Xi Road, Hexi District, Tianjin, 300060, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.,Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, China
| | - Yan-Jun Zhou
- The First Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huan-Hu-Xi Road, Hexi District, Tianjin, 300060, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.,Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, China
| | - Jiang-Rui Chi
- The First Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huan-Hu-Xi Road, Hexi District, Tianjin, 300060, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.,Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, China
| | - Jie Ge
- The First Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huan-Hu-Xi Road, Hexi District, Tianjin, 300060, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.,Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, China
| | - Xu-Chen Cao
- The First Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huan-Hu-Xi Road, Hexi District, Tianjin, 300060, China. .,Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China. .,Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China. .,Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, China.
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14
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Li BL, Wan XP. The role of lncRNAs in the development of endometrial carcinoma. Oncol Lett 2018; 16:3424-3429. [PMID: 30127944 DOI: 10.3892/ol.2018.9065] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Accepted: 07/03/2017] [Indexed: 01/23/2023] Open
Abstract
Endometrial carcinoma (EC) is one of the most common types of gynecological cancer. Long noncoding RNAs (lncRNAs) are associated with the carcinogenesis and progression of EC. In the following review, the emerging role of lncRNAs in EC initiation and progression is considered. The profile of lncRNAs is becoming higher as the contribution of lncRNAs to carcinogenesis through diverse mechanisms is being increasingly recognized, including in EC. A number of lncRNA-profiling studies have identified aberrantly expressed lncRNAs in EC tissue, and the regulatory network associated with these lncRNAs may be critical in EC progression. Additionally, certain lncRNAs may have diagnostic and/or prognostic significance. The potential function of lncRNAs as prospective therapeutic and prognostic targets in EC will be evaluated.
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Affiliation(s)
- Bi-Lan Li
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, P.R. China
| | - Xiao-Ping Wan
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, P.R. China
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15
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Yu Y, Luo W, Yang ZJ, Chi JR, Li YR, Ding Y, Ge J, Wang X, Cao XC. miR-190 suppresses breast cancer metastasis by regulation of TGF-β-induced epithelial-mesenchymal transition. Mol Cancer 2018; 17:70. [PMID: 29510731 PMCID: PMC5838994 DOI: 10.1186/s12943-018-0818-9] [Citation(s) in RCA: 96] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Accepted: 02/26/2018] [Indexed: 01/23/2023] Open
Abstract
Background Breast cancer is the most common cancer among women worldwide and metastasis is the leading cause of death among patients with breast cancer. The transforming growth factor-β (TGF-β) pathway plays critical roles during breast cancer epithelial–mesenchymal transition (EMT) and metastasis. SMAD2, a positive regulator of TGF-β signaling, promotes breast cancer metastasis through induction of EMT. Methods The expression of miR-190 and SMAD2 in breast cancer tissues, adjacent normal breast tissues and cell lines were determined by RT-qPCR. The protein expression levels and localization were analyzed by western blotting and immunofluorescence. ChIP and dual-luciferase report assays were used to validate the regulation of ZEB1-miR-190-SMAD2 axis. The effect of miR-190 on breast cancer progression was investigated both in vitro and in vivo. Results miR-190 down-regulation is required for TGF-β-induced EMT. miR-190 suppresses breast cancer metastasis both in vitro and in vivo by targeting SMAD2. miR-190 expression is down-regulated and inversely correlates with SMAD2 in breast cancer samples, and its expression level was associated with outcome in patients with breast cancer. Furthermore, miR-190 is transcriptionally regulated by ZEB1. Conclusions Our data uncover the ZEB1-miR-190-SMAD2 axis and provide a mechanism to explain the TGF-β network in breast cancer metastasis. Electronic supplementary material The online version of this article (10.1186/s12943-018-0818-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yue Yu
- The First Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huanhuxi Road, Hexi District, Tianjin, 300060, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.,Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, China
| | - Wei Luo
- The First Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huanhuxi Road, Hexi District, Tianjin, 300060, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.,Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, China
| | - Zheng-Jun Yang
- The First Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huanhuxi Road, Hexi District, Tianjin, 300060, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.,Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, China
| | - Jiang-Rui Chi
- The First Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huanhuxi Road, Hexi District, Tianjin, 300060, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.,Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, China
| | - Yun-Rui Li
- The First Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huanhuxi Road, Hexi District, Tianjin, 300060, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.,Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, China
| | - Yu Ding
- The First Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huanhuxi Road, Hexi District, Tianjin, 300060, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.,Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, China
| | - Jie Ge
- The First Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huanhuxi Road, Hexi District, Tianjin, 300060, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.,Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, China
| | - Xin Wang
- The First Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huanhuxi Road, Hexi District, Tianjin, 300060, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.,Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, China
| | - Xu-Chen Cao
- The First Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huanhuxi Road, Hexi District, Tianjin, 300060, China. .,Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China. .,Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China. .,Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, China.
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16
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Shang G, Wang Y, Xu Y, Zhang S, Sun X, Guan H, Zhao X, Wang Y, Li Y, Zhao G. Long non-coding RNA TCONS_00041960 enhances osteogenesis and inhibits adipogenesis of rat bone marrow mesenchymal stem cell by targeting miR-204-5p and miR-125a-3p. J Cell Physiol 2018; 233:6041-6051. [PMID: 29319166 PMCID: PMC5947671 DOI: 10.1002/jcp.26424] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2017] [Accepted: 01/05/2018] [Indexed: 12/15/2022]
Abstract
A growing number of long non‐coding RNAs (lncRNAs) have been found to be involved in diverse biological processes such as cell cycle regulation, embryonic development, and cell differentiation. However, limited knowledge is available concerning the underlying mechanisms of lncRNA functions. In this study, we found down‐regulation of TCONS_00041960 during adipogenic and osteogenic differentiation of glucocorticoid‐treated bone marrow mesenchymal stem cells (BMSCs). Furthermore, up‐regulation of TCONS_00041960 promoted expression of osteogenic genes Runx2, osterix, and osteocalcin, and anti‐adipogenic gene glucocorticoid‐induced leucine zipper (GILZ). Conversely, expression of adipocyte‐specific markers was decreased in the presence of over‐expressed TCONS_00041960. Mechanistically, we determined that TCONS_00041960 as a competing endogenous RNA interacted with miR‐204‐5p and miR‐125a‐3p to regulate Runx2 and GILZ, respectively. Overall, we identified a new TCONS_00041960‐miR‐204‐5p/miR‐125a‐3p‐Runx2/GILZ axis involved in regulation of adipogenic and osteogenic differentiation of glucocorticoid‐treated BMSCs.
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Affiliation(s)
- Guowei Shang
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yadong Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Yan Xu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Shanfeng Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Xiaoya Sun
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Hongya Guan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Xuefeng Zhao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Yisheng Wang
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yuebai Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Guoqiang Zhao
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
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17
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Wang WT, Li Z, Shi M, Zhu H, Xiong X, Shang J, Liu J, Teng M, Yang M. Association of the GLB1 rs4678680 genetic variant with risk of HBV-related hepatocellular carcinoma. Oncotarget 2018; 7:56501-56507. [PMID: 27489354 PMCID: PMC5302931 DOI: 10.18632/oncotarget.10963] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Accepted: 07/19/2016] [Indexed: 01/22/2023] Open
Abstract
Accumulated evidences demonstrated that GLB1 is involved in cell senescence and cancer development. The GLB1 rs4678680 single nucleotide polymorphism (SNP) has been identified as a hepatocellular carcinoma (HCC) susceptibility polymorphism by a genome-wide association study in Korean population previously. However, little or nothing was known about its involvement and functional significance in hepatitis B viruses (HBV)-related HCC in Chinese. Therefore, we investigated the association between the GLB1 rs4678680 SNP and HBV-related HCC risk as well as its biological function in vivo. Genotypes were determined in two independent case-control sets from two medical centers of China. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression. The potential regulation role the rs4678680 genetic variant on GLB1 expression was examined with HCC and normal liver tissues. We found that The rs4678680 G allele was showed to be risk allele; individuals with the TG genotype had an OR of 1.51 (95% CI = 1.10–2.07, P = 0.010, Shandong set) or 1.49 (95% CI = 1.11–1.99, P = 0.008, Jiangsu set) for developing HBV-related HCC, respectively, compared with individuals with the TT genotype. This association was more pronounced in males, individuals aged older than 57 years and drinkers (all P < 0.05). In the genotype-phenotype correlation analyses of fifty-six human liver tissue samples, rs4678680 TG or GG was associated with a statistically significant increase of GLB1 mRNA expression (P < 0.05). Our data indicated that the GLB1 rs4678680 SNP contributes to susceptibility to develop HBV-related HCC, highlighting the involvement of GLB1 and cell senescence in etiology of HCC.
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Affiliation(s)
- Wen-Tao Wang
- Department of Hepatobiliary Surgery, Qianfoshan Hospital, Shandong University, Jinan, Shandong Province, China
| | - Ziqiang Li
- Department of Hepatobiliary Surgery, Qianfoshan Hospital, Shandong University, Jinan, Shandong Province, China
| | - Meng Shi
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, Shandong Province, China.,College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
| | - Hui Zhu
- Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
| | - Xiangyu Xiong
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
| | - Jinhua Shang
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
| | - Jibing Liu
- Department of Intervention Surgery, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
| | - Mujian Teng
- Department of Hepatobiliary Surgery, Qianfoshan Hospital, Shandong University, Jinan, Shandong Province, China
| | - Ming Yang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
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18
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El Khodiry A, Afify M, El Tayebi HM. Behind the curtain of non-coding RNAs; long non-coding RNAs regulating hepatocarcinogenesis. World J Gastroenterol 2018; 24:549-572. [PMID: 29434445 PMCID: PMC5799857 DOI: 10.3748/wjg.v24.i5.549] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 01/17/2018] [Accepted: 01/23/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common and aggressive cancers worldwide. HCC is the fifth common malignancy in the world and the second leading cause of cancer death in Asia. Long non-coding RNAs (lncRNAs) are RNAs with a length greater than 200 nucleotides that do not encode proteins. lncRNAs can regulate gene expression and protein synthesis in several ways by interacting with DNA, RNA and proteins in a sequence specific manner. They could regulate cellular and developmental processes through either gene inhibition or gene activation. Many studies have shown that dysregulation of lncRNAs is related to many human diseases such as cardiovascular diseases, genetic disorders, neurological diseases, immune mediated disorders and cancers. However, the study of lncRNAs is challenging as they are poorly conserved between species, their expression levels aren't as high as that of mRNAs and have great interpatient variations. The study of lncRNAs expression in cancers have been a breakthrough as it unveils potential biomarkers and drug targets for cancer therapy and helps understand the mechanism of pathogenesis. This review discusses many long non-coding RNAs and their contribution in HCC, their role in development, metastasis, and prognosis of HCC and how to regulate and target these lncRNAs as a therapeutic tool in HCC treatment in the future.
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Affiliation(s)
- Aya El Khodiry
- Genetic Pharmacology Research Group, Clinical Pharmacy Unit, Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt
| | - Menna Afify
- Genetic Pharmacology Research Group, Clinical Pharmacy Unit, Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt
| | - Hend M El Tayebi
- Genetic Pharmacology Research Group, Clinical Pharmacy Unit, Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt
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19
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Yamamura S, Imai-Sumida M, Tanaka Y, Dahiya R. Interaction and cross-talk between non-coding RNAs. Cell Mol Life Sci 2018; 75:467-484. [PMID: 28840253 PMCID: PMC5765200 DOI: 10.1007/s00018-017-2626-6] [Citation(s) in RCA: 235] [Impact Index Per Article: 33.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2017] [Revised: 08/07/2017] [Accepted: 08/09/2017] [Indexed: 02/06/2023]
Abstract
Non-coding RNA (ncRNA) has been shown to regulate diverse cellular processes and functions through controlling gene expression. Long non-coding RNAs (lncRNAs) act as a competing endogenous RNAs (ceRNAs) where microRNAs (miRNAs) and lncRNAs regulate each other through their biding sites. Interactions of miRNAs and lncRNAs have been reported to trigger decay of the targeted lncRNAs and have important roles in target gene regulation. These interactions form complicated and intertwined networks. Certain lncRNAs encode miRNAs and small nucleolar RNAs (snoRNAs), and may regulate expression of these small RNAs as precursors. SnoRNAs have also been reported to be precursors for PIWI-interacting RNAs (piRNAs) and thus may regulate the piRNAs as a precursor. These miRNAs and piRNAs target messenger RNAs (mRNAs) and regulate gene expression. In this review, we will present and discuss these interactions, cross-talk, and co-regulation of ncRNAs and gene regulation due to these interactions.
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Affiliation(s)
- Soichiro Yamamura
- Department of Urology, University of California, San Francisco, San Francisco, CA, USA.
- San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA.
| | - Mitsuho Imai-Sumida
- Department of Urology, University of California, San Francisco, San Francisco, CA, USA
- San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA
| | - Yuichiro Tanaka
- Department of Urology, University of California, San Francisco, San Francisco, CA, USA
- San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA
| | - Rajvir Dahiya
- Department of Urology, University of California, San Francisco, San Francisco, CA, USA
- San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA
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20
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Ren Y, Shang J, Li J, Liu W, Zhang Z, Yuan J, Yang M. The long noncoding RNA PCAT-1 links the microRNA miR-215 to oncogene CRKL-mediated signaling in hepatocellular carcinoma. J Biol Chem 2017; 292:17939-17949. [PMID: 28887306 DOI: 10.1074/jbc.m116.773978] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Revised: 08/29/2017] [Indexed: 12/11/2022] Open
Abstract
The long non-coding RNA (lncRNA) PCAT-1 resides in the chromosome 8q24 cancer-risk locus and acts as a vital oncogene during tumorigenesis and progression. However, how PCAT-1 is post-transcriptionally regulated, for example, by small ncRNAs, such as microRNAs (miRNAs) is largely unknown. Here, we report how miRNAs regulate PCAT-1 expression and also investigate the biological significance of this regulation in hepatocellular carcinoma (HCC). We found that miR-215, a P53-inducible miRNA, is a key regulator of PCAT-1 expression in HCC and identified an interaction between miR-215 and PCAT-1 in dual luciferase reporter gene assays. We also found that post-transcriptional silencing of PCAT-1 by miR-215 or PCAT-1 siRNAs significantly inhibited proliferation of HCC cells and, conversely, that inhibition of endogenous miR-215 up-regulated PCAT-1 expression and promoted cell viability. The tumor-suppressing role of miR-215 was further confirmed in an in vivo mouse HCC xenograft model. Of note, gene profiling assays suggested that the kinase CRK-like proto-oncogene, adaptor protein (CRKL), is a potential downstream target of the miR-215-PCAT-1 axis in HCC, and we demonstrated that CRKL silencing significantly suppresses cell proliferation. Taken together and considering the essential role of CRKL in cancer cells, we propose that the TP53-miR-215-PCAT-1-CRKL axis might represent an important regulatory pathway in HCC. In summary, our results highlight the involvement of several ncRNAs in HCC and thus provide critical insights into the molecular pathways operating in this malignancy.
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Affiliation(s)
- Yanli Ren
- From the Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan 250117, Shandong Province, China and
| | - Jinhua Shang
- the College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100021, China
| | - Jinliang Li
- the College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100021, China
| | - Wenjuan Liu
- From the Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan 250117, Shandong Province, China and
| | - Zhao Zhang
- the College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100021, China
| | - Jupeng Yuan
- From the Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan 250117, Shandong Province, China and
| | - Ming Yang
- From the Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan 250117, Shandong Province, China and
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21
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Ren Y, Chen Y, Liang X, Lu Y, Pan W, Yang M. MiRNA-638 promotes autophagy and malignant phenotypes of cancer cells via directly suppressing DACT3. Cancer Lett 2017; 390:126-136. [PMID: 28108314 DOI: 10.1016/j.canlet.2017.01.009] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2016] [Revised: 12/30/2016] [Accepted: 01/10/2017] [Indexed: 01/06/2023]
Abstract
Dyregulation of autophagy is implicated in human cancers and the mechanism details remains largely unclear. Herein we report the regulatory role of miR-638 in autophagy of esophageal squamous cell carcinoma (ESCC) and breast cancer cells. We found that miR-638 overexpression promotes starvation- and rapamycin-induced autophagy. In ESCC and breast cancer cells, miR-638 acts as an oncogene and promotes cell proliferation, migration, as well as invasion in vitro and in vivo. In accordance with this, we observed significantly higher miR-638 expression in ESCC and breast cancer tissues compared to normal tissues. To further elucidate regulatory mechanisms of miR-638 in autophagy, we performed a computational nomination of its target genes through intersecting the results of multiple prediction algorithms. DACT3, a key regulator of Wnt/β-catenin signaling, was predicted to be regulated by miR-638 by all programs and confirmed by experimental results. Depletion of DACT3 phenocopied effects of miR-638 overexpression, demonstrating its importance in autophagy. These results elucidate that the miR-638-DACT3 axis might be an important molecular pathway in controlling autophagy and tumorigenesis. Our data in clinical tissue samples highlight miR-638 and DACT3 as histological marker for cancer detection and their potentially therapeutic implications.
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Affiliation(s)
- Yanli Ren
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, Shandong, China; College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
| | - Yujie Chen
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Xue Liang
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
| | - Yan Lu
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
| | - Wenting Pan
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
| | - Ming Yang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, Shandong, China.
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