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Wang F, Mu HF, Wang C, Tang Y, Si MY, Peng J. LncRNA PCAT6 promotes progression and metastasis of colonic neuroendocrine carcinoma via MAPK pathway. World J Gastrointest Oncol 2025; 17:96230. [PMID: 39958556 PMCID: PMC11755991 DOI: 10.4251/wjgo.v17.i2.96230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 09/18/2024] [Accepted: 12/02/2024] [Indexed: 01/18/2025] Open
Abstract
BACKGROUND Colonic neuroendocrine carcinomas (NECs) are highly malignant and invasive with poor prognosis. Long noncoding RNAs (LncRNAs) participate in the tumorigenesis and metastasis of multiple cancers. AIM To detect the roles and mechanisms of lncRNA prostate cancer associated transcript 6 (PCAT6) in the progression of colonic NEC. METHODS Human NEC and adjacent normal samples were collected for immunohistochemistry staining of CgA and real-time quantitative polymerase chain reaction (RT-qPCR) of PCAT6 mRNA level. Subcutaneous xenograft tumor model and lung metastasis model were established in nude mice. The lung tissues were stained by hematoxylin and eosin to assess pulmonary metastasis. The expression of epithelial-mesenchymal transition (EMT)-related markers and pathway-related genes was measured by RT-qPCR and western blotting. CD56 expression was assessed by immunofluorescence staining. The biological functions of PCAT6 were examined by cell counting kit-8, colony formation assays, Transwell assays and wound healing assays. The interaction between PCAT6 and its potential downstream target was verified by luciferase reporter assays. RESULTS LncRNA PCAT6 was upregulated in human NEC samples and LCC-18 cells, and its high expression was positively correlated with poor prognosis in patients with colonic NEC. Additionally, the expression of PCAT6 was positively associated with the proliferation, migration, invasion, and EMT of LCC-18 cells. Moreover, PCAT6 facilitated tumor growth, lung metastasis and EMT in xenografts. Mechanistically, PCAT6 promoted the activation of MAPK to enhance the EMT in colonic NEC by targeting miR-326. CONCLUSION In conclusion, lncRNA PCAT6 accelerates the process of colonic NEC by activating ERK/p38 MAPK signaling through targeting miR-326. These results might provide useful information for exploring the potential therapeutic targets in colonic NEC.
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Affiliation(s)
- Fei Wang
- Department of General Surgery, Nanjing Tongren Hospital, Nanjing 211100, Jiangsu Province, China
| | - Hai-Feng Mu
- Department of General Surgery, Nanjing Tongren Hospital, Nanjing 211100, Jiangsu Province, China
| | - Chun Wang
- Department of General Surgery, Nanjing Tongren Hospital, Nanjing 211100, Jiangsu Province, China
| | - Yue Tang
- Department of General Surgery, Nanjing Tongren Hospital, Nanjing 211100, Jiangsu Province, China
| | - Ming-Yuan Si
- Department of Pathology, Nanjing Tongren Hospital, Nanjing 211100, Jiangsu Province, China
| | - Jing Peng
- Department of General Surgery, Nanjing Tongren Hospital, Nanjing 211100, Jiangsu Province, China
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Zhao Y, Wang F, Lei X, Li Z, Cao Q, Jiang R, Xu C, Li K. High throughput sequencing reveals alterations in B cell receptor repertoires associated with the progression of hepatic cirrhosis to hepatocellular carcinoma. TUMORI JOURNAL 2024; 110:462-469. [PMID: 39482814 DOI: 10.1177/03008916241290638] [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] [Indexed: 11/03/2024]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is developed as a consequence of chronic liver cirrhosis, and both diseases are difficult to diagnose and differentiate. Accurate noninvasive biomarkers for HCC and liver cirrhosis are urgently needed. METHODS Here we used high-throughput sequencing to characterize the B cell receptor (BCR) repertoires from 36 HCC tumor samples and 10 liver cirrhosis (LC) tissue biopsies to understand the immune alterations during hepatic carcinogenesis. RESULTS The principal components analysis (PCA) showed that the pattern of BCR in HCC was distinct from that in LC. As measured by Clonality and Shannon indexes, the diversity of BCR repertoire was significantly lower in HCC than in LC (P < 0.01). CONCLUSION Our results corroborated that the BCR diversity and composition could be closely correlated with hepatic carcinogenesis. And BCR repertoire may be used to predict the progression of HCC and design targeting immunotherapy in the near future.
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Affiliation(s)
- Yingying Zhao
- Department of Gastroenterology, The First Affiliated Hospital of Shandong First Medical University&Shandong provincial Qianfoshan Hospital, Jinan, 250013, China
| | - Fengyan Wang
- Department of Gastroenterology, The First Affiliated Hospital of Shandong First Medical University&Shandong provincial Qianfoshan Hospital, Jinan, 250013, China
- Shandong Provincial Key Laboratory of Neuroprotective Drugs, Zibo 255400, China
| | - Xiaofei Lei
- Department of Gastroenterology, The First Affiliated Hospital of Shandong First Medical University&Shandong provincial Qianfoshan Hospital, Jinan, 250013, China
| | - Ziqiang Li
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250013, China
| | - Qiwei Cao
- Department of Pathology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Clinical Pathology, Shandong Lung Cancer Institute, Shandong Institute of Nephrology, Jinan, 250013, China
| | - Runze Jiang
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, 250013, China
| | - Changqing Xu
- Department of Gastroenterology, The First Affiliated Hospital of Shandong First Medical University&Shandong provincial Qianfoshan Hospital, Jinan, 250013, China
| | - Kun Li
- Department of Gastroenterology, The First Affiliated Hospital of Shandong First Medical University&Shandong provincial Qianfoshan Hospital, Jinan, 250013, China
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Kadian LK, Verma D, Lohani N, Yadav R, Ranga S, Gulshan G, Pal S, Kumari K, Chauhan SS. Long non-coding RNAs in cancer: multifaceted roles and potential targets for immunotherapy. Mol Cell Biochem 2024; 479:3229-3254. [PMID: 38413478 DOI: 10.1007/s11010-024-04933-1] [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: 06/06/2023] [Accepted: 01/05/2024] [Indexed: 02/29/2024]
Abstract
Cancer remains a major global health concern with high mortality rates mainly due to late diagnosis and poor prognosis. Long non-coding RNAs (lncRNAs) are emerging as key regulators of gene expression in human cancer, functioning through various mechanisms including as competing endogenous RNAs (ceRNAs) and indirectly regulating miRNA expression. LncRNAs have been found to have both oncogenic and tumor-suppressive roles in cancer, with the former promoting cancer cell proliferation, migration, invasion, and poor prognosis. Recent research has shown that lncRNAs are expressed in various immune cells and are involved in cancer cell immune escape and the modulation of the tumor microenvironment, thus highlighting their potential as targets for cancer immunotherapy. Targeting lncRNAs in cancer or immune cells could enhance the anti-tumor immune response and improve cancer immunotherapy outcomes. However, further research is required to fully understand the functional roles of lncRNAs in cancer and the immune system and their potential as targets for cancer immunotherapy. This review offers a comprehensive examination of the multifaceted roles of lncRNAs in human cancers, with a focus on their potential as targets for cancer immunotherapy. By exploring the intricate mechanisms underlying lncRNA-mediated regulation of cancer cell proliferation, invasion, and immune evasion, we provide insights into the diverse therapeutic applications of these molecules.
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Affiliation(s)
- Lokesh K Kadian
- Dept of Biochemistry, All India Institute of Medical Sciences, New Delhi, 110029, India
- Dept of Dermatology, Indiana University School of Medicine, Indianapolis, 46202, USA
| | - Deepika Verma
- Dept of Biochemistry, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Neelam Lohani
- Dept of Biochemistry, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Ritu Yadav
- Dept of Genetics, MD University, Rohtak, 124001, India
| | - Shalu Ranga
- Dept of Genetics, MD University, Rohtak, 124001, India
| | - Gulshan Gulshan
- Department of Biosciences and Bioengineering, IIT Bombay, Mumbai, Maharashtra, India
| | - Sanghapriya Pal
- Dept of Biochemistry, Maulana Azad Medical College and Associated Hospital, New Delhi, 110002, India
| | - Kiran Kumari
- Dept of Forensic Science, Lovely Professional University, Jalandhar, Punjab, 144411, India
| | - Shyam S Chauhan
- Dept of Biochemistry, All India Institute of Medical Sciences, New Delhi, 110029, India.
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Noches V, Campos-Melo D, Droppelmann CA, Strong MJ. Epigenetics in the formation of pathological aggregates in amyotrophic lateral sclerosis. Front Mol Neurosci 2024; 17:1417961. [PMID: 39290830 PMCID: PMC11405384 DOI: 10.3389/fnmol.2024.1417961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 08/23/2024] [Indexed: 09/19/2024] Open
Abstract
The progressive degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) is accompanied by the formation of a broad array of cytoplasmic and nuclear neuronal inclusions (protein aggregates) largely containing RNA-binding proteins such as TAR DNA-binding protein 43 (TDP-43) or fused in sarcoma/translocated in liposarcoma (FUS/TLS). This process is driven by a liquid-to-solid phase separation generally from proteins in membrane-less organelles giving rise to pathological biomolecular condensates. The formation of these protein aggregates suggests a fundamental alteration in the mRNA expression or the levels of the proteins involved. Considering the role of the epigenome in gene expression, alterations in DNA methylation, histone modifications, chromatin remodeling, non-coding RNAs, and RNA modifications become highly relevant to understanding how this pathological process takes effect. In this review, we explore the evidence that links epigenetic mechanisms with the formation of protein aggregates in ALS. We propose that a greater understanding of the role of the epigenome and how this inter-relates with the formation of pathological LLPS in ALS will provide an attractive therapeutic target.
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Affiliation(s)
- Veronica Noches
- Molecular Medicine Group, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Danae Campos-Melo
- Molecular Medicine Group, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Cristian A Droppelmann
- Molecular Medicine Group, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Michael J Strong
- Molecular Medicine Group, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
- Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
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Yang X, Feng H, Kim J, Ti G, Wang L, Wang K, Song D. PRR34-AS1 promotes mitochondrial division and glycolytic reprogramming in hepatocellular carcinoma cells through upregulation of MIEF2. Acta Biochim Biophys Sin (Shanghai) 2024; 56:1604-1617. [PMID: 38779765 PMCID: PMC11659787 DOI: 10.3724/abbs.2024083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 03/20/2024] [Indexed: 05/25/2024] Open
Abstract
LncRNA PRR34-AS1 overexpression promotes the proliferation and invasion of hepatocellular carcinoma (HCC) cells, but whether it affects HCC energy metabolism remains unclear. Mitochondrial division and glycolytic reprogramming play important roles in tumor development. In this study, the differential expression of PRR34-AS1 is explored via TCGA analysis, and higher levels of PRR34-AS1 are detected in patients with liver cancer than in healthy individuals. A series of experiments, such as CCK-8, PCR, and immunofluorescence staining, reveal that the proliferation, invasion, glycolysis, and mitochondrial division of PRR34-AS1-overexpressing hepatoma cells are significantly promoted. TCGA analysis and immunohistochemistry reveal high expression of the mitochondrial dynamin MIEF2 in liver cancer tissues. Dual-luciferase reporter assays confirm that miR-498 targets and binds to mitochondrial elongation factor 2 (MIEF2). In addition, we show that PRR34-AS1 can sponge miR-498. Therefore, we further investigate the effects of the lncRNA PRR34-AS1/miR-498/MIEF2 axis on the growth, glucose metabolism, and mitochondrial division in hepatocellular carcinoma cells. A series of experiments are performed on hepatocellular carcinoma cells after different treatments. The results show that the proliferative activity, invasive ability, and glycolytic level of hepatocellular carcinoma cells are decreased in HCC cells with low PRR34-AS1 expression, and the miR-498 expression level is increased in these cells. Inhibition of miR-498 or overexpression of MIEF2 restored the proliferative activity, invasive ability, glycolysis, and mitochondrial division in hepatocellular carcinoma cells. Thus, PRR34-AS1 regulates MIEF2 by sponging miR-498, thereby promoting mitochondrial division, mediating glycolytic reprogramming and ultimately driving the growth and invasion of HCC cells. Furthermore, in vivo mouse experiments yield results similar to those of the in vitro experiments, verifying the above results.
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Affiliation(s)
- Xuejing Yang
- Cancer CenterShanxi Bethune HospitalShanxi Academy of Medical SciencesTongji Shanxi HospitalThird Hospital of Shanxi Medical UniversityTaiyuan030032China
- Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Huijing Feng
- Cancer CenterShanxi Bethune HospitalShanxi Academy of Medical SciencesTongji Shanxi HospitalThird Hospital of Shanxi Medical UniversityTaiyuan030032China
- Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Jonghwa Kim
- Department of Pharmaceutical EngineeringWoosuk UniversityWanjuJeonbukSouthKorea
| | - Gang Ti
- Cancer CenterShanxi Bethune HospitalShanxi Academy of Medical SciencesTongji Shanxi HospitalThird Hospital of Shanxi Medical UniversityTaiyuan030032China
- Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Lin Wang
- Cancer CenterShanxi Bethune HospitalShanxi Academy of Medical SciencesTongji Shanxi HospitalThird Hospital of Shanxi Medical UniversityTaiyuan030032China
- Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Kun Wang
- Department of Pharmaceutical EngineeringWoosuk UniversityWanjuJeonbukSouthKorea
| | - Dong Song
- Cancer CenterShanxi Bethune HospitalShanxi Academy of Medical SciencesTongji Shanxi HospitalThird Hospital of Shanxi Medical UniversityTaiyuan030032China
- Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
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Xu J, Liu C, Qu K, Zhang J, Liu S, Meng F, Wan Y. m6A methyltransferase METTL14‑mediated RP1‑228H13.5 promotes the occurrence of liver cancer by targeting hsa‑miR‑205/ZIK1. Oncol Rep 2024; 51:59. [PMID: 38426536 PMCID: PMC10926101 DOI: 10.3892/or.2024.8718] [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: 06/19/2023] [Accepted: 01/25/2024] [Indexed: 03/02/2024] Open
Abstract
The aim of the present study was to explore the association between N6‑methyladenosine (m6A) modification regulatory gene‑related long noncoding (lnc)RNA RP1‑228H13.5 and cancer prognosis through bioinformatics analysis, as well as the impact of RP1‑228H13.5 on cell biology‑related behaviors and specific molecular mechanisms. Bioinformatics analysis was used to construct a risk model consisting of nine genes. This model can reflect the survival time and differentiation degree of cancer. Subsequently, a competing endogenous RNA network consisting of 3 m6A‑related lncRNAs, six microRNAs (miRs) and 201 mRNAs was constructed. A cell assay confirmed that RP1‑228H13.5 is significantly upregulated in liver cancer cells, which can promote liver cancer cell proliferation, migration and invasion, and inhibit liver cancer cell apoptosis. The specific molecular mechanism may be the regulation of the expression of zinc finger protein interacting with K protein 1 (ZIK1) by targeting the downstream hsa‑miR‑205. Further experiments found that the m6A methyltransferase 14, N6‑adenosine‑methyltransferase subunit mediates the regulation of miR‑205‑5p expression by RP1‑228H13.5. m6A methylation regulatory factor‑related lncRNA has an important role in cancer. The targeting of hsa‑miR‑205 by RP1‑228H13.5 to regulate ZIK1 may serve as a potential mechanism in the occurrence and development of liver cancer.
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Affiliation(s)
- Jia Xu
- Department of Hepatobiliary Pancreatic and Liver Transplantation Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
- Department of General Surgery, Leping People's Hospital, Jingdezhen, Jiangxi 333300, P.R. China
| | - Chang Liu
- Department of Hepatobiliary Pancreatic and Liver Transplantation Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Kai Qu
- Department of Hepatobiliary Pancreatic and Liver Transplantation Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Jingyao Zhang
- Department of SICU, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Sinan Liu
- Department of SICU, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Fandi Meng
- Department of Geriatric Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Yong Wan
- Department of Geriatric Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
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Ding Y, Gong Y, Zeng H, Song G, Yu Z, Fu B, Liu Y, Huang D, Zhong Y. ZNF765 is a prognostic biomarker of hepatocellular carcinoma associated with cell cycle, immune infiltration, m 6A modification, and drug susceptibility. Aging (Albany NY) 2023; 15:6179-6211. [PMID: 37400985 PMCID: PMC10373972 DOI: 10.18632/aging.204827] [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: 09/21/2022] [Accepted: 06/05/2023] [Indexed: 07/05/2023]
Abstract
Hepatocellular carcinoma (HCC) is an ongoing challenge worldwide. Zinc finger protein 765 (ZNF765) is an important zinc finger protein that is related to the permeability of the blood-tumor barrier. However, the role of ZNF765 in HCC is unclear. This study evaluated the expression of ZNF765 in hepatocellular carcinoma and the impact of its expression on patient prognosis based on The Cancer Genome Atlas (TCGA). Immunohistochemical assays (IHC) were used to examine protein expression. Besides, a colony formation assay was used to examine cell viability. We also explored the relationship between ZNF765 and chemokines in the HCCLM3 cells by qRT-PCR. Moreover, we examined the effect of ZNF765 on cell resistance by measurement of the maximum half-inhibitory concentration. Our research revealed that ZNF765 expression in HCC samples was higher than that in normal samples, whose upregulation was not conducive to the prognosis. The results of GO, KEGG, and GSEA showed that ZNF765 was associated with the cell cycle and immune infiltration. Furthermore, we confirmed that the expression of ZNF765 had a strong connection with the infiltration level of various immune cells, such as B cells, CD4+ T cells, macrophages, and neutrophils. In addition, we found that ZNF765 was associated with m6A modification, which may affect the progression of HCC. Finally, drug sensitivity testing found that patients with HCC were sensitive to 20 drugs when they expressed high levels of ZNF765. In conclusion, ZNF765 may be a prognostic biomarker related to cell cycle, immune infiltration, m6A modification, and drug sensitivity for hepatocellular carcinoma.
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Affiliation(s)
- Yongqi Ding
- Second Affiliated Hospital of Nanchang University, Nanchang, China
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Yiyang Gong
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Hong Zeng
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Gelin Song
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Zichuan Yu
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Bidong Fu
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Yue Liu
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Da Huang
- Department of Thyroid Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yanying Zhong
- Department of Obstetrics and Gynecology, Second Affiliated Hospital of Nanchang University, Nanchang, China
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Yang L, Jia X, Fu Y, Tian J, Liu Y, Lin J. Creation of a Prognostic Model Using Cuproptosis-Associated Long Noncoding RNAs in Hepatocellular Carcinoma. Int J Mol Sci 2023; 24:9987. [PMID: 37373132 DOI: 10.3390/ijms24129987] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 06/03/2023] [Accepted: 06/06/2023] [Indexed: 06/29/2023] Open
Abstract
Cuproptosis is an unusual form of cell death caused by copper accumulation in mitochondria. Cuproptosis is associated with hepatocellular carcinoma (HCC). Long noncoding RNAs (LncRNAs) have been shown to be effective prognostic biomarkers, yet the link between lncRNAs and cuproptosis remains unclear. We aimed to build a prognostic model of lncRNA risk and explore potential biomarkers of cuproptosis in HCC. Pearson correlations were used to derive lncRNAs co-expressed in cuproptosis. The model was constructed using Cox, Lasso, and multivariate Cox regressions. Kaplan-Meier survival analysis, principal components analysis, receiver operating characteristic curve, and nomogram analyses were carried out for validation. Seven lncRNAs were identified as prognostic factors. A risk model was an independent prognostic predictor. Among these seven lncRNAs, prostate cancer associated transcript 6 (PCAT6) is highly expressed in different types of cancer, activating Wnt, PI3K/Akt/mTOR, and other pathways; therefore, we performed further functional validation of PCAT6 in HCC. Reverse transcription-polymerase chain reaction results showed that PCAT6 was aberrantly highly expressed in HCC cell lines (HepG2 and Hep3B) compared to LO2 (normal hepatocytes). When its expression was knocked down, cells proliferated and migrated less. PCAT6 might be a potential biomarker for predicting prognosis in HCC.
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Affiliation(s)
- Lihong Yang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300000, China
| | - Xiao Jia
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300000, China
| | - Yueyue Fu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300000, China
| | - Jiao Tian
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300000, China
| | - Yijin Liu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300000, China
| | - Jianping Lin
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300000, China
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Zhang C, Peng L, Gu H, Wang J, Wang Y, Xu Z. ANXA10 is a prognostic biomarker and suppressor of hepatocellular carcinoma: a bioinformatics analysis and experimental validation. Sci Rep 2023; 13:1583. [PMID: 36709331 PMCID: PMC9884230 DOI: 10.1038/s41598-023-28527-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 01/19/2023] [Indexed: 01/30/2023] Open
Abstract
Liver hepatocellular carcinoma (LIHC) is one of the main cancers worldwide and has high morbidity and mortality rates. Although previous studies have shown that ANXA10 is expressed at low levels in LIHC tumor tissues, the biological function of ANXA10 in LIHC is still unclear. Therefore, we utilized TCGA, TIMER, GEPIA2, TISIDB, LinkedOmics, ssGSEA algorithms and CIBERSORT methodology to preliminarily evaluate the potential mechanism of ANXA10 in LIHC. In vitro experiments were used to further verify some functions of ANXA10. Consequently, we found that ANXA10 mRNA/protein expression was downregulated in LIHC tissue compared to normal tissue. ANXA10 was significantly linked with clinicopathological features, immunocytes, multiple cancer-related pathways, m6A modification and a ceRNA network. A three-gene prognostic signature rooted in ANXA10-related immunomodulators was determined and found to be an independent prognostic predictor. A nomogram was constructed to predict survival with good accuracy. Additionally, in vitro trials revealed that ANXA10 upregulation inhibited LIHC cell proliferation and migration. This study reveals that ANXA10 may serve as a prognostic marker and promising therapeutic target in LIHC clinical practice through various biologic functions.
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Affiliation(s)
- Chaohua Zhang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400000, China
| | - Linglong Peng
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400000, China
| | - Haitao Gu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400000, China
| | - Jijian Wang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400000, China
| | - Yaxu Wang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400000, China
| | - Zhiquan Xu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400000, China.
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Cuproptosis-Related LncRNA Signature for Predicting Prognosis of Hepatocellular Carcinoma: A Comprehensive Analysis. DISEASE MARKERS 2022; 2022:3265212. [PMID: 36452343 PMCID: PMC9705118 DOI: 10.1155/2022/3265212] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 10/21/2022] [Accepted: 10/25/2022] [Indexed: 11/23/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide and has a poor prognosis. Cuproptosis is a novel mode of cell death that has only recently been discovered. Considering the critical role of lncRNAs in liver cancer development, the aim of this study was to construct a prognostic signature based on cuproptosis-related lncRNAs (CRlncRNAs). We downloaded RNA-sequencing data and corresponding clinical information of patients with HCC from The Cancer Genome Atlas (TCGA) database. To verify the robustness of the model, we added an external validation set obtained from the Gene Expression Omnibus (GEO): GSE40144. In addition, we identified the cuproptosis-related genes (CRGs) based on previous reports. Pearson correlation analysis, univariate Cox regression, and least absolute shrinkage and selection operator (LASSO) Cox regression analysis were utilized to screen for genes associated with prognosis. On this basis, multivariate Cox regression and stepAIC were used to further construct and optimize the prognostic model. The simplified signature with the lowest Akaike information criterion (AIC) value was considered the prognostic signature. Seven different algorithms were used to perform immune infiltration analysis. The single-sample Gene Set Enrichment Analysis (ssGSEA) algorithm was utilized to find the difference in immune function between the high- and low-risk groups. Finally, in vitro experiments were performed by quantitative real-time PCR (qRT-PCR) analysis using HCC cell lines to validate the expression of prognostic genes. We identified 3 lncRNAs (CYTOR, LINC00205, and LINC01184) as independent risk factors for HCC. The receiver operating characteristic (ROC) curves calculated that the AUC at 1, 3, and 5 years reached 0.717, 0.633, and 0.607, respectively. The expression levels of 41 immune checkpoints differed significantly between the high- and low-risk groups, and there were significant differences in sensitivity to immunotherapy between the high- and low-risk groups. The risk model could also serve as a promising predictor of immunotherapeutic response, which has been verified by the TIDE algorithm (p < 0.001). Overall, we propose a signature related to CRlncRNAs that can be used to predict the prognosis of HCC patients, which was validated in external cohort and in vitro experiments.
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Hashemi M, Moosavi MS, Abed HM, Dehghani M, Aalipour M, Heydari EA, Behroozaghdam M, Entezari M, Salimimoghadam S, Gunduz ES, Taheriazam A, Mirzaei S, Samarghandian S. Long non-coding RNA (lncRNA) H19 in human cancer: From proliferation and metastasis to therapy. Pharmacol Res 2022; 184:106418. [PMID: 36038043 DOI: 10.1016/j.phrs.2022.106418] [Citation(s) in RCA: 102] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/24/2022] [Accepted: 08/24/2022] [Indexed: 02/07/2023]
Abstract
Initiation and development of cancer depend on multiple factors that mutations in genes and epigenetic level can be considered as important drivers. Epigenetic factors include a large family of members and understanding their function in cancer has been a hot topic. LncRNAs are RNA molecules with no capacity in synthesis of proteins, and they have regulatory functions in cells. LncRNAs are localized in nucleus and cytoplasm, and their abnormal expression is related to development of tumor. This manuscript emphasizes on the role of lncRNA H19 in various cancers and its association with tumor hallmarks. The function of lncRNA H19 in most tumors is oncogenic and therefore, tumor cells increase its expression for promoting their progression. LncRNA H19 contributes to enhancing growth and cell cycle of cancers and by EMT induction, it is able to elevate metastasis rate. Silencing H19 induces apoptotic cell death and disrupts progression of tumors. LncRNA H19 triggers chemo- and radio-resistance in cancer cells. miRNAs are dually upregulated/down-regulated by lncRNA H19 in increasing tumor progression. Anti-cancer agents reduce lncRNA H19 in impairing tumor progression and increasing therapy sensitivity. A number of downstream targets and molecular pathways for lncRNA H19 have been detected in cancers including miRNAs, RUNX1, STAT3, β-catenin, Akt2 and FOXM1. Clinical studies have revealed potential of lncRNA H19 as biomarker and its association with poor prognosis. LncRNA H19 can be transferred to cancer cells via exosomes in enhancing their progression.
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Affiliation(s)
- Mehrdad Hashemi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Marzieh Sadat Moosavi
- Department of Biochemistry, Faculty of Advanced Science and Technology, Tehran Medical Science, Islamic Azad University, Tehran, Iran
| | - Hedyeh Maghareh Abed
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Maryam Dehghani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Masoumeh Aalipour
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Elaheh Ali Heydari
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mitra Behroozaghdam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Maliheh Entezari
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Shokooh Salimimoghadam
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Emine Selda Gunduz
- Vocational School of Health Services, Department of First and Emergency Aid, Akdeniz University, Antalya, Turkey.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran.
| | - Saeed Samarghandian
- Healthy Ageing Research Centre, Neyshabur University of Medical Sciences, Neyshabur, Iran.
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Heterogeneous nuclear ribonucleoprotein A/B: an emerging group of cancer biomarkers and therapeutic targets. Cell Death Dis 2022; 8:337. [PMID: 35879279 PMCID: PMC9314375 DOI: 10.1038/s41420-022-01129-8] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/11/2022] [Accepted: 07/13/2022] [Indexed: 11/20/2022]
Abstract
Heterogeneous nuclear ribonucleoprotein A/B (hnRNPA/B) is one of the core members of the RNA binding protein (RBP) hnRNPs family, including four main subtypes, A0, A1, A2/B1 and A3, which share the similar structure and functions. With the advance in understanding the molecular biology of hnRNPA/B, it has been gradually revealed that hnRNPA/B plays a critical role in almost the entire steps of RNA life cycle and its aberrant expression and mutation have important effects on the occurrence and progression of various cancers. This review focuses on the clinical significance of hnRNPA/B in various cancers and systematically summarizes its biological function and molecular mechanisms.
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Whyte SS, Karns R, Min K, Cho J, Lee S, Lake C, Bondoc A, Yoon J, Shin S. Integrated analysis using ToppMiR uncovers altered miRNA- mRNA regulatory networks in pediatric hepatocellular carcinoma-A pilot study. Cancer Rep (Hoboken) 2022; 6:e1685. [PMID: 35859536 PMCID: PMC9875636 DOI: 10.1002/cnr2.1685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 06/23/2022] [Accepted: 07/12/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Pediatric hepatocellular carcinoma (HCC) is a group of liver cancers whose mechanisms behind their pathogenesis and progression are poorly understood. AIM We aimed to identify alterations in the expression of miRNAs and their putative target mRNAs in not only tumor tissues of patients with pediatric HCC but also in corresponding non-tumorous background livers by using liver tissues without underlying liver disease as a control. METHODS AND RESULTS We performed a small-scale miRNA and mRNA profiling of pediatric HCC (consisting of fibrolamellar carcinoma [FLC] and non-FLC HCC) and paired liver tissues to identify miRNAs whose expression levels differed significantly from control livers without underlying liver disease. ToppMiR was used to prioritize both miRNAs and their putative target mRNAs in a gene-annotation network, and the mRNA profile was used to refine the prioritization. Our analysis generated prioritized lists of miRNAs and mRNAs from the following three sets of analyses: (a) pediatric HCC versus control; (b) FLC versus control; and (c) corresponding non-tumorous background liver tissues from the same patients with pediatric HCC versus control. No liver disease liver tissues were used as the control group for all analyses. Many miRNAs whose expressions were deregulated in pediatric HCC were consistent with their roles in adult HCC and/or other non-hepatic cancers. Our gene ontology analysis of target mRNAs revealed enrichment of biological processes related to the sustenance and propagation of cancer and significant downregulation of metabolic processes. CONCLUSION Our pilot study indicates that alterations in miRNA-mRNA networks were detected in not only tumor tissues but also corresponding non-tumorous liver tissues from patients with pediatric HCC, suggesting multi-faceted roles of miRNAs in disease progression. Our results may lead to novel hypotheses for future large-scale studies.
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Affiliation(s)
- Senyo S. Whyte
- Division of Pediatric General and Thoracic SurgeryCincinnati Children's Hospital Medical CenterCincinnatiOhioUSA
| | - Rebekah Karns
- Division of Gastroenterology, Hepatology & NutritionCincinnati Children's Hospital Medical CenterCincinnatiOhioUSA
| | - Kyung‐Won Min
- Department of BiologyGangneung‐Wonju National UniversityGangneungRepublic of Korea
| | - Jung‐Hyun Cho
- Department of Biochemistry and Molecular BiologyMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - Sanghoon Lee
- Division of Pediatric General and Thoracic SurgeryCincinnati Children's Hospital Medical CenterCincinnatiOhioUSA
| | - Charissa Lake
- Division of Pediatric General and Thoracic SurgeryCincinnati Children's Hospital Medical CenterCincinnatiOhioUSA
| | - Alexander Bondoc
- Division of Pediatric General and Thoracic SurgeryCincinnati Children's Hospital Medical CenterCincinnatiOhioUSA,Department of SurgeryUniversity of Cincinnati College of MedicineCincinnatiOhioUSA
| | - Je‐Hyun Yoon
- Department of Biochemistry and Molecular BiologyMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - Soona Shin
- Division of Pediatric General and Thoracic SurgeryCincinnati Children's Hospital Medical CenterCincinnatiOhioUSA,Department of SurgeryUniversity of Cincinnati College of MedicineCincinnatiOhioUSA
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14
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Alternative Splicing, Epigenetic Modifications and Cancer: A Dangerous Triangle, or a Hopeful One? Cancers (Basel) 2022; 14:cancers14030560. [PMID: 35158828 PMCID: PMC8833605 DOI: 10.3390/cancers14030560] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 01/15/2022] [Accepted: 01/18/2022] [Indexed: 12/15/2022] Open
Abstract
Simple Summary Epigenetics studies the alteration of gene expression without changing DNA sequence and very often, epigenetic dysregulation causes cancer. Alternative splicing is a mechanism that results in the production of several mRNA isoforms from a single gene and aberrant splicing is also a frequent cause of cancer. The present review is built on the interrelations of epigenetics and alternative splicing. In an intuitive way, we say that epigenetic modifications and alternative splicing are at two vertices of a triangle, the third vertex being occupied by cancer. Interconnection between alternative splicing and epigenetic modifications occurs backward and forward and the mechanisms involved are widely reviewed. These connections also provide novel diagnostic or prognostic tools, which are listed. Finally, as epigenetic alterations are reversible and aberrant alternative splicing may be corrected, the therapeutic possibilities to break the triangle are discussed. Abstract The alteration of epigenetic modifications often causes cancer onset and development. In a similar way, aberrant alternative splicing may result in oncogenic products. These issues have often been individually reviewed, but there is a growing body of evidence for the interconnection of both causes of cancer. Actually, aberrant splicing may result from abnormal epigenetic signalization and epigenetic factors may be altered by alternative splicing. In this way, the interrelation between epigenetic marks and alternative splicing form the base of a triangle, while cancer may be placed at the vertex. The present review centers on the interconnections at the triangle base, i.e., between alternative splicing and epigenetic modifications, which may result in neoplastic transformations. The effects of different epigenetic factors, including DNA and histone modifications, the binding of non-coding RNAs and the alterations of chromatin organization on alternative splicing resulting in cancer are first considered. Other less-frequently considered questions, such as the epigenetic regulation of the splicing machinery, the aberrant splicing of epigenetic writers, readers and erasers, etc., are next reviewed in their connection with cancer. The knowledge of the above-mentioned relationships has allowed increasing the collection of biomarkers potentially useful as cancer diagnostic and/or prognostic tools. Finally, taking into account on one hand that epigenetic changes are reversible, and some epigenetic drugs already exist and, on the other hand, that drugs intended for reversing aberrations in alternative splicing, therapeutic possibilities for breaking the mentioned cancer-related triangle are discussed.
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PCAT6 May Be a Whistler and Checkpoint Target for Precision Therapy in Human Cancers. Cancers (Basel) 2021; 13:cancers13236101. [PMID: 34885209 PMCID: PMC8656686 DOI: 10.3390/cancers13236101] [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: 10/19/2021] [Revised: 11/21/2021] [Accepted: 11/29/2021] [Indexed: 11/17/2022] Open
Abstract
Simple Summary Prostate cancer-associated transcript 6 (PCAT6), as a newly discovered carcinogenic long non-coding RNA (lncRNA), is abnormally expressed in multiple diseases. With the accumulation of studies on PCAT6, we have a deeper understanding of its biological functions and mechanisms. Therefore, in this review, the various molecular mechanisms by which PCAT6 promotes multiple tumorigenesis and progression are summarized and discussed. Furthermore, its potential diagnostic, prognostic, and immunotherapeutic values are also clarified. Abstract LncRNAs are involved in the occurrence and progressions of multiple cancers. Emerging evidence has shown that PCAT6, a newly discovered carcinogenic lncRNA, is abnormally elevated in various human malignant tumors. Until now, PCAT6 has been found to sponge various miRNAs to activate the signaling pathways, which further affects tumor cell proliferation, migration, invasion, cycle, apoptosis, radioresistance, and chemoresistance. Moreover, PCAT6 has been shown to exert biological functions beyond ceRNAs. In this review, we summarize the biological characteristics of PCAT6 in a variety of human malignancies and describe the biological mechanisms by which PCAT6 can facilitate tumor progression. Finally, we discuss its diagnostic and prognostic values and clinical applications in various human malignancies.
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Ghafouri-Fard S, Khoshbakht T, Taheri M, Ebrahimzadeh K. A review on the role of PCAT6 lncRNA in tumorigenesis. Biomed Pharmacother 2021; 142:112010. [PMID: 34388529 DOI: 10.1016/j.biopha.2021.112010] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Revised: 08/02/2021] [Accepted: 08/03/2021] [Indexed: 12/18/2022] Open
Abstract
Prostate cancer-associated transcript 6 (PCAT6) is a long non-coding RNA (lncRNA) firstly identified in 2013 through an integrative genomic analysis of different cancer tissues. This oncogenic lncRNA has been found to regulate carcinogenesis process in different tissues, including breast, ovary, stomach, bladder, colon, pancreas and liver. The role of PCAT6 in sequestering certain microRNAs has been well established. For instance, miR-4723-5p, miR-185-5p, miR-143-3p, miR-30, miR-15a, miR-513a and miR-204, and miR-326 are among those being sequestered by PCAT6. Over-expression of PCAT6 has been associated with poor clinical outcomes in diverse types of cancers including ovarian, bladder, colorectal and pancreatic cancers. In the present review, we summarize the impact of PCAT6 in the development of diverse types of cancers, based on the results of functional studies in cell lines, experiments in xenograft models of cancers and expression studies in samples obtained from human subjects.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Tayyebeh Khoshbakht
- Men's Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Taheri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Kaveh Ebrahimzadeh
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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