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1
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Zamudio-Cuevas Y, Fernández-Torres J, Martínez-Flores K, López-Macay A. The importance of ALPK1 kinase functionality as a potential biomarker for inflammatory diseases. Mol Biol Rep 2025; 52:575. [PMID: 40493324 DOI: 10.1007/s11033-025-10528-w] [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: 11/22/2024] [Accepted: 04/17/2025] [Indexed: 06/12/2025]
Abstract
Currently, molecules with the potential to act as biomarkers in the prevention and early diagnosis of diseases are being sought. The above implies that these molecules play key roles in specific stages of the disease or are associated with them. However, before proposing these types of molecules as biomarkers or therapeutic targets, it is essential to thoroughly understand their action mechanism. In this work, the most relevant findings on the function, regulation, disease´s association studies of the ALPK1 protein with kinase activity (α kinase-1) are highlighted. Unlike other protein kinases, ALPK1 specifically recognizes the conformation part of the alpha helix as the phosphorylation site. The objective of this review is to analyze the functions of ALPK1 in different pathologies and to determine whether this protein plays an important role in these diseases, and if it could be used as a biomarker for the progression or prediction of an inflammatory disease.
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Affiliation(s)
- Yessica Zamudio-Cuevas
- Synovial Fluid Laboratory, Instituto Nacional de Rehabilitación, Calzada México-Xochimilco N.289, Arenal de Guadalupe, C. P. 14389, Tlalpan, CDMX, Mexico
| | - Javier Fernández-Torres
- Synovial Fluid Laboratory, Instituto Nacional de Rehabilitación, Calzada México-Xochimilco N.289, Arenal de Guadalupe, C. P. 14389, Tlalpan, CDMX, Mexico
| | - Karina Martínez-Flores
- Synovial Fluid Laboratory, Instituto Nacional de Rehabilitación, Calzada México-Xochimilco N.289, Arenal de Guadalupe, C. P. 14389, Tlalpan, CDMX, Mexico
| | - Ambar López-Macay
- Synovial Fluid Laboratory, Instituto Nacional de Rehabilitación, Calzada México-Xochimilco N.289, Arenal de Guadalupe, C. P. 14389, Tlalpan, CDMX, Mexico.
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2
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Zhao S, Chen F, Hu L, Li X, Gao Z, Chen M, Wang X, Song Z. Long non-coding rnas as key modulators of the immune microenvironment in hepatocellular carcinoma: implications for Immunotherapy. Front Immunol 2025; 16:1523190. [PMID: 40352941 PMCID: PMC12061944 DOI: 10.3389/fimmu.2025.1523190] [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: 11/05/2024] [Accepted: 04/02/2025] [Indexed: 05/14/2025] Open
Abstract
Hepatocellular carcinoma (HCC) represents a major global health challenge, characterized by its complex immune microenvironment that plays a pivotal role in tumor progression and therapeutic response. Long non-coding RNAs (lncRNAs) have emerged as critical regulators of various biological processes, including gene expression and immune cell function. This review explores the multifaceted roles of lncRNAs in modulating the immune microenvironment of HCC. We discuss how lncRNAs influence the infiltration and activation of immune cells, shape cytokine profiles, and regulate immune checkpoint molecules, thereby affecting the tumor's immunogenicity and response to immunotherapy. Furthermore, we highlight specific lncRNAs implicated in immune evasion mechanisms and their potential as biomarkers and therapeutic targets. By elucidating the intricate interplay between lncRNAs and the immune landscape in HCC, this review aims to provide insights into novel strategies for enhancing immunotherapeutic efficacy and improving patient outcomes.
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Affiliation(s)
| | | | | | | | | | - Minjie Chen
- Department of Surgery, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Xiaoguang Wang
- Department of Surgery, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Zhengwei Song
- Department of Surgery, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
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3
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Yu X, Xu H, Xing Y, Sun D, Li D, Shi J, Sui G, Li G. Identifying Essential Hub Genes and circRNA-Regulated ceRNA Networks in Hepatocellular Carcinoma. Int J Mol Sci 2025; 26:1408. [PMID: 40003874 PMCID: PMC11855757 DOI: 10.3390/ijms26041408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Revised: 02/05/2025] [Accepted: 02/05/2025] [Indexed: 02/27/2025] Open
Abstract
Competitive endogenous RNAs (ceRNAs) absorb microRNAs and subsequently promote corresponding mRNA and long noncoding RNA (lncRNA) expression, which may alter cancer cell malignancy. Thus, dissecting ceRNA networks may reveal novel targets in cancer therapies. In this study, we analyzed differentially expressed genes (DEGs) of mRNAs and lncRNAs, and differentially expressed microRNAs (DE-miRNAs) and circular RNAs (DE-circRNAs) extracted from high-throughput sequencing datasets of hepatocellular carcinoma patients. Based on these data, we identified 26 gene modules using weighted gene co-expression network analysis (WGCNA), of which 5 were associated with tumor differentiation. In these modules, 269 genes were identified by GO and KEGG enrichment and patient's survival correlation analyses. Next, 40 DE-miRNAs, each of which potentially bound a pair of DE-circRNA and hub gene, were discovered. Together with 201 circRNAs and 24 hub genes potentially bound by these miRNAs, 1151 ceRNA networks were constructed. Among them, 75 ceRNA networks consisting of 24 circRNAs, 28 miRNAs and 17 hub genes showed a positive circRNA-hub gene correlation. For validation, we carried out experiments for 4 randomly selected circRNAs regulating 19 potential ceRNA networks and verified 5 of them. This study represents a powerful strategy to identify essential gene networks and provides insights into designing effective therapeutic strategies.
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Affiliation(s)
- Xiaoqian Yu
- College of Life Science, Northeast Forestry University, Harbin 150040, China; (X.Y.); (H.X.); (Y.X.); (D.S.); (D.L.); (J.S.)
| | - Hao Xu
- College of Life Science, Northeast Forestry University, Harbin 150040, China; (X.Y.); (H.X.); (Y.X.); (D.S.); (D.L.); (J.S.)
| | - Yutao Xing
- College of Life Science, Northeast Forestry University, Harbin 150040, China; (X.Y.); (H.X.); (Y.X.); (D.S.); (D.L.); (J.S.)
| | - Dehui Sun
- College of Life Science, Northeast Forestry University, Harbin 150040, China; (X.Y.); (H.X.); (Y.X.); (D.S.); (D.L.); (J.S.)
| | - Dangdang Li
- College of Life Science, Northeast Forestry University, Harbin 150040, China; (X.Y.); (H.X.); (Y.X.); (D.S.); (D.L.); (J.S.)
| | - Jinming Shi
- College of Life Science, Northeast Forestry University, Harbin 150040, China; (X.Y.); (H.X.); (Y.X.); (D.S.); (D.L.); (J.S.)
| | - Guangchao Sui
- College of Life Science, Northeast Forestry University, Harbin 150040, China; (X.Y.); (H.X.); (Y.X.); (D.S.); (D.L.); (J.S.)
| | - Guangyue Li
- College of Life Science, Northeast Forestry University, Harbin 150040, China; (X.Y.); (H.X.); (Y.X.); (D.S.); (D.L.); (J.S.)
- Institute of Biology, Westlake Institute for Advanced Study, Hangzhou 310030, China
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Solhi R, Pourhamzeh M, Zarrabi A, Hassan M, Mirzaei H, Vosough M. Novel biomarkers for monitoring and management of hepatocellular carcinoma. Cancer Cell Int 2024; 24:428. [PMID: 39719624 DOI: 10.1186/s12935-024-03600-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Accepted: 12/05/2024] [Indexed: 12/26/2024] Open
Abstract
Due to current challenges in the early detection, less than 40% of individuals diagnosed with hepatocellular carcinoma (HCC) are viable candidates for surgical intervention. Therefore, validating and launching of a novel precise diagnostic approach is essential for early diagnosis. Based on developing evidence using circulating tumor cells and their derivatives, circulating miRNAs, and extracellular vesicles (EVs), liquid biopsy may offer a reliable platform for the HCC's early diagnosis. Each liquid biopsy analyte may provide significant areas for diagnosis, prognostic assessment, and treatment monitoring of HCC patients depending on its kind, sensitivity, and specificity. The current review addresses potential clinical applications, current research, and future developments for liquid biopsy in HCC management.
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Affiliation(s)
- Roya Solhi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Mahsa Pourhamzeh
- Departments of Pathology and Medicine, UC San Diego, La Jolla, CA, USA
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul, 34396, Turkey
| | - Moustapha Hassan
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran.
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.
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5
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Gong B, Qu T, Zhang J, Jia Y, Song Z, Chen C, Yang J, Wang C, Liu Y, Jin Y, Cao W, Zhao Q. Downregulation of ABLIM3 confers to the metastasis of neuroblastoma via regulating the cell adhesion molecules pathway. Comput Struct Biotechnol J 2024; 23:1547-1561. [PMID: 38645433 PMCID: PMC11031727 DOI: 10.1016/j.csbj.2024.04.024] [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: 01/15/2024] [Revised: 03/30/2024] [Accepted: 04/07/2024] [Indexed: 04/23/2024] Open
Abstract
Neuroblastoma (NB) is the most prevalent extracranial solid tumor in pediatric patients, and its treatment failure often associated with metastasis. In this study, LASSO, SVM-RFE, and random forest tree algorithms, was used to identify the pivotal gene involved in NB metastasis. NB cell lines (SK-N-AS and SK-N-BE2), in conjunction with NB tissue were used for further study. ABLIM3 was identified as the hub gene and can be an independent prognostic factor for patients with NB. The immunohistochemical analysis revealed that ABLIM3 is negatively correlated with the metastasis of NB. Patients with low expression of ABLIM3 had a poor prognosis. High ABLIM3 expression correlated with APC co-stimulation and Type1 IFN response, and TIDE analysis indicated that patients with low ABLIM3 expression exhibited enhanced responses to immunotherapy. Downregulation of ABLIM3 by shRNA transfection increased the migration and invasion ability of NB cells. Gene Set Enrichment Analysis (GSEA) revealed that genes associated with ABLIM3 were primarily enriched in the cell adhesion molecules (CAMs) pathway. RT-qPCR and western blot analyses demonstrated that downregulation of ABLIM3 led to decreased expression of ITGA3, ITGA8, and KRT19, the key components of CAMs. This study indicated that ABLIM3 can be an independent prognostic factor for NB patients, and CAMs may mediate the effect of ABLIM3 on the metastasis of NB, suggesting that ABLIM3 is a potential therapeutic target for NB metastasis, which provides a novel strategy for future research and treatment strategies for NB patients.
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Affiliation(s)
- Baocheng Gong
- Department of Pediatric Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Tongyuan Qu
- Department of Pediatric Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China
- Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Jiaojiao Zhang
- Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Yubin Jia
- Department of Pediatric Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Zian Song
- Department of Pediatric Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Chong Chen
- Department of Clinical Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Jiaxing Yang
- Department of Pediatric Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Chaoyu Wang
- Department of Pediatric Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Yun Liu
- Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Yan Jin
- Department of Pediatric Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Wenfeng Cao
- Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Qiang Zhao
- Department of Pediatric Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China
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6
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Chen P, Ni S, Liu QF, Ou-Yang L. Retinol intake and PCOS management: a plasma metabolite and protein analysis via Mendelian randomization and NHANES 2011-2016. Front Nutr 2024; 11:1434648. [PMID: 39507894 PMCID: PMC11537956 DOI: 10.3389/fnut.2024.1434648] [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: 05/18/2024] [Accepted: 10/09/2024] [Indexed: 11/08/2024] Open
Abstract
Background Polycystic Ovary Syndrome (PCOS) represents a complex endocrine disorder characterized by a significant interplay with metabolic dysfunction and obesity. This research endeavors to elucidate the causal dynamics among plasma metabolites, proteins, and PCOS, alongside Body Mass Index (BMI), to pinpoint prospective therapeutic interventions. Methods This investigation employed Mendelian randomization (MR) analyses combined with data derived from the National Health and Nutrition Examination Survey (NHANES) to explore the relationships between 1,400 plasma metabolites and PCOS, factoring in BMI adjustments. Additionally, the study examined the influence of plasma proteins and performed a retrospective cross-sectional analysis focusing on retinol consumption and testosterone levels. Results MR analyses showed metabolite Glycosyl-N-(2-hydroxynervonoyl)-sphingosine (GNS) and protein Keratin 19 (KRT19) were identified as significant markers in the context of PCOS and BMI adjustments. A Phenome-Wide Association Study (PheWAS) underscored the linkage between KRT19 and BMI, while gene-drug interaction findings demonstrated a connection between KRT19 and retinol. Analysis for NHANES data disclosed a negative correlation between retinol intake and testosterone levels, particularly within normal weight and obese cohorts, suggesting the feasibility of dietary interventions for PCOS management. Conclusion The study sheds light on the intricate interactions between plasma metabolites, proteins, and PCOS, considering BMI variations, and highlights KRT19 protein as a promising therapeutic target. The outcomes support the integration of retinol consumption into dietary strategies to regulate testosterone levels and potentially alleviate PCOS symptoms, underscoring the necessity for personalized nutritional and therapeutic approaches in the effective management of PCOS.
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Affiliation(s)
| | | | - Qi-Fang Liu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
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Xia Y, Yu X, Yuan Z, Yang Y, Liu Y. Whole-Transcriptome Analysis Reveals Potential CeRNA Regulatory Mechanism in Takifugu rubripes against Cryptocaryon irritans Infection. BIOLOGY 2024; 13:788. [PMID: 39452097 PMCID: PMC11504436 DOI: 10.3390/biology13100788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 08/21/2024] [Accepted: 08/29/2024] [Indexed: 10/26/2024]
Abstract
Cryptocaryon irritans (C. irritans) is a proto-ciliate parasite that infects marine fishes, including the cultured species Takifugu rubripes (T. rubripes), causing disease and potential mortality. In host organisms, infection by parasites triggers an immune response that is modulated by regulatory elements including proteins and non-coding RNAs. In this study, the whole transcriptome RNA sequencing of T. rubripes gill tissue before and after infection with C. irritans was performed to reveal the competitive endogenous RNA (ceRNA) regulatory network. Histomorphology revealed gill segment swelling and parasitic invasion in the infected group. The analysis identified 18 differentially expressed miRNAs (DEMs), 214 lncRNAs (DELs), 2501 genes (DEGs), and 7 circRNAs (DECs) in the infected group. Gene Ontology (GO) enrichment analysis revealed that these genes were notably enriched in the Wnt signaling pathway and mTOR signaling pathway. The co-expression networks (lncRNA/circRNA-miRNA-mRNA) were constructed based on correlation analysis of the differentially expressed RNAs. Further analysis suggested that the LOC105418663-circ_0000361-fru-miR-204a-fzd3a ceRNA axis was potentially involved in the regulation of immune responses against C. irritans infection. Finally, the expression levels of DEG, DEL, and DEM were validated. This study reveals the regulatory mechanism of a candidate ceRNA network, providing insights into the potential mechanism of T. rubripes' infection with C. irritans.
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Affiliation(s)
- Yuqing Xia
- Key Laboratory of Environment Controlled Aquaculture, Dalian Ocean University, Ministry of Education, 52 Heishijiao Street, Dalian 116023, China; (Y.X.); (Y.Y.)
- College of Fisheries and Life Science, Dalian Ocean University, 52 Heishijiao Street, Dalian 116023, China
| | - Xiaoqing Yu
- Key Laboratory of Environment Controlled Aquaculture, Dalian Ocean University, Ministry of Education, 52 Heishijiao Street, Dalian 116023, China; (Y.X.); (Y.Y.)
| | - Zhen Yuan
- Key Laboratory of Environment Controlled Aquaculture, Dalian Ocean University, Ministry of Education, 52 Heishijiao Street, Dalian 116023, China; (Y.X.); (Y.Y.)
| | - Yi Yang
- Key Laboratory of Environment Controlled Aquaculture, Dalian Ocean University, Ministry of Education, 52 Heishijiao Street, Dalian 116023, China; (Y.X.); (Y.Y.)
| | - Ying Liu
- Key Laboratory of Environment Controlled Aquaculture, Dalian Ocean University, Ministry of Education, 52 Heishijiao Street, Dalian 116023, China; (Y.X.); (Y.Y.)
- College of Biosystems Engineering and Food Science, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China
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8
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Zhang S, Xia Y, Chen W, Dong H, Cui B, Liu C, Liu Z, Wang F, Du J. Regulation and Therapeutic Application of Long non-Coding RNA in Tumor Angiogenesis. Technol Cancer Res Treat 2024; 23:15330338241273239. [PMID: 39110070 PMCID: PMC11307360 DOI: 10.1177/15330338241273239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Revised: 06/20/2024] [Accepted: 07/08/2024] [Indexed: 08/10/2024] Open
Abstract
Tumor growth and metastasis rely on angiogenesis. In recent years, long non-coding RNAs have been shown to play an important role in regulating tumor angiogenesis. Here, we review the multidimensional modes and relevant molecular mechanisms of long non-coding RNAs in regulating tumor angiogenesis. In addition, we summarize new strategies for tumor anti-angiogenesis therapies by targeting long non-coding RNAs. The aim of this study is to provide new diagnostic targets and treatment strategies for anti-angiogenic tumor therapy.
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Affiliation(s)
- Shuo Zhang
- Medical Research Center, Binzhou Medical University Hospital, Binzhou, P.R. China
- Department of Gynecology, Binzhou Medical University Hospital, Binzhou, P.R. China
- The First School of Clinical Medicine of Binzhou Medical University, Binzhou Medical University Hospital, Binzhou, P.R. China
| | - Yunxiu Xia
- Medical Research Center, Binzhou Medical University Hospital, Binzhou, P.R. China
- Department of Gynecology, Binzhou Medical University Hospital, Binzhou, P.R. China
- The First School of Clinical Medicine of Binzhou Medical University, Binzhou Medical University Hospital, Binzhou, P.R. China
| | - Weiwei Chen
- Medical Research Center, Binzhou Medical University Hospital, Binzhou, P.R. China
| | - Hongliang Dong
- Medical Research Center, Binzhou Medical University Hospital, Binzhou, P.R. China
| | - Bingjie Cui
- Medical Research Center, Binzhou Medical University Hospital, Binzhou, P.R. China
| | - Cuilan Liu
- Medical Research Center, Binzhou Medical University Hospital, Binzhou, P.R. China
| | - Zhiqiang Liu
- Medical Research Center, Binzhou Medical University Hospital, Binzhou, P.R. China
- Department of Gynecology, Binzhou Medical University Hospital, Binzhou, P.R. China
| | - Fei Wang
- Medical Research Center, Binzhou Medical University Hospital, Binzhou, P.R. China
- Medical Integration and Practice Center, Shandong University, Jinan, P.R. China
- Qilu Hospital of Shandong University, Jinan, P.R. China
| | - Jing Du
- Medical Research Center, Binzhou Medical University Hospital, Binzhou, P.R. China
- Department of Gynecology, Binzhou Medical University Hospital, Binzhou, P.R. China
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El-Aziz MKA, Dawoud A, Kiriacos CJ, Fahmy SA, Hamdy NM, Youness RA. Decoding hepatocarcinogenesis from a noncoding RNAs perspective. J Cell Physiol 2023; 238:1982-2009. [PMID: 37450612 DOI: 10.1002/jcp.31076] [Citation(s) in RCA: 53] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 06/11/2023] [Accepted: 06/19/2023] [Indexed: 07/18/2023]
Abstract
Being a leading lethal malignancy worldwide, the pathophysiology of hepatocellular carcinoma (HCC) has gained a lot of interest. Yet, underlying mechanistic basis of the liver tumorigenesis is poorly understood. The role of some coding genes and their respective translated proteins, then later on, some noncoding RNAs (ncRNAs) such as microRNAs have been extensively studied in context of HCC pathophysiology; however, the implication of long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) in HCC is indeed less investigated. As a subclass of the ncRNAs which has been elusive for long time ago, lncRNAs was found to be involved in plentiful cellular functions such as DNA, RNA, and proteins regulation. Hence, it is undisputed that lncRNAs dysregulation profoundly contributes to HCC via diverse etiologies. Accordingly, lncRNAs represent a hot research topic that requires prime focus in HCC. In this review, the authors discuss breakthrough discoveries involving lncRNAs and circRNAs dysregulation that have contributed to the contemporary concepts of HCC pathophysiology and how these concepts could be leveraged as potential novel diagnostic and prognostic HCC biomarkers. Further, this review article sheds light on future trends, thereby discussing the pathological roles of lncRNAs and circRNAs in HCC proliferation, migration, and epithelial-to-mesenchymal transition. Along this line of reasoning, future recommendations of how these targets could be exploited to achieve effective HCC-related drug development is highlighted.
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Affiliation(s)
- Mostafa K Abd El-Aziz
- Biochemistry Department, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, Egypt
- Molecular Genetics Research Team (MGRT), Biology and Biochemistry Department, School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, Cairo, Egypt
| | - Alyaa Dawoud
- Molecular Genetics Research Team (MGRT), Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Caroline J Kiriacos
- Molecular Genetics Research Team (MGRT), Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Sherif Ashraf Fahmy
- Chemistry Department, School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, Cairo, Egypt
| | - Nadia M Hamdy
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Rana A Youness
- Molecular Genetics Research Team (MGRT), Biology and Biochemistry Department, School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, Cairo, Egypt
- Molecular Genetics Research Team (MGRT), Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
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10
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Jesenko T, Brezar SK, Cemazar M, Biasin A, Tierno D, Scaggiante B, Grassi M, Grassi C, Dapas B, Truong NH, Abrami M, Zanconati F, Bonazza D, Rizzolio F, Parisi S, Pastorin G, Grassi G. Targeting Non-Coding RNAs for the Development of Novel Hepatocellular Carcinoma Therapeutic Approaches. Pharmaceutics 2023; 15:1249. [PMID: 37111734 PMCID: PMC10145575 DOI: 10.3390/pharmaceutics15041249] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Revised: 04/12/2023] [Accepted: 04/13/2023] [Indexed: 04/29/2023] Open
Abstract
Hepatocellular carcinoma (HCC) remains a global health challenge, representing the third leading cause of cancer deaths worldwide. Although therapeutic advances have been made in the few last years, the prognosis remains poor. Thus, there is a dire need to develop novel therapeutic strategies. In this regard, two approaches can be considered: (1) the identification of tumor-targeted delivery systems and (2) the targeting of molecule(s) whose aberrant expression is confined to tumor cells. In this work, we focused on the second approach. Among the different kinds of possible target molecules, we discuss the potential therapeutic value of targeting non-coding RNAs (ncRNAs), which include micro interfering RNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs). These molecules represent the most significant RNA transcripts in cells and can regulate many HCC features, including proliferation, apoptosis, invasion and metastasis. In the first part of the review, the main characteristics of HCC and ncRNAs are described. The involvement of ncRNAs in HCC is then presented over five sections: (a) miRNAs, (b) lncRNAs, (c) circRNAs, (d) ncRNAs and drug resistance and (e) ncRNAs and liver fibrosis. Overall, this work provides the reader with the most recent state-of-the-art approaches in this field, highlighting key trends and opportunities for more advanced and efficacious HCC treatments.
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Affiliation(s)
- Tanja Jesenko
- Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska 2, SI-1000 Ljubljana, Slovenia; (T.J.); (S.K.B.); (M.C.)
| | - Simona Kranjc Brezar
- Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska 2, SI-1000 Ljubljana, Slovenia; (T.J.); (S.K.B.); (M.C.)
| | - Maja Cemazar
- Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska 2, SI-1000 Ljubljana, Slovenia; (T.J.); (S.K.B.); (M.C.)
- Faculty of Health Sciences, University of Primorska, Polje 42, SI-6310 Izola, Slovenia
| | - Alice Biasin
- Department of Engineering and Architecture, Trieste University, via Valerio 6, I-34127 Trieste, Italy; (A.B.); (M.G.); (M.A.)
| | - Domenico Tierno
- Department of Life Sciences, Cattinara University Hospital, Trieste University, Strada di Fiume 447, I-34149 Trieste, Italy; (D.T.); (B.S.); (B.D.)
| | - Bruna Scaggiante
- Department of Life Sciences, Cattinara University Hospital, Trieste University, Strada di Fiume 447, I-34149 Trieste, Italy; (D.T.); (B.S.); (B.D.)
| | - Mario Grassi
- Department of Engineering and Architecture, Trieste University, via Valerio 6, I-34127 Trieste, Italy; (A.B.); (M.G.); (M.A.)
| | - Chiara Grassi
- Degree Course in Medicine, University of Trieste, I-34149 Trieste, Italy;
| | - Barbara Dapas
- Department of Life Sciences, Cattinara University Hospital, Trieste University, Strada di Fiume 447, I-34149 Trieste, Italy; (D.T.); (B.S.); (B.D.)
| | - Nhung Hai Truong
- Faculty of Biology and Biotechnology, VNUHCM-University of Science, Ho Chi Minh City 70000, Vietnam;
| | - Michela Abrami
- Department of Engineering and Architecture, Trieste University, via Valerio 6, I-34127 Trieste, Italy; (A.B.); (M.G.); (M.A.)
| | - Fabrizio Zanconati
- Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Hospital, Strada di Fiume, 447, I-34149 Trieste, Italy; (F.Z.)
| | - Deborah Bonazza
- Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Hospital, Strada di Fiume, 447, I-34149 Trieste, Italy; (F.Z.)
| | - Flavio Rizzolio
- Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, I-33081 Aviano, Italy;
- Department of Molecular Sciences and Nanosystems, Ca’ Foscari University of Venice, I-30172 Venezia, Italy;
| | - Salvatore Parisi
- Department of Molecular Sciences and Nanosystems, Ca’ Foscari University of Venice, I-30172 Venezia, Italy;
- Doctoral School in Molecular Biomedicine, University of Trieste, I-34149 Trieste, Italy
| | - Giorgia Pastorin
- Pharmacy Department, National University of Singapore, Block S9, Level 15, 4 Science Drive 2, Singapore 117544, Singapore;
| | - Gabriele Grassi
- Department of Life Sciences, Cattinara University Hospital, Trieste University, Strada di Fiume 447, I-34149 Trieste, Italy; (D.T.); (B.S.); (B.D.)
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11
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Zhao H, Liu C, Zhao C, Che C, Liu W, Mei Y. Alternatively-spliced lncRNA-PNUTS promotes HCC cell EMT via regulating ZEB1 expression. TUMORI JOURNAL 2023; 109:28-37. [PMID: 35139713 DOI: 10.1177/03008916211072585] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Long non-coding RNAs have been implicated in various cancers as they regulate critical cellular processes such as proliferation, migration, invasion, and apoptosis in tumorous tissues. lncRNA-PNUTS is newly reported as an alternatively-spliced lncRNA from PNUTS pre-mRNA that promotes oncogenesis in breast cancer. However, whether LncRNA-PNUTS plays a role in other forms of cancers, such as liver cancer, remains unknown. METHOD In the current study, we investigated the potential role of lncRNA-PNUTS in hepatocellular carcinoma (HCC). The levels of lncRNA-PNUTS in tumorous tissues obtained from HCC patients were measured. The potential impacts of lncPNUTS on metastasis and invasion were investigated through gain- or loss- of function experiments in cell models of liver cancers, as well as other cellular assays such as trans-well assays and wound-healing assays. RESULTS Here, we report that lncPNUTS was upregulated in human HCC tissues. Loss- and gain-of-function experiments indicated lncPNUTS promoted metastasis and invasion. In addition, ZEB1, which is involved in the activation of epithelial-mesenchymal-transition (EMT), was identified as a downstream target of lncPNUTS. CONCLUSION Our findings indicated lncPNUTS promotes HCC cancer cell metastasis and invasion via targeting ZEB1 to activate the EMT pathway, suggesting that lncPNUTS is a potential prognostic marker and therapeutic target for HCC patients.
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Affiliation(s)
- Haiyan Zhao
- Medical Faculty of Kunming University of Science and Technology, Kunming, Yunnan, China.,Department of Ophthalmology, The Affiliated Hospital of Kunming University of Science and Technology, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China
| | - Chang Liu
- The Second Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Chongyu Zhao
- The Second Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Chi Che
- The Second Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Wuguang Liu
- The Second Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Yan Mei
- Medical Faculty of Kunming University of Science and Technology, Kunming, Yunnan, China.,Department of Ophthalmology, The Affiliated Hospital of Kunming University of Science and Technology, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China
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12
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Chen T. Circulating Non-Coding RNAs as Potential Diagnostic Biomarkers in Hepatocellular Carcinoma. J Hepatocell Carcinoma 2022; 9:1029-1040. [PMID: 36132427 PMCID: PMC9484560 DOI: 10.2147/jhc.s380237] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 09/06/2022] [Indexed: 11/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is currently the second leading cause of cancer-related deaths worldwide, with high morbidity and mortality. The clinical diagnosis of HCC mainly depends on imaging technology, such as ultrasound and computed tomography, and serum biomarkers, such as alpha-fetoprotein (AFP). However, HCC is still hard to diagnose at an early stage due to the low sensitivity of the above mentioned traditional methods. Typically, HCC is diagnosed at an advanced stage when limited treatment options are available. It is urgent to identify effective biomarkers for the early diagnosis of HCC. Increasing evidence uncovered ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), could be used in HCC diagnosis. The aim of this review is to summarize our understanding of circulating miRNAs, lncRNAs and circRNAs as fluid-based non-invasive biomarkers, and aiming at providing new insights into the diagnosis of HCC.
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Affiliation(s)
- Tingsong Chen
- The Second Department of Oncology, the Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China
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13
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Khan A, Zhang X. Function of the Long Noncoding RNAs in Hepatocellular Carcinoma: Classification, Molecular Mechanisms, and Significant Therapeutic Potentials. Bioengineering (Basel) 2022; 9:406. [PMID: 36004931 PMCID: PMC9405066 DOI: 10.3390/bioengineering9080406] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 08/15/2022] [Accepted: 08/16/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common and serious type of primary liver cancer. HCC patients have a high death rate and poor prognosis due to the lack of clear signs and inadequate treatment interventions. However, the molecular pathways that underpin HCC pathogenesis remain unclear. Long non-coding RNAs (lncRNAs), a new type of RNAs, have been found to play important roles in HCC. LncRNAs have the ability to influence gene expression and protein activity. Dysregulation of lncRNAs has been linked to a growing number of liver disorders, including HCC. As a result, improved understanding of lncRNAs could lead to new insights into HCC etiology, as well as new approaches for the early detection and treatment of HCC. The latest results with respect to the role of lncRNAs in controlling multiple pathways of HCC were summarized in this study. The processes by which lncRNAs influence HCC advancement by interacting with chromatin, RNAs, and proteins at the epigenetic, transcriptional, and post-transcriptional levels were examined. This critical review also highlights recent breakthroughs in lncRNA signaling pathways in HCC progression, shedding light on the potential applications of lncRNAs for HCC diagnosis and therapy.
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Affiliation(s)
| | - Xiaobo Zhang
- College of Life Sciences, Zhejiang University, Hangzhou 310058, China
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14
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Samadi P, Soleimani M, Nouri F, Rahbarizadeh F, Najafi R, Jalali A. An integrative transcriptome analysis reveals potential predictive, prognostic biomarkers and therapeutic targets in colorectal cancer. BMC Cancer 2022; 22:835. [PMID: 35907803 PMCID: PMC9339198 DOI: 10.1186/s12885-022-09931-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 07/25/2022] [Indexed: 12/09/2022] Open
Abstract
BACKGROUND A deep understanding of potential molecular biomarkers and therapeutic targets related to the progression of colorectal cancer (CRC) from early stages to metastasis remain mostly undone. Moreover, the regulation and crosstalk among different cancer-driving molecules including messenger RNAs (mRNAs), long non-coding RNAs (lncRNAs) and micro-RNAs (miRNAs) in the transition from stage I to stage IV remain to be clarified, which is the aim of this study. METHODS We carried out two separate differential expression analyses for two different sets of samples (stage-specific samples and tumor/normal samples). Then, by the means of robust dataset analysis we identified distinct lists of differently expressed genes (DEGs) for Robust Rank Aggregation (RRA) and weighted gene co-expression network analysis (WGCNA). Then, comprehensive computational systems biology analyses including mRNA-miRNA-lncRNA regulatory network, survival analysis and machine learning algorithms were also employed to achieve the aim of this study. Finally, we used clinical samples to carry out validation of a potential and novel target in CRC. RESULTS We have identified the most significant stage-specific DEGs by combining distinct results from RRA and WGCNA. After finding stage-specific DEGs, a total number of 37 DEGs were identified to be conserved across all stages of CRC (conserved DEGs). We also found DE-miRNAs and DE-lncRNAs highly associated to these conserved DEGs. Our systems biology approach led to the identification of several potential therapeutic targets, predictive and prognostic biomarkers, of which lncRNA LINC00974 shown as an important and novel biomarker. CONCLUSIONS Findings of the present study provide new insight into CRC pathogenesis across all stages, and suggests future assessment of the functional role of lncRNA LINC00974 in the development of CRC.
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Affiliation(s)
- Pouria Samadi
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Meysam Soleimani
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Fatemeh Nouri
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Fatemeh Rahbarizadeh
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Rezvan Najafi
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Akram Jalali
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
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15
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Long non-coding RNAs involved in different steps of cancer metastasis. Clin Transl Oncol 2022; 24:997-1013. [PMID: 35119654 DOI: 10.1007/s12094-021-02761-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 12/14/2021] [Indexed: 11/09/2022]
Abstract
Non-proteincoding transcripts bearing 200 base pairs known as long non-coding RNAs (lncRNAs) play a role in a variety of molecular mechanisms, including cell differentiation, apoptosis and metastasis. Previous studies have suggested that frequently dysregulated lncRNAs play a crucial role in various aspects of cancer metastasis. Metastasis is the main leading cause of death in cancer. The role of lncRNAs in different stages of metastasis is the subject of this review. Based on in vitro and in vivo investigations on metastasis, we categorized lncRNAs into distinct stages of metastasis including angiogenesis, invasion, intravasation, survival in circulation, and extravasation. The involvement of lncRNAs in angiogenesis and invasion has been extensively studied. Here, we comprehensively discuss the role and functions of these lncRNAs with a particular focus on the molecular mechanisms.
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16
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Lu SY, Hua J, Liu J, Wei MY, Liang C, Meng QC, Zhang B, Yu XJ, Wang W, Xu J. Construction of a paclitaxel-related competitive endogenous RNA network and identification of a potential regulatory axis in pancreatic cancer. Transl Oncol 2022; 20:101419. [PMID: 35413498 PMCID: PMC9018166 DOI: 10.1016/j.tranon.2022.101419] [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: 02/14/2022] [Revised: 03/17/2022] [Accepted: 03/30/2022] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND Increasing numbers of studies have elucidated the role of competitive endogenous RNA (ceRNA) networks in carcinogenesis. However, the potential role of the paclitaxel-related ceRNA network in the innate mechanism and prognosis of pancreatic cancer has not been identified. METHODS Comprehensive bioinformatics analyses were performed to identify drug-related miRNAs (DRmiRNAs), drug-related mRNAs (DRmRNAs) and drug-related lncRNAs (DRlncRNAs) and construct a ceRNA network. The ssGSEA and CIBERSORT algorithms were utilized for immune cell infiltration analysis. Additionally, we validated our paclitaxel-related ceRNA regulatory axis at the gene expression level; functional experiments were conducted to explore the biological functions of the key genes. RESULTS A total of 182 mRNAs, 13 miRNAs, and 53 lncRNAs were confirmed in the paclitaxel-related ceRNA network. In total, 6 mRNAs, 4 miRNAs, and 6 lncRNAs were identified to establish a risk signature and exhibited optimal prognostic effects. The mRNA signature can predict the abundance of immune cell infiltration and the sensitivity of different chemotherapeutic drugs and may also have a guiding effect in immune checkpoint therapy. A potential PART1/hsa-mir-21/SCRN1 axis was confirmed according to the ceRNA theory and was verified by qPCR. The results indicated that PART1 knockdown markedly increased hsa-mir-21 expression but inhibited SCRN1 expression, weakening the proliferation and migration abilities. CONCLUSIONS We hypothesized that the paclitaxel-related ceRNA network strongly influences the innate mechanism, prognosis, and immune infiltration of pancreatic cancer. Our risk signatures can accurately predict survival outcomes and provide a clinical basis.
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Affiliation(s)
- Si Yuan Lu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, No. 270 Dong'An Road, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Jie Hua
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, No. 270 Dong'An Road, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Jiang Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, No. 270 Dong'An Road, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Miao Yan Wei
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, No. 270 Dong'An Road, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Chen Liang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, No. 270 Dong'An Road, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Qing Cai Meng
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, No. 270 Dong'An Road, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Bo Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, No. 270 Dong'An Road, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xian Jun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, No. 270 Dong'An Road, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Wei Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, No. 270 Dong'An Road, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, China.
| | - Jin Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, No. 270 Dong'An Road, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, China.
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17
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Li W, Li T, Sun C, Du Y, Chen L, Du C, Shi J, Wang W. Identification and prognostic analysis of biomarkers to predict the progression of pancreatic cancer patients. Mol Med 2022; 28:43. [PMID: 35428170 PMCID: PMC9013045 DOI: 10.1186/s10020-022-00467-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 04/04/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Pancreatic cancer (PC) is a malignancy with a poor prognosis and high mortality. Surgical resection is the only "curative" treatment. However, only a minority of patients with PC can obtain surgery. Improving the overall survival (OS) rate of patients with PC is still a major challenge. Molecular biomarkers are a significant approach for diagnostic and predictive use in PCs. Several prediction models have been developed for patients newly diagnosed with PC that is operable or patients with advanced and metastatic PC; however, these models require further validation. Therefore, precise biomarkers are urgently required to increase the efficiency of predicting a disease-free survival (DFS), OS, and sensitivity to immunotherapy in PC patients and to improve the prognosis of PC. METHODS In the present study, we first evaluated the highly and selectively expressed targets in PC, using the GeoMxTM Digital Spatial Profiler (DSP) and then, we analyzed the roles of these targets in PCs using TCGA database. RESULTS LAMB3, FN1, KRT17, KRT19, and ANXA1 were defined as the top five upregulated targets in PC compared with paracancer. The TCGA database results confirmed the expression pattern of LAMB3, FN1, KRT17, KRT19, and ANXA1 in PCs. Significantly, LAMB3, FN1, KRT19, and ANXA1 but not KRT17 can be considered as biomarkers for survival analysis, univariate and multivariate Cox proportional hazards model, and risk model analysis. Furthermore, in combination, LAMB3, FN1, KRT19, and ANXA1 predict the DFS and, in combination, LAMB3, KRT19, and ANXA1 predict the OS. Immunotherapy is significant for PCs that are inoperable. The immune checkpoint blockade (ICB) analysis indicated that higher expressions of FN1 or ANXA1 are correlated with lower ICB response. In contrast, there are no significant differences in the ICB response between high and low expression of LAMB3 and KRT19. CONCLUSIONS In conclusion, LAMB3, FN1, KRT19, and ANXA1 are good predictors of PC prognosis. Furthermore, FN1 and ANXA1 can be predictors of immunotherapy in PCs.
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Affiliation(s)
- Wei Li
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
- The Academy of Medical Science, College of Medical, Zhengzhou University, Zhengzhou, 450052, Henan, China.
| | - Tiandong Li
- College of Public Health, Zhengzhou University, Zhengzhou, 450000, Henan, China
| | - Chenguang Sun
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Yimeng Du
- The Academy of Medical Science, College of Medical, Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Linna Chen
- The Academy of Medical Science, College of Medical, Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Chunyan Du
- Laboratory Animal Center, School of Medical Sciences, Zhengzhou University, Zhengzhou, 450052, Henan, China.
| | - Jianxiang Shi
- BGI College and Henan Institute of Medical and Pharmaceutical Sciences in Academy of Medical Science, Zhengzhou University, Zhengzhou, 450052, Henan, China.
| | - Weijie Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
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18
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Liu W, Cheng P, Zhang K, Gong M, Zhang Z, Zhang R. Systematic identification and characterization of long noncoding RNAs (lncRNAs) during Aedes albopictus development. PLoS Negl Trop Dis 2022; 16:e0010245. [PMID: 35417446 PMCID: PMC9007367 DOI: 10.1371/journal.pntd.0010245] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 02/10/2022] [Indexed: 12/13/2022] Open
Abstract
Background
Aedes albopictus originated in the tropical forests of Southeast Asia and can currently be found on all continents. As one of the main arboviral vectors, the control of Ae. albopictus requires novel strategies, informed by a deep knowledge of its biology. Little is known regarding mosquito long noncoding RNAs (lncRNAs), which are transcripts longer than 200 nucleotides that lack protein-coding potential and have roles in developmental regulation.
Results
Based on RNA-seq data from five developmental time points, eggs, early larvae, late larvae, pupae, and adults (female and male) of Ae. albopictus, 21,414 lncRNAs were characterized in this study. Differential expression analysis revealed that lncRNAs exhibited developmental stage specificity. The expression of most lncRNAs was upregulated at the onset of metamorphosis developmental stages. More differentially expressed lncRNAs were observed between eggs and early larvae. Weighted gene co-expression network analysis (WGCNA) further confirmed that the expression patterns of lncRNAs were obviously correlated with specific developmental time points. Functional annotation using co-expression analysis revealed that lncRNAs may be involved in the regulation of metamorphic developmental transitions of Ae. albopictus. The hub lncRNAs and hub gene clusters were identified for each module that were highly associated with specific developmental time points.
Conclusions
The results of this study will facilitate future researches to elucidate the regulatory mechanisms of lncRNAs in the development of Ae. albopictus and utilize lncRNAs to assist with mosquito control.
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Affiliation(s)
- Wenjuan Liu
- Collaborative Innovation Center for the Origin and Control of Emerging Infectious Diseases, Shandong First Medical University (Shandong Academy of Medical Sciences), Tai’an, China
- School of Basic Medical Science, Shandong First Medical University (Shandong Academy of Medical Sciences), Tai’an, China
| | - Peng Cheng
- Collaborative Innovation Center for the Origin and Control of Emerging Infectious Diseases, Shandong First Medical University (Shandong Academy of Medical Sciences), Tai’an, China
- Shandong Institute of Parasitic Diseases, Shandong First Medical University (Shandong Academy of Medical Sciences), Jining, China
| | - Kexin Zhang
- Collaborative Innovation Center for the Origin and Control of Emerging Infectious Diseases, Shandong First Medical University (Shandong Academy of Medical Sciences), Tai’an, China
- School of Basic Medical Science, Shandong First Medical University (Shandong Academy of Medical Sciences), Tai’an, China
| | - Maoqing Gong
- Collaborative Innovation Center for the Origin and Control of Emerging Infectious Diseases, Shandong First Medical University (Shandong Academy of Medical Sciences), Tai’an, China
- Shandong Institute of Parasitic Diseases, Shandong First Medical University (Shandong Academy of Medical Sciences), Jining, China
- * E-mail: (MG); (ZZ); (RZ)
| | - Zhong Zhang
- Collaborative Innovation Center for the Origin and Control of Emerging Infectious Diseases, Shandong First Medical University (Shandong Academy of Medical Sciences), Tai’an, China
- School of Basic Medical Science, Shandong First Medical University (Shandong Academy of Medical Sciences), Tai’an, China
- * E-mail: (MG); (ZZ); (RZ)
| | - Ruiling Zhang
- Collaborative Innovation Center for the Origin and Control of Emerging Infectious Diseases, Shandong First Medical University (Shandong Academy of Medical Sciences), Tai’an, China
- School of Basic Medical Science, Shandong First Medical University (Shandong Academy of Medical Sciences), Tai’an, China
- * E-mail: (MG); (ZZ); (RZ)
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Cai S, Zhang Y, Zhang X, Wang L, Wu Z, Fang W, Chen X. A microarray expression profile and bioinformatic analysis of circular RNA in human esophageal carcinoma. J Gastrointest Oncol 2022; 13:510-526. [PMID: 35557573 PMCID: PMC9086029 DOI: 10.21037/jgo-22-137] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 03/08/2022] [Indexed: 03/31/2025] Open
Abstract
BACKGROUND Recent studies indicate that non-coding circular RNAs (circRNAs) are involved in the development of esophageal carcinoma (EC). This study aimed to identify differential expression of circRNAs in EC, which can provide potential biomarkers and therapeutic targets for EC treatment and improve the understanding of tumorigenesis mechanism. METHODS First, samples (n=5) of EC tissues and adjacent normal tissue were sent for circRNA microarray detection, Second, further bioinformatic analysis was performed, including circRNA-microRNA (miRNA), co-expression network analysis, Spearman correlation test, and cancer-related circRNA-miRNA axis analysis. Finally, the expression of circRNA that our analysis predicted to be hub genes was verified in samples (n=15) of EC tissues and adjacent normal tissue by real-time polymerase chain reaction (RT-PCR). RESULTS Microarray identified 102 upregulated and 67 significantly downregulated circRNAs were in EC patients' tumors relative to adjacent normal tissue. One upregulated circRNA (hsa_circRNA_401955) showed the most connection with MREs, therefore was regarded as the hub gene by the Spearman correlation test. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses showed that four primary pathways (mRNA surveillance, cytoskeleton actin regulation, spliceosome, and the NOD-like receptor signaling pathway) were predicted in the hub circRNA's five connected miRNA response elements (MREs). Furthermore, cancer-related circRNA-miRNA axis analyses showed that hsa_circRNA_100375 and its four connected MREs participated in the cancer-related pathway. RT-PCR showed that hsa_circRNA_100375 and hsa_circRNA_401955 were significantly increased in the tumor tissues of EC patients. CONCLUSIONS Abnormal expression of circRNAs was involved in the tumorigenesis of EC. Key circRNAs, namely hsa_circRNA_401955 and hsa_circRNA_100375, may be as potential biomarkers and therapeutic targets for the treatment of EC.
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Affiliation(s)
- Sina Cai
- Department of Oncology, the Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Yuqin Zhang
- Department of Clinical Oncology, The Affiliated Chenzhou Hospital, Hengyang Medical School, University of South China, Chenzhou, China
| | - Xiaona Zhang
- Graceland Medical Center, the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Liping Wang
- Department of Clinical Oncology, South University of Science and Technology Hospital, Shenzhen, China
| | - Ziqing Wu
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Weiyi Fang
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Xiaohua Chen
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
- South China Normal University-Panyu Central Hospital Joint Laboratory of Translational Medical Research, Panyu Central Hospital, Guangzhou, China
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20
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Li D, Fan X, Li Y, Yang J, Lin H. The paradoxical functions of long noncoding RNAs in hepatocellular carcinoma: Implications in therapeutic opportunities and precision medicine. Genes Dis 2022; 9:358-369. [PMID: 35224152 PMCID: PMC8843871 DOI: 10.1016/j.gendis.2020.11.014] [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: 06/03/2020] [Revised: 10/22/2020] [Accepted: 11/24/2020] [Indexed: 11/20/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is among the most aggressive and lethal diseases with poor prognosis, worldwide. However, the mechanisms underlying HCC have not been comprehensively elucidated. With the recent application of high-throughput sequencing techniques, a diverse catalogue of differentially expressed long non-coding RNAs (lncRNA) in cancer have been shown to participate in HCC. Rather than being "transcriptional noise," they are emerging as important regulators of many biological processes, including chromatin remodelling, transcription, alternative splicing, translational and post-translational modification. Moreover, lncRNAs have dual effects in the development and progression of HCC, including oncogenic and tumour-suppressive roles. Collectively, recently data point to lncRNAs as novel diagnostic and prognostic biomarkers with satisfactory sensitivity and specificity, as well as being therapeutic targets for HCC patients. In this review, we highlight recent progress of the molecular patterns of lncRNAs and discuss their potential clinical application in human HCC.
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Affiliation(s)
- Duguang Li
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China
- Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China
| | - Xiaoxiao Fan
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China
- Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China
| | - Yirun Li
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China
- Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China
| | - Jing Yang
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China
- Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China
| | - Hui Lin
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China
- Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China
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21
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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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22
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Li L, Cao Y, Fan Y, Li R. Gene signature to predict prognostic survival of hepatocellular carcinoma. Open Med (Wars) 2022; 17:135-150. [PMID: 35071775 PMCID: PMC8742913 DOI: 10.1515/med-2021-0405] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 10/18/2021] [Accepted: 11/09/2021] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) has a high incidence and poor prognosis and is the second most fatal cancer, and certain HCC patients also show high heterogeneity. This study developed a prognostic model for predicting clinical outcomes of HCC. RNA and microRNA (miRNA) sequencing data of HCC were obtained from the cancer genome atlas. RNA dysregulation between HCC tumors and adjacent normal liver tissues was examined by DESeq algorithms. Survival analysis was conducted to determine the basic prognostic indicators. We identified competing endogenous RNA (ceRNA) containing 15,364 pairs of mRNA–long noncoding RNA (lncRNA). An imbalanced ceRNA network comprising 8 miRNAs, 434 mRNAs, and 81 lncRNAs was developed using hypergeometric test. Functional analysis showed that these RNAs were closely associated with biosynthesis. Notably, 53 mRNAs showed a significant prognostic correlation. The least absolute shrinkage and selection operator’s feature selection detected four characteristic genes (SAPCD2, DKC1, CHRNA5, and UROD), based on which a four-gene independent prognostic signature for HCC was constructed using Cox regression analysis. The four-gene signature could stratify samples in the training, test, and external validation sets (p <0.01). Five-year survival area under ROC curve (AUC) in the training and validation sets was greater than 0.74. The current prognostic gene model exhibited a high stability and accuracy in predicting the overall survival (OS) of HCC patients.
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Affiliation(s)
- Li Li
- Department of Oncology, The Comprehensive Cancer Centre of Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University , Nanjing , Jiangsu, 210000 , China
| | - Yundi Cao
- Department of Medical Oncology, Affiliated Taikang Xianlin Drum Tower Hospital, Medical School of Nanjing University , Nanjing , Jiangsu , China
| | - YingRui Fan
- Department of Medical Oncology, Affiliated Taikang Xianlin Drum Tower Hospital, Medical School of Nanjing University , Nanjing , Jiangsu , China
| | - Rong Li
- Department of Medical Oncology, Affiliated Taikang Xianlin Drum Tower Hospital, Medical School of Nanjing University , Nanjing , Jiangsu , China
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23
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Liu W, Cheng J. LINC00974 sponges miR-33a to facilitate cell proliferation, invasion, and EMT of ovarian cancer through HMGB2 upregulation. Genet Mol Biol 2022; 45:e20210224. [PMID: 35129574 PMCID: PMC8805187 DOI: 10.1590/1678-4685-gmb-2021-0224] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 11/23/2021] [Indexed: 01/17/2023] Open
Abstract
The function and mechanism of long intergenic non-protein coding RNA 974
(LINC00974) are rarely reported in ovarian cancer (OC). The study aimed to
investigate how LINC00974 affects the progression of OC. The expression levels
of LINC00974, microRNA-33a (miR-33a), and high mobility group box 2 (HMGB2) mRNA
were detected by qRT-PCR. The LINC00974/miR-33a/HMGB2 axis was confirmed by
dual-luciferase reporter, RNA-binding protein immunoprecipitation (RIP), and
biotinylated RNA pull-down assays. A series of in vitro
experiments were employed to assess the effects of LINC00974/miR-33a/HMGB2 axis
on the proliferation, invasion and epithelial mesenchymal transition (EMT) of OC
cells. Results showed that LINC00974 and HMGB2 mRNA expression were upregulated
in OC cells, while miR-33a expression was downregulated. HMGB2 was a direct
target gene of miR-33a. LINC00974 act as a competing endogenous RNA (ceRNA) to
directly bind with miR-33a, thereby upregulated HMGB2 expression. Notably,
silencing of LINC00974 suppressed cell proliferation, invasion and EMT of OC
cells, whereas miR-33a knockdown partially reversed the phenotypes of LINC00974
on OC cells. Overall, our study demonstrated that LINC00974 sponges miR-33a to
promote cell proliferation, invasion, and EMT of OC through HMGB2 upregulation.
LINC00974/miR-33a/HMGB2 axis may be an important signaling pathway in the
progression of OC.
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Affiliation(s)
- Weiwei Liu
- Maternal and Child Health Hospital of Hubei Province, China
| | - Jing Cheng
- Renmin Hospital of Wuhan University, China
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24
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Shi Y, Liu JB, Deng J, Zou DZ, Wu JJ, Cao YH, Yin J, Ma YS, Da F, Li W. The role of ceRNA-mediated diagnosis and therapy in hepatocellular carcinoma. Hereditas 2021; 158:44. [PMID: 34758879 PMCID: PMC8582193 DOI: 10.1186/s41065-021-00208-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 10/12/2021] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide due to its high degree of malignancy, high incidence, and low survival rate. However, the underlying mechanisms of hepatocarcinogenesis remain unclear. Long non coding RNA (lncRNA) has been shown as a novel type of RNA. lncRNA by acting as ceRNA can participate in various biological processes of HCC cells, such as tumor cell proliferation, migration, invasion, apoptosis and drug resistance by regulating downstream target gene expression and cancer-related signaling pathways. Meanwhile, lncRNA can predict the efficacy of treatment strategies for HCC and serve as a potential target for the diagnosis and treatment of HCC. Therefore, lncRNA serving as ceRNA may become a vital candidate biomarker for clinical diagnosis and treatment. In this review, the epidemiology of HCC, including morbidity, mortality, regional distribution, risk factors, and current treatment advances, was briefly discussed, and some biological functions of lncRNA in HCC were summarized with emphasis on the molecular mechanism and clinical application of lncRNA-mediated ceRNA regulatory network in HCC. This paper can contribute to the better understanding of the mechanism of the influence of lncRNA-mediated ceRNA networks (ceRNETs) on HCC and provide directions and strategies for future studies.
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Affiliation(s)
- Yi Shi
- College of Life Sciences and Chemistry, Hunan University of Technology, Zhuzhou, 412007, Hunan, China.,Cancer Institute, Affiliated Tumor Hospital of Nantong University, Nantong, 226631, China.,National Engineering Laboratory for Deep Process of Rice and Byproducts, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha, 410004, Hunan, China
| | - Ji-Bin Liu
- Cancer Institute, Affiliated Tumor Hospital of Nantong University, Nantong, 226631, China
| | - Jing Deng
- National Engineering Laboratory for Deep Process of Rice and Byproducts, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha, 410004, Hunan, China
| | - Da-Zhi Zou
- Department of Spine Surgery, Longhui County People's Hospital, Longhui, 422200, Hunan, China
| | - Jian-Jun Wu
- Nantong Haimen Yuelai Health Centre, Haimen, 226100, China
| | - Ya-Hong Cao
- Department of Respiratory, Nantong Traditional Chinese Medicine Hospital, Nantong, 226019, Jiangsu Province, China
| | - Jie Yin
- Department of General Surgery, Haian people's Hospital, Haian, 226600, Jiangsu, China
| | - Yu-Shui Ma
- Cancer Institute, Affiliated Tumor Hospital of Nantong University, Nantong, 226631, China.
| | - Fu Da
- Cancer Institute, Affiliated Tumor Hospital of Nantong University, Nantong, 226631, China. .,National Engineering Laboratory for Deep Process of Rice and Byproducts, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha, 410004, Hunan, China.
| | - Wen Li
- College of Life Sciences and Chemistry, Hunan University of Technology, Zhuzhou, 412007, Hunan, China. .,National Engineering Laboratory for Deep Process of Rice and Byproducts, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha, 410004, Hunan, China.
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25
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Liu O, Wang C, Wang S, Hu Y, Gou R, Dong H, Li S, Li X, Lin B. Keratin 80 regulated by miR-206/ETS1 promotes tumor progression via the MEK/ERK pathway in ovarian cancer. J Cancer 2021; 12:6835-6850. [PMID: 34659572 PMCID: PMC8517993 DOI: 10.7150/jca.64031] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 09/18/2021] [Indexed: 12/16/2022] Open
Abstract
Introduction: Keratin 80 (KRT80) is a type II epithelial keratin protein that plays an important role in cell differentiation and tumor progression. However, its role and mechanisms in ovarian cancer remain unclear. Methods: The effect of KRT80 on the survival and prognosis of patients with ovarian cancer was determined using immunohistochemistry. Cell lines overexpressing KRT80 and with KRT80 knockdown were established to study its effect on the malignant behavior of ovarian cancer cells. Western blotting was used to detect changes in related molecules, and in the MEK/ERK signal transduction pathway. ChIP assay was used to confirm that ETS1 regulates KRT80 at the transcriptional level. A double luciferase assay was used to confirm the target of miR-206. Results: The expression levels of KRT80 were high in ovarian cancer tissue, and were related to survival and prognosis. KRT80 expression is an independent prognostic factor in patients with ovarian cancer. KRT80 overexpression promotes the proliferation of ovarian cancer cells, the transition from G1 phase to S phase, invasion, and migration. KRT80 overexpression increased the expression of BCL2/BAX, CyclinD1, MMP2, MMP9, and N-cadherin, decreased the expression of E-cadherin, and increased the phosphorylation of MEK and ERK. ETS1 binds to the upstream promoter sequence of KRT80 and regulates KRT80 expression at the transcriptional level. ETS1 is a direct target of miR-206 in ovarian cancer cells. Conclusion: KRT80 regulated by miR-206/ETS1 promotes tumor progression via the MEK/ERK pathway in ovarian cancer, and KRT80 may have applications as a screening biomarker and potential therapeutic target for ovarian cancer.
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Affiliation(s)
- Ouxuan Liu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Liaoning, China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Liaoning, China
| | - Caixia Wang
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Shuang Wang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Liaoning, China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Liaoning, China
| | - Yuexin Hu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Liaoning, China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Liaoning, China
| | - Rui Gou
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Liaoning, China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Liaoning, China
| | - Hui Dong
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Liaoning, China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Liaoning, China
| | - Siting Li
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Liaoning, China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Liaoning, China
| | - Xiao Li
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Liaoning, China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Liaoning, China
| | - Bei Lin
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Liaoning, China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Liaoning, China
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26
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ceRNAs in Cancer: Mechanism and Functions in a Comprehensive Regulatory Network. JOURNAL OF ONCOLOGY 2021; 2021:4279039. [PMID: 34659409 PMCID: PMC8516523 DOI: 10.1155/2021/4279039] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 09/14/2021] [Accepted: 09/16/2021] [Indexed: 12/15/2022]
Abstract
Noncoding RNAs have been shown with powerful ability in post-transcriptional regulation, enabling intertwined RNA crosstalk and global molecular interaction in a large amount of dysfunctional conditions including cancer. Competing endogenous RNAs (ceRNAs) are those competitively binding with shared microRNAs (miRNAs), freeing their counterparts from miRNA-induced degradation, thus actively influencing and connecting with each other. Constantly updated analytical approaches boost outstanding advancement achieved in this burgeoning hotspot in multilayered intracellular communication, providing new insights into pathogenesis and clinical treatment. Here, we summarize the mechanisms and correlated factors under this RNA interplay and deregulated transcription profile in neoplasm and tumor progression, underscoring the great significance of ceRNAs for diagnostic values, monitoring biomarkers, and prognosis evaluation in cancer.
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27
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Beveridge DJ, Richardson KL, Epis MR, Brown RAM, Stuart LM, Woo AJ, Leedman PJ. The tumor suppressor miR-642a-5p targets Wilms Tumor 1 gene and cell-cycle progression in prostate cancer. Sci Rep 2021; 11:18003. [PMID: 34504167 PMCID: PMC8429423 DOI: 10.1038/s41598-021-97190-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 08/17/2021] [Indexed: 12/19/2022] Open
Abstract
RNA-based therapeutics are emerging as innovative options for cancer treatment, with microRNAs being attractive targets for therapy development. We previously implicated microRNA-642a-5p (miR-642a-5p) as a tumor suppressor in prostate cancer (PCa), and here we characterize its mode of action, using 22Rv1 PCa cells. In an in vivo xenograft tumor model, miR-642a-5p induced a significant decrease in tumor growth, compared to negative control. Using RNA-Sequencing, we identified gene targets of miR-642a-5p which were enriched for gene sets controlling cell cycle; downregulated genes included Wilms Tumor 1 gene (WT1), NUAK1, RASSF3 and SKP2; and upregulated genes included IGFBP3 and GPS2. Analysis of PCa patient datasets showed a higher expression of WT1, NUAK1, RASSF3 and SKP2; and a lower expression of GPS2 and IGFBP3 in PCa tissue compared to non-malignant prostate tissue. We confirmed the prostatic oncogene WT1, as a direct target of miR-642a-5p, and treatment of 22Rv1 and LNCaP PCa cells with WT1 siRNA or a small molecule inhibitor of WT1 reduced cell proliferation. Taken together, these data provide insight into the molecular mechanisms by which miR-642a-5p acts as a tumor suppressor in PCa, an effect partially mediated by regulating genes involved in cell cycle control; and restoration of miR-642-5p in PCa could represent a novel therapeutic approach.
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Affiliation(s)
- Dianne J Beveridge
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, 6 Verdun St, Nedlands, 6009, Australia
- Centre for Medical Research, The University of Western Australia, Crawley, WA, 6009, Australia
| | - Kirsty L Richardson
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, 6 Verdun St, Nedlands, 6009, Australia
- Centre for Medical Research, The University of Western Australia, Crawley, WA, 6009, Australia
| | - Michael R Epis
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, 6 Verdun St, Nedlands, 6009, Australia
- Centre for Medical Research, The University of Western Australia, Crawley, WA, 6009, Australia
| | - Rikki A M Brown
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, 6 Verdun St, Nedlands, 6009, Australia
- Centre for Medical Research, The University of Western Australia, Crawley, WA, 6009, Australia
| | - Lisa M Stuart
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, 6 Verdun St, Nedlands, 6009, Australia
- Centre for Medical Research, The University of Western Australia, Crawley, WA, 6009, Australia
| | - Andrew J Woo
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, 6 Verdun St, Nedlands, 6009, Australia
- Centre for Medical Research, The University of Western Australia, Crawley, WA, 6009, Australia
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, 6027, Australia
| | - Peter J Leedman
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, 6 Verdun St, Nedlands, 6009, Australia.
- Centre for Medical Research, The University of Western Australia, Crawley, WA, 6009, Australia.
- School of Medicine and Pharmacology, The University of Western Australia, Crawley, WA, 6009, Australia.
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28
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Barik GK, Sahay O, Behera A, Naik D, Kalita B. Keep your eyes peeled for long noncoding RNAs: Explaining their boundless role in cancer metastasis, drug resistance, and clinical application. Biochim Biophys Acta Rev Cancer 2021; 1876:188612. [PMID: 34391844 DOI: 10.1016/j.bbcan.2021.188612] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 08/07/2021] [Accepted: 08/08/2021] [Indexed: 12/12/2022]
Abstract
Cancer metastasis and drug resistance are two major obstacles in the treatment of cancer and therefore, the leading cause of cancer-associated mortalities worldwide. Hence, an in-depth understanding of these processes and identification of the underlying key players could help design a better therapeutic regimen to treat cancer. Earlier thought to be merely transcriptional junk and having passive or secondary function, recent advances in the genomic research have unravelled that long noncoding RNAs (lncRNAs) play pivotal roles in diverse physiological as well as pathological processes including cancer metastasis and drug resistance. LncRNAs can regulate various steps of the complex metastatic cascade such as epithelial-mesenchymal transition (EMT), invasion, migration and metastatic colonization, and also affect the sensitivity of cancer cells to various chemotherapeutic drugs. A substantial body of literature for more than a decade of research evince that lncRNAs can regulate gene expression at different levels such as epigenetic, transcriptional, posttranscriptional, translational and posttranslational levels, depending on their subcellular localization and through their ability to interact with DNA, RNA and proteins. In this review, we mainly focus on how lncRNAs affect cancer metastasis by modulating expression of key metastasis-associated genes at various levels of gene regulation. We also discuss how lncRNAs confer cancer cells either sensitivity or resistance to various chemo-therapeutic drugs via different mechanisms. Finally, we highlight the immense potential of lncRNAs as prognostic and diagnostic biomarkers as well as therapeutic targets in cancer.
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Affiliation(s)
- Ganesh Kumar Barik
- Cancer Biology Division, National Centre for Cell Science, Savitribai Phule Pune University, Ganeshkhind Road, Pune, Maharashtra 411007, India
| | - Osheen Sahay
- Proteomics Laboratory, National Centre for Cell Science, Savitribai Phule Pune University, Ganeshkhind Road, Pune, Maharashtra 411007, India
| | - Abhayananda Behera
- Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad 500046, India
| | - Debasmita Naik
- Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad 500046, India
| | - Bhargab Kalita
- Proteomics Laboratory, National Centre for Cell Science, Savitribai Phule Pune University, Ganeshkhind Road, Pune, Maharashtra 411007, India.
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Future Screening Prospects for Ovarian Cancer. Cancers (Basel) 2021; 13:cancers13153840. [PMID: 34359740 PMCID: PMC8345180 DOI: 10.3390/cancers13153840] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 06/19/2021] [Accepted: 07/26/2021] [Indexed: 12/20/2022] Open
Abstract
Simple Summary Ovarian cancer (OC) has the highest mortality rate of all gynecological cancers. It is usually diagnosed in late stages (FIGO III-IV), and therefore, overall survival is very poor. If diagnosed at the early stages, ovarian cancer has a 90% five-year survival rate. Liquid biopsy has a good potential to improve early ovarian cancer detection and is discussed in this review. Abstract Current diagnostic tools used in clinical practice such as transvaginal ultrasound, CA 125, and HE4 are not sensitive and specific enough to diagnose OC in the early stages. A lack of early symptoms and an effective asymptomatic population screening strategy leads to a poor prognosis in OC. New diagnostic and screening methods are urgently needed for early OC diagnosis. Liquid biopsies have been considered as a new noninvasive and promising method, using plasma/serum, uterine lavage, and urine samples for early cancer detection. We analyzed recent studies on molecular biomarkers with specific emphasis on liquid biopsy methods and diagnostic efficacy for OC through the detection of circulating tumor cells, circulating cell-free DNA, small noncoding RNAs, and tumor-educated platelets.
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30
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Zeng C, Tang Y, Jiang Y, Zuo Z, Tao H. Long noncoding RNAs as biomarkers for the diagnosis of hepatocellular carcinoma: A meta-analysis. Pathol Res Pract 2021; 224:153546. [PMID: 34332221 DOI: 10.1016/j.prp.2021.153546] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 07/06/2021] [Accepted: 07/07/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND Long non-coding RNAs (lncRNAs) are often aberrantly expressed in hepatocellular carcinoma (HCC). The role of lncRNAs in the diagnosis of HCC has attracted increasing attention. Hence, we performed a meta-analysis based on current studies to assess the diagnostic value of lncRNAs for HCC. METHODS A systematic search was performed using PubMed, Web of Science, and Embase databases for relevant studies. The quality of the studies was assessed with the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2). A fixed-effect model was used if the value of I2 statistics < 50%; otherwise, a bivariate random effects model was applied (I2 ≥ 50%). In addition, subgroup analysis and meta-regression analysis were conducted to explore the sources of heterogeneity. Statistical analyses were based on Meta-Disc statistical software (Version 1.4) and STATA software (Version 15.1). RESULTS A total of 52 studies in 20 related articles were selected for this meta-analysis, including 4930 patients and 4614 controls. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the curve (AUC) were 0.85 [95% confidence interval (CI) 0.82-0.88], 0.76 (95% CI 0.73-0.80), 3.6 (95% CI 3.1-4.2), 0.19 (95% CI 0.16-0.24), 19 (95% CI 14-26), and 0.88 (95% CI 0.85-0.91), respectively. The publication bias was evaluated by the Deek's funnel plot in our meta-analysis. CONCLUSIONS LncRNAs can serve as feasible HCC diagnostic biomarkers. However, further studies are necessary to confirm its diagnostic and clinical value.
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Affiliation(s)
- Chuyi Zeng
- Department of Clinical Laboratory, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yan Tang
- Department of Clinical Laboratory, Traditional Chinese Medicine Hospital Affiliated to Southwest Medical University, Luzhou, China
| | - Yao Jiang
- Department of Clinical Laboratory, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Zhihua Zuo
- Department of Clinical Laboratory, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Hualin Tao
- Department of Clinical Laboratory, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
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Zhang L, Li X, Lu J, Qian Y, Qian T, Wu X, Xu Q. The EGFR Polymorphism Increased the Risk of Hepatocellular Carcinoma Through the miR-3196-Dependent Approach in Chinese Han Population. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2021; 14:469-476. [PMID: 33935511 PMCID: PMC8079348 DOI: 10.2147/pgpm.s304524] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 03/16/2021] [Indexed: 12/17/2022]
Abstract
Background Previous studies have shown that epidermal growth factor receptor (EGFR) promotes cell proliferation through the PI3K-Akt-mTOR signaling pathway and participates in the occurrence and development of hepatocellular carcinoma (HCC). Here, we focused on the functional polymorphism of EGFR in the 3ʹ-untranslated region (UTR), aiming to reveal the potential mechanisms by which functional polymorphism is associated with the risk and development of HCC in the Han Chinese population. Methods This study was a hospital-based case-control study. A total of 600 patients were enrolled, and another 600 healthy volunteers served as controls. The miR-associated SNPs in EGFR were screened, and genotyping was performed by TaqMan allele differential analysis. In this study, genotyping, real-time PCR, cell transfection and double luciferase reporter gene were used for subsequent analysis. Results HBV/HCV infection instead of alcohol exposure, smoking exposure, hypertension or diabetes mellitus was associated with an increased risk of HCC. Compared with TT genotypes, TG and GG genotypes of EGFR rs884225 were significantly associated with reduced HCC risk. The stratified analysis of association between rs884225 and HCC subgroup feature reveal a highly correlation with tumor size. Furthermore, qRT-PCR confirmed that EGFR rs884225, TG and GG genotypes were more likely to bind to miR-3196 and down-regulate EGFR level in cells, thereby inhibiting cell proliferation. Conclusion This study suggested that EGFR rs884225 is associated with a reduced risk of liver cancer and may be a developing biomarker.
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Affiliation(s)
- Li Zhang
- Department of Hepatobiliary and Pancreatic Surgery, LiYang People's Hospital, LiYang, 213300, Jiangsu, People's Republic of China
| | - Xiaoping Li
- Department of Hepatobiliary and Pancreatic Surgery, LiYang People's Hospital, LiYang, 213300, Jiangsu, People's Republic of China
| | - Jiang Lu
- Department of Hepatobiliary and Pancreatic Surgery, LiYang People's Hospital, LiYang, 213300, Jiangsu, People's Republic of China
| | - Yi Qian
- Department of Hepatobiliary and Pancreatic Surgery, LiYang People's Hospital, LiYang, 213300, Jiangsu, People's Republic of China
| | - Tao Qian
- Department of Hepatobiliary and Pancreatic Surgery, LiYang People's Hospital, LiYang, 213300, Jiangsu, People's Republic of China
| | - Xing Wu
- Department of Hepatobiliary and Pancreatic Surgery, LiYang People's Hospital, LiYang, 213300, Jiangsu, People's Republic of China
| | - Qinghua Xu
- Department of Hepatobiliary and Pancreatic Surgery, LiYang People's Hospital, LiYang, 213300, Jiangsu, People's Republic of China
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Xie G, Jiang R, Wang X, Liu P, Zhao A, Wu Y, Huang F, Liu Z, Rajani C, Zheng X, Qiu J, Zhang X, Zhao S, Bian H, Gao X, Sun B, Jia W. Conjugated secondary 12α-hydroxylated bile acids promote liver fibrogenesis. EBioMedicine 2021; 66:103290. [PMID: 33752128 PMCID: PMC8010625 DOI: 10.1016/j.ebiom.2021.103290] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Revised: 02/24/2021] [Accepted: 03/04/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Significantly elevated serum and hepatic bile acid (BA) concentrations have been known to occur in patients with liver fibrosis. However, the roles of different BA species in liver fibrogenesis are not fully understood. METHODS We quantitatively measured blood BA concentrations in nonalcoholic steatohepatitis (NASH) patients with liver fibrosis and healthy controls. We characterized BA composition in three mouse models induced by carbon tetrachloride (CCl4), streptozotocin-high fat diet (STZ-HFD), and long term HFD, respectively. The molecular mechanisms underlying the fibrosis-promoting effects of BAs were investigated in cell line models, a 3D co-culture system, and a Tgr5 (HSC-specific) KO mouse model. FINDINGS We found that a group of conjugated 12α-hydroxylated (12α-OH) BAs, such as taurodeoxycholate (TDCA) and glycodeoxycholate (GDCA), significantly increased in NASH patients and liver fibrosis mouse models. 12α-OH BAs significantly increased HSC proliferation and protein expression of fibrosis-related markers. Administration of TDCA and GDCA directly activated HSCs and promoted liver fibrogenesis in mouse models. Blockade of BA binding to TGR5 or inhibition of ERK1/2 and p38 MAPK signaling both significantly attenuated the BA-induced fibrogenesis. Liver fibrosis was attenuated in mice with Tgr5 depletion. INTERPRETATION Increased hepatic concentrations of conjugated 12α-OH BAs significantly contributed to liver fibrosis via TGR5 mediated p38MAPK and ERK1/2 signaling. Strategies to antagonize TGR5 or inhibit ERK1/2 and p38 MAPK signaling may effectively prevent or reverse liver fibrosis. FUNDINGS This study was supported by the National Institutes of Health/National Cancer Institute Grant 1U01CA188387-01A1, the National Key Research and Development Program of China (2017YFC0906800); the State Key Program of National Natural Science Foundation (81430062); the National Natural Science Foundation of China (81974073, 81774196), China Postdoctoral Science Foundation funded project, China (2016T90381), and E-institutes of Shanghai Municipal Education Commission, China (E03008).
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Affiliation(s)
- Guoxiang Xie
- Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China; Human Metabolomics Institute, Inc., Shenzhen, Guangdong 518109, China
| | - Runqiu Jiang
- Department of Hepatobiliary Surgery, The Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, Jiangsu 210009, China
| | - Xiaoning Wang
- E-institute of Shanghai Municipal Education Committee, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Ping Liu
- E-institute of Shanghai Municipal Education Committee, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Aihua Zhao
- Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Yiran Wu
- The iHuman Institute, ShanghaiTech University, Shanghai 201210, China
| | - Fengjie Huang
- Human Metabolomics Institute, Inc., Shenzhen, Guangdong 518109, China
| | - Zhipeng Liu
- Medical School of Southeast University, Nanjing, Jiangsu 210096, China
| | - Cynthia Rajani
- University of Hawaii Cancer Center, Honolulu, HI 96813, USA
| | - Xiaojiao Zheng
- Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Jiannan Qiu
- E-institute of Shanghai Municipal Education Committee, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xiaoling Zhang
- Department of Hygienic Analysis and Detection, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Suwen Zhao
- The iHuman Institute, ShanghaiTech University, Shanghai 201210, China
| | - Hua Bian
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Xin Gao
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Beicheng Sun
- Department of Hepatobiliary Surgery, The Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, Jiangsu 210009, China
| | - Wei Jia
- Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China; University of Hawaii Cancer Center, Honolulu, HI 96813, USA; Hong Kong Traditional Chinese Medicine Phenome Research Centre, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong 999077, China; Lead contact.
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Ghafouri-Fard S, Glassy MC, Abak A, Hussen BM, Niazi V, Taheri M. The interaction between miRNAs/lncRNAs and Notch pathway in human disorders. Biomed Pharmacother 2021; 138:111496. [PMID: 33743335 DOI: 10.1016/j.biopha.2021.111496] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 03/07/2021] [Accepted: 03/09/2021] [Indexed: 02/07/2023] Open
Abstract
Notch pathway is a signaling cascade with important impacts on cell proliferation, differentiation, developmental processes and tissue homeostasis. This pathway also regulates stem cell properties, thus being involved in both normal developmental processes and metastatic capacity of cancer cells. Lots of lncRNAs and miRNAs have been recognized that control Notch pathway at some levels or their expression is regulated by this pathway. FOXD2-AS1, MEG3, ANRIL, linc-OIP5, lincRNA-p21, CBR3-AS1, HOTAIR, PVT1 and GAS5 are among lncRNAs that interact with Notch signaling. miR-19, miR-21, miR-33a, miR-8/200, miR-34a, miR-146a, miR-37, miR-100, miR-107 and several other miRNAs have functional interplay with this signaling cascade. In the present review article, we have illuminated the interplay between lncRNAs/miRNAs and Notch pathway in two distinct contexts i.e. cancers and non-neoplastic conditions.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mark C Glassy
- Translational Neuro-Oncology Laboratory, San Diego (UCSD) Moores Cancer Center, University of California, CA, United States
| | - Atefe Abak
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Bashdar Mahmud Hussen
- Pharmacognosy Department, College of Pharmacy, Hawler Medical University, Erbil, Iraq
| | - Vahid Niazi
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Taheri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Zhang W, Liu Y, Yan Z, Yang H, Sun W, Yao Y, Chen Y, Jiang R. IL-6 promotes PD-L1 expression in monocytes and macrophages by decreasing protein tyrosine phosphatase receptor type O expression in human hepatocellular carcinoma. J Immunother Cancer 2021; 8:jitc-2019-000285. [PMID: 32581055 PMCID: PMC7319788 DOI: 10.1136/jitc-2019-000285] [Citation(s) in RCA: 120] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/14/2020] [Indexed: 12/11/2022] Open
Abstract
Background We have previously discovered a relationship between the low expression of protein tyrosine phosphatase, receptor type O (PTPRO) in tumor-infiltrating T cells and immunosuppression. The aim of the present study was to investigate the relationship between decreased PTPRO and increased programmed death ligand 1 (PD-L1) in both the peripheral monocytes and tumor-infiltrating macrophages of human hepatocellular carcinoma (HCC). Methods The expression and correlation of all the indices were explored in monocytes and tumor-infiltrating macrophages within both human and mice HCC. The mechanic regulations were studied by using both in vitro and in vivo studies. Results We found a significant decrease in PTPRO in HCC peripheral monocytes that was associated with increased PD-L1 expression in peripheral monocytes and tumor-associated macrophages (TAMs) in HCC. Monocyte PD-L1 and PTPRO therefore could serve as valuable prognostic indicators for post-surgery patients with HCC and were associated with increased T-cell exhaustion (Tim3+T cells). A depletion of PTPRO promoted PD-L1 secretion in both monocytes and macrophages through the JAK2/STAT1 and JAK2/STAT3/c-MYC pathways. Increased IL-6 expression was associated with activation of JAK2/STAT3/c-MYC and with decreased PTPRO expression through the STAT3/c-MYC/miR-25–3 p axis. Monocytes and TAMs showed significantly increased miR-25–3 p expression, which could target the 3′ untranslated region of PTPRO. The miR-25–3 p expression positively correlated with serum IL-6 levels, but inversely correlated with PTPRO in HCC monocytes. IL-6/STAT3/c-MYC activation enhanced in vitro miR-25–3 p transcription and decreased PTPRO, while further promoting PD-L1 secretion. Adoptive cell transfer of c-MYC/miR-25–3 p–modified monocytes promoted tumor growth by downregulating PTPRO and causing a PD-L1–induced immunosuppression in an orthotopic tumor transplantation model. Conclusions Increased serum IL-6 downregulated PTPRO expression in HCC monocytes and macrophages by activating STAT3/c-MYC/miR-25–3 p and by further enhancing PD-L1 expression through JAK2/STAT1 and JAK2/STAT3/c-MYC signaling.
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Affiliation(s)
- Wenjie Zhang
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Yang Liu
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Zhongyi Yan
- Department of Immunology, Nanjing Medical University, Nanjing, China
| | - Hui Yang
- Department of Hematology, The first affiliated Hospital to Nanjing Medical University, Nanjing, China
| | - Wei Sun
- Medical School of Nanjing University, Nanjing, China
| | - Yongliang Yao
- Department of Clinical Laboratory, Kunshan First People's Hospital, Affiliated to Jiangsu University, Kunshan, China
| | - Yun Chen
- Department of Immunology, Nanjing Medical University, Nanjing, China .,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Research Center for Clinical Oncology, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of 15 Nanjing Medical University, Nanjing, China
| | - Runqiu Jiang
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China .,Medical School of Nanjing University, Nanjing, China.,Jiangsu Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China
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35
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Song T, Li L, Wu S, Liu Y, Guo C, Wang W, Dai L, Zhang T, Wu H, Su B. Peripheral Blood Genetic Biomarkers for the Early Diagnosis of Hepatocellular Carcinoma. Front Oncol 2021; 11:583714. [PMID: 33777736 PMCID: PMC7991745 DOI: 10.3389/fonc.2021.583714] [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: 10/12/2020] [Accepted: 02/18/2021] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has high mortality. Biomarkers related to HCC, such as alpha-fetoprotein, and imaging technology, such as ultrasound and computed tomography, have been used to screen and monitor HCC, but HCC is still difficult to diagnose effectively in the early stage due to the low sensitivity of the above mentioned traditional methods. There is an urgent need for noninvasive biomarkers to facilitate the screening and early diagnosis of HCC. With the advancement of next-generation sequencing, genetic biomarkers are becoming the core of cancer diagnosis. Genetic biomarkers such as peripheral blood circulating tumor DNA, microRNAs, long noncoding RNAs, circular RNAs, and exosomes have become the focus of early HCC diagnostics. HCC genetic biomarkers have been implemented in clinical practice. In this review, we describe the available literature on peripheral blood genetic biomarkers in the diagnosis of early HCC.
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Affiliation(s)
- Ting Song
- Department of Infectious Diseases and Medical Immunology, Beijing Youan Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory for HIV/AIDS Research, Beijing, China.,Department of Hepatology, The Sixth People's Hospital of Qingdao, Qingdao, China
| | - Li Li
- Department of Infectious Diseases and Medical Immunology, Beijing Youan Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory for HIV/AIDS Research, Beijing, China
| | - Shaobo Wu
- Center of Transfusion-Transmitted Infectious Diseases, Institute of Blood Transfusion, Chinese Academy of Medical Sciences (CAMS), Chengdu, China
| | - Yan Liu
- Department of Infectious Diseases and Medical Immunology, Beijing Youan Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory for HIV/AIDS Research, Beijing, China
| | - Caiping Guo
- Department of Infectious Diseases and Medical Immunology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Wen Wang
- Department of Infectious Diseases and Medical Immunology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Lili Dai
- Department of Infectious Diseases and Medical Immunology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Tong Zhang
- Department of Infectious Diseases and Medical Immunology, Beijing Youan Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory for HIV/AIDS Research, Beijing, China
| | - Hao Wu
- Department of Infectious Diseases and Medical Immunology, Beijing Youan Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory for HIV/AIDS Research, Beijing, China
| | - Bin Su
- Department of Infectious Diseases and Medical Immunology, Beijing Youan Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory for HIV/AIDS Research, Beijing, China
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36
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Ruggiero C, Lalli E. Targeting the cytoskeleton against metastatic dissemination. Cancer Metastasis Rev 2021; 40:89-140. [PMID: 33471283 DOI: 10.1007/s10555-020-09936-0] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Accepted: 10/08/2020] [Indexed: 02/08/2023]
Abstract
Cancer is a pathology characterized by a loss or a perturbation of a number of typical features of normal cell behaviour. Indeed, the acquisition of an inappropriate migratory and invasive phenotype has been reported to be one of the hallmarks of cancer. The cytoskeleton is a complex dynamic network of highly ordered interlinking filaments playing a key role in the control of fundamental cellular processes, like cell shape maintenance, motility, division and intracellular transport. Moreover, deregulation of this complex machinery contributes to cancer progression and malignancy, enabling cells to acquire an invasive and metastatic phenotype. Metastasis accounts for 90% of death from patients affected by solid tumours, while an efficient prevention and suppression of metastatic disease still remains elusive. This results in the lack of effective therapeutic options currently available for patients with advanced disease. In this context, the cytoskeleton with its regulatory and structural proteins emerges as a novel and highly effective target to be exploited for a substantial therapeutic effort toward the development of specific anti-metastatic drugs. Here we provide an overview of the role of cytoskeleton components and interacting proteins in cancer metastasis with a special focus on small molecule compounds interfering with the actin cytoskeleton organization and function. The emerging involvement of microtubules and intermediate filaments in cancer metastasis is also reviewed.
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Affiliation(s)
- Carmen Ruggiero
- Institut de Pharmacologie Moléculaire et Cellulaire, Université Côte d'Azur, CNRS, 660 route des Lucioles-Sophia Antipolis, 06560, Valbonne, France.
- NEOGENEX-CANCER CNRS International Associated Laboratory, 660 route des Lucioles, Sophia Antipolis, 06560, Valbonne, France.
| | - Enzo Lalli
- NEOGENEX-CANCER CNRS International Associated Laboratory, 660 route des Lucioles, Sophia Antipolis, 06560, Valbonne, France
- Inserm, Institut de Pharmacologie Moléculaire et Cellulaire, 660 route des Lucioles - Sophia Antipolis, 06560, Valbonne, France
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37
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Hull R, Mbita Z, Dlamini Z. Long non-coding RNAs (LncRNAs), viral oncogenomics, and aberrant splicing events: therapeutics implications. Am J Cancer Res 2021; 11:866-883. [PMID: 33791160 PMCID: PMC7994164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 12/21/2020] [Indexed: 06/12/2023] Open
Abstract
It has been estimated that worldwide up to 10% of all human cancers are the result of viral infection, with 7.2% of all cancers in the developed world have a viral aetiology. In contrast, 22.9% of infections in the developing world are the result of viral infections. This number increases to 30% in Sub-Saharan Africa. The ability of viral infections to induce the transformation of normal cells into cancerous cells is well documented. These viruses are mainly Hepatitis B and C viruses, Epstein Barr virus, Human papillomavirus and Human Cytomegalovirus. They can induce the transformation of normal cells into cancer cells and this may be the underlying cause of carcinogenesis in many different types of cancer. These include liver cancer, lymphoma, nasopharyngeal cancer, cervical cancer, gastric cancer and even glioblastoma. Long non-coding RNAs (LncRNAs) can function by regulating the expression of their target genes by controlling the stability of the target mRNAs or by blocking translation of the target mRNA. They can control transcription by regulating the recruitment of transcription factors or chromatin modification complexes. Finally, lncRNAs can control the phosphorylation, acetylation, and ubiquitination of proteins at the post-translation level. Thus, altering protein localisation, function, folding, stability and ultimately expression. In addition to these functions, lncRNA also regulate alternate pre-mRNA splicing in ways that contribute to the formation of tumours. This mainly involves the interaction of lncRNAs with splicing factors, which alters their activity and function. The ability of lncRNAs to regulate the stability, expression and function of tumour suppressor proteins is important in the development and progression of cancers. LncRNAs also regulate viral replication and latency, leading to carcinogenesis. These factors all make lncRNAs ideal targets for the development of biomarker arrays that can be based on secreted lncRNAs leading to the development of affordable non-invasive biomarker tests for the stage specific diagnosis of tumours. These lncRNAs can also serve as targets for the development of new anticancer drug treatments.
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Affiliation(s)
- Rodney Hull
- SA-MRC/UP Precision Prevention & Novel Drug Targets for HIV-Associated Cancers Extramural Unit, Pan African Cancer Research Institute, University of Pretoria Hatfield0028, South Africa
| | - Zukile Mbita
- Department of Biochemistry, Microbiology and Biochemistry, University of LimpopoSovenga 0727, South Africa
| | - Zodwa Dlamini
- SA-MRC/UP Precision Prevention & Novel Drug Targets for HIV-Associated Cancers Extramural Unit, Pan African Cancer Research Institute, University of Pretoria Hatfield0028, South Africa
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Liang H, Bai Y, Wang H, Yang X. Identification of LncRNA Prognostic Markers for Ovarian Cancer by Integration of Co-expression and CeRNA Network. Front Genet 2021; 11:566497. [PMID: 33664764 PMCID: PMC7920993 DOI: 10.3389/fgene.2020.566497] [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: 05/28/2020] [Accepted: 11/03/2020] [Indexed: 02/05/2023] Open
Abstract
Background Ovarian cancer (OC), one of the most prevalent gynecological malignancies, is characterized by late detection and dismal prognosis. Recent studies show that long non-coding RNAs (lncRNAs) in competitive endogenous RNA (ceRNA) networks influence immune infiltration and cancer prognosis. However, the function of lncRNA in OC immune infiltration and prognosis remains unclear. Methods Transcriptomes of 378 OC samples and clinical data were retrieved from the TCGA repository. Modules related to immune cells were identified using weighted gene co-expression network analysis (WGCNA). Functional enrichment analysis and survival analysis were then performed for the identification of immune-related lncRNAs in the brown module using Cox regression model. Finally, a ceRNA network was constructed by using the lncRNAs and mRNAs from the brown module. Results We found lncRNAs and mRNAs in the brown module to be significantly associated with immune cells in OC and identified 4 lncRNAs as potential OC prognostic markers. We further established that lncRNAs in the ceRNA network influence OC immune infiltration and prognosis by regulating miRNA, ultimately modulating mRNA levels. Conclusion We have identified 4 lncRNAs as independent immune prognostic factors for OC. Furthermore, our findings offer novel insight into lncRNAs as OC immune and prognostic biomarkers.
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Affiliation(s)
- Huisheng Liang
- Department of Gynecology and Obstetrics, The Affiliated Zhongshan Hospital of Xiamen University, Xiamen, China.,Organ Transplantation Institute, School of Medicine, Xiamen University, Xiamen, China
| | - Yuquan Bai
- Department of Thoracic Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Hailong Wang
- Organ Transplantation Institute, School of Medicine, Xiamen University, Xiamen, China.,Department of Basic Medicine, School of Medicine, Xiamen University, Xiamen, China
| | - Xiangjun Yang
- Department of Gynecology and Obstetrics, The Affiliated Zhongshan Hospital of Xiamen University, Xiamen, China
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Zhang X, Xu X, Zhang Z, Xue C, Kong Z, Wu S, Yun X, Fu Y, Zhu C, Qin X. Linc-KILH potentiates Notch1 signaling through inhibiting KRT19 phosphorylation and promotes the malignancy of hepatocellular carcinoma. Int J Biol Sci 2021; 17:768-780. [PMID: 33767587 PMCID: PMC7975697 DOI: 10.7150/ijbs.52279] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Accepted: 01/16/2021] [Indexed: 02/06/2023] Open
Abstract
Long noncoding RNAs (LncRNAs) are emerging as crucial regulators in the pathophysiological process of various tumors, including HCC. Here, we identify a novel lncRNA Linc-KILH (KRT19 interacting long noncoding RNA in hepatocellular carcinoma), which is significantly up-regulated in HCC tissues and positively correlated with larger tumor size, severer microvascular invasion, more intrahepatic metastasis and decreased survival of HCC patients. Silence of Linc-KILH remarkably inhibited the proliferation and metastasis abilities of KRT19-positive HCC cells in vitro and in vivo. Mechanistically, Linc-KILH interacts with KRT19 and then inhibits the phosphorylation of KRT19 on Ser35, thereby, enhancing the translocation of KRT19 from cytoplasm to membrane in KRT19 positive HCC cells. Additionally, we validated that KRT19 interacts with β-catenin but not RAC1 in HCC cells. Linc-KILH enhanced the interaction between β-catenin and KRT19 in cytoplasm and promoted the nuclear translocation of β-catenin in HCC cells. Furthermore, Linc-KILH could enhance the promoting function of KRT19 on Notch1 signaling with the existence of KRT19 in HCC cells. Collectively, we revealed that Linc-KILH exerts a vital function in KRT19 positive HCC progression and may likely be developed into an effective therapeutic target for HCC.
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Affiliation(s)
- Xudong Zhang
- The Affiliated Changzhou NO.2 People's Hospital of Nanjing Medical University, 29 XingLongXiang Road, Changzhou, Jiangsu 213000, P.R. China
| | - Xiaoliang Xu
- School of medicine, Southeast University, Nanjing, China
- Department of Hepatobiliary Surgery of Nanjing Drum Tower Hospital, Nanjing Medical University, Nanjing, China
| | - Zechuan Zhang
- Department of Hepatobiliary Surgery of Nanjing Drum Tower Hospital, Nanjing Medical University, Nanjing, China
| | - Cailin Xue
- The Affiliated Changzhou NO.2 People's Hospital of Nanjing Medical University, 29 XingLongXiang Road, Changzhou, Jiangsu 213000, P.R. China
| | - Zhijun Kong
- The Affiliated Changzhou NO.2 People's Hospital of Nanjing Medical University, 29 XingLongXiang Road, Changzhou, Jiangsu 213000, P.R. China
| | - Siyuan Wu
- The Affiliated Changzhou NO.2 People's Hospital of Nanjing Medical University, 29 XingLongXiang Road, Changzhou, Jiangsu 213000, P.R. China
| | - Xiao Yun
- The Affiliated Changzhou NO.2 People's Hospital of Nanjing Medical University, 29 XingLongXiang Road, Changzhou, Jiangsu 213000, P.R. China
| | - Yue Fu
- The Affiliated Changzhou NO.2 People's Hospital of Nanjing Medical University, 29 XingLongXiang Road, Changzhou, Jiangsu 213000, P.R. China
| | - Chunfu Zhu
- The Affiliated Changzhou NO.2 People's Hospital of Nanjing Medical University, 29 XingLongXiang Road, Changzhou, Jiangsu 213000, P.R. China
| | - Xihu Qin
- The Affiliated Changzhou NO.2 People's Hospital of Nanjing Medical University, 29 XingLongXiang Road, Changzhou, Jiangsu 213000, P.R. China
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Tian Y, Zhong L, Gao S, Yu Y, Sun D, Liu X, Ji J, Yao Y, Liu Y, Jiang Z. LncRNA LINC00974 Downregulates miR-122 to Upregulate RhoA in Oral Squamous Cell Carcinoma. Cancer Biother Radiopharm 2021; 36:18-22. [PMID: 31702382 DOI: 10.1089/cbr.2019.2907] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Affiliation(s)
- Yanyan Tian
- Department of Stomatology, The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, China
| | - Lin Zhong
- Department of Stomatology, The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, China
| | - Shanling Gao
- Department of Stomatology, Baotou Eighth Hospital, Baotou, China
| | - Yunzhi Yu
- Department of Stomatology, Hospital of FIRMACO, The Fourth Affiliated of Inner Mongolia Medical University, Baotou, China
| | | | - Xiaxia Liu
- Department of Stomatology, The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, China
| | - Junying Ji
- Department of Stomatology, The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, China
| | - Yanan Yao
- Department of Stomatology, The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, China
| | - Yuexin Liu
- Department of Stomatology, The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, China
| | - Zhiwei Jiang
- Department of Stomatology, The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, China
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Ludwig-Słomczyńska AH, Seweryn MT, Kapusta P, Pitera E, Mantaj U, Cyganek K, Gutaj P, Dobrucka Ł, Wender-Ożegowska E, Małecki MT, Wołkow PP. The transcriptome-wide association search for genes and genetic variants which associate with BMI and gestational weight gain in women with type 1 diabetes. Mol Med 2021; 27:6. [PMID: 33472578 PMCID: PMC7818927 DOI: 10.1186/s10020-020-00266-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 12/30/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Clinical data suggest that BMI and gestational weight gain (GWG) are strongly interconnected phenotypes; however, the genetic basis of the latter is rather unclear. Here we aim to find genes and genetic variants which influence BMI and/or GWG. METHODS We have genotyped 316 type 1 diabetics using Illumina Infinium Omni Express Exome-8 v1.4 arrays. The GIANT, ARIC and T2D-GENES summary statistics were used for TWAS (performed with PrediXcan) in adipose tissue. Next, the analysis of association of imputed expression with BMI in the general and diabetic cohorts (Analysis 1 and 2) or GWG (Analysis 3 and 4) was performed, followed by variant association analysis (1 Mb around identified loci) with the mentioned phenotypes. RESULTS In Analysis 1 we have found 175 BMI associated genes and 19 variants (p < 10-4) which influenced GWG, with the strongest association for rs11465293 in CCL24 (p = 3.18E-06). Analysis 2, with diabetes included in the model, led to discovery of 1812 BMI associated loci and 207 variants (p < 10-4) influencing GWG, with the strongest association for rs9690213 in PODXL (p = 9.86E-07). In Analysis 3, among 648 GWG associated loci, 2091 variants were associated with BMI (FDR < 0.05). In Analysis 4, 7 variants in GWG associated loci influenced BMI in the ARIC cohort. CONCLUSIONS Here, we have shown that loci influencing BMI might have an impact on GWG and GWG associated loci might influence BMI, both in the general and T1DM cohorts. The results suggest that both phenotypes are related to insulin signaling, glucose homeostasis, mitochondrial metabolism, ubiquitinoylation and inflammatory responses.
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Affiliation(s)
| | - Michał T Seweryn
- Center for Medical Genomics OMICRON, Jagiellonian University Medical College, Kraków, Poland
- Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Przemysław Kapusta
- Center for Medical Genomics OMICRON, Jagiellonian University Medical College, Kraków, Poland
| | - Ewelina Pitera
- Center for Medical Genomics OMICRON, Jagiellonian University Medical College, Kraków, Poland
| | - Urszula Mantaj
- Department of Reproduction, Poznan University of Medical Sciences, Poznan, Poland
| | - Katarzyna Cyganek
- Department of Metabolic Diseases, University Hospital Kraków, Kraków, Poland
- Department of Metabolic Diseases, Jagiellonian University Medical College, Kraków, Poland
| | - Paweł Gutaj
- Department of Reproduction, Poznan University of Medical Sciences, Poznan, Poland
| | - Łucja Dobrucka
- Department of Metabolic Diseases, University Hospital Kraków, Kraków, Poland
| | - Ewa Wender-Ożegowska
- Department of Reproduction, Poznan University of Medical Sciences, Poznan, Poland
| | - Maciej T Małecki
- Department of Metabolic Diseases, University Hospital Kraków, Kraków, Poland
- Department of Metabolic Diseases, Jagiellonian University Medical College, Kraków, Poland
| | - Paweł P Wołkow
- Center for Medical Genomics OMICRON, Jagiellonian University Medical College, Kraków, Poland.
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Brex D, Barbagallo C, Mirabella F, Caponnetto A, Battaglia R, Barbagallo D, Caltabiano R, Broggi G, Memeo L, Di Pietro C, Purrello M, Ragusa M. LINC00483 Has a Potential Tumor-Suppressor Role in Colorectal Cancer Through Multiple Molecular Axes. Front Oncol 2021; 10:614455. [PMID: 33552987 PMCID: PMC7855711 DOI: 10.3389/fonc.2020.614455] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 12/04/2020] [Indexed: 12/20/2022] Open
Abstract
Long non-coding RNAs (lncRNAs) are the most heterogeneous class of non-protein-coding RNAs involved in a broad spectrum of molecular mechanisms controlling genome function, including the generation of complex networks of RNA-RNA competitive interactions. Accordingly, their dysregulation contributes to the onset of many tumors, including colorectal cancer (CRC). Through a combination of in silico approaches (statistical screening of expression datasets) and in vitro analyses (enforced expression, artificial inhibition, or activation of pathways), we identified LINC00483 as a potential tumor suppressor lncRNA in CRC. LINC00483 was downregulated in CRC biopsies and metastases and its decreased levels were associated with severe clinical features. Inhibition of the MAPK pathway and cell cycle arrest by starvation induced an upregulation of LINC00483, while the epithelial to mesenchymal transition activation by TGFβ-1 and IL-6 caused its down-modulation. Moreover, enforced expression of LINC00483 provoked a slowing down of cell migration rate without affecting cell proliferation. Since LINC00483 was predominantly cytoplasmic, we hypothesized a “miRNA sponge” role for it. Accordingly, we computationally reconstructed the LINC00483/miRNA/mRNA axes and evaluated the expression of mRNAs in different experimental conditions inducing LINC00483 alteration. By this approach, we identified a set of mRNAs sharing the miRNA response elements with LINC00483 and modulated in accordance with it. Moreover, we found that LINC00483 is potentially under negative control of transcription factor HNF4α. In conclusion, we propose that LINC00483 is a tumor suppressor in CRC that, through an RNA-RNA network, may control cell migration and participate in proliferation signaling.
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Affiliation(s)
- Duilia Brex
- Department of Biomedical and Biotechnological Sciences - Section of Biology and Genetics "Giovanni Sichel," University of Catania, Catania, Italy
| | - Cristina Barbagallo
- Department of Biomedical and Biotechnological Sciences - Section of Biology and Genetics "Giovanni Sichel," University of Catania, Catania, Italy
| | - Federica Mirabella
- Department of Biomedical and Biotechnological Sciences - Section of Biology and Genetics "Giovanni Sichel," University of Catania, Catania, Italy
| | - Angela Caponnetto
- Department of Biomedical and Biotechnological Sciences - Section of Biology and Genetics "Giovanni Sichel," University of Catania, Catania, Italy
| | - Rosalia Battaglia
- Department of Biomedical and Biotechnological Sciences - Section of Biology and Genetics "Giovanni Sichel," University of Catania, Catania, Italy
| | - Davide Barbagallo
- Department of Biomedical and Biotechnological Sciences - Section of Biology and Genetics "Giovanni Sichel," University of Catania, Catania, Italy
| | - Rosario Caltabiano
- Department of Medical, Surgical Sciences and Advanced Technologies G.F. Ingrassia, University of Catania, Catania, Italy
| | - Giuseppe Broggi
- Department of Medical, Surgical Sciences and Advanced Technologies G.F. Ingrassia, University of Catania, Catania, Italy
| | - Lorenzo Memeo
- Department of Experimental Oncology, Mediterranean Institute of Oncology (IOM), Catania, Italy
| | - Cinzia Di Pietro
- Department of Biomedical and Biotechnological Sciences - Section of Biology and Genetics "Giovanni Sichel," University of Catania, Catania, Italy
| | - Michele Purrello
- Department of Biomedical and Biotechnological Sciences - Section of Biology and Genetics "Giovanni Sichel," University of Catania, Catania, Italy
| | - Marco Ragusa
- Department of Biomedical and Biotechnological Sciences - Section of Biology and Genetics "Giovanni Sichel," University of Catania, Catania, Italy
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Sukowati CHC, Cabral LKD, Tiribelli C, Pascut D. Circulating Long and Circular Noncoding RNA as Non-Invasive Diagnostic Tools of Hepatocellular Carcinoma. Biomedicines 2021; 9:90. [PMID: 33477833 PMCID: PMC7832835 DOI: 10.3390/biomedicines9010090] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 01/14/2021] [Accepted: 01/16/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide, partially due to late diagnosis of the disease. Growing evidence in the field of biomarker discovery has shown the promising use of nucleic acid in the early detection of many cancers, including HCC. Here, we review data on how various long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) could be used as a diagnostic tool for HCC being differentially expressed in HCC compared to non-HCC patients. These non-coding RNAs (ncRNAs) showed high stability in the blood being present as free-circulating molecules or encapsulated into exosomes. This review reports some recent evidence on the use of lncRNAs and circRNAs as possible diagnostic biomarkers for HCC. Further, their pathophysiological mechanism in liver carcinogenesis was also described, elucidating the complex regulatory networks making these ncRNAs of particular relevance for the study of liver malignancy cancer.
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Affiliation(s)
- Caecilia H. C. Sukowati
- Fondazione Italiana Fegato ONLUS, AREA Science Park, Campus Basovizza, SS14, km 163.5, 34149 Trieste, Italy; (C.H.C.S.); (L.K.D.C.); (C.T.)
| | - Loraine Kay D. Cabral
- Fondazione Italiana Fegato ONLUS, AREA Science Park, Campus Basovizza, SS14, km 163.5, 34149 Trieste, Italy; (C.H.C.S.); (L.K.D.C.); (C.T.)
- Doctoral School in Molecular Biomedicine, University of Trieste, 34100 Trieste, Italy
| | - Claudio Tiribelli
- Fondazione Italiana Fegato ONLUS, AREA Science Park, Campus Basovizza, SS14, km 163.5, 34149 Trieste, Italy; (C.H.C.S.); (L.K.D.C.); (C.T.)
| | - Devis Pascut
- Fondazione Italiana Fegato ONLUS, AREA Science Park, Campus Basovizza, SS14, km 163.5, 34149 Trieste, Italy; (C.H.C.S.); (L.K.D.C.); (C.T.)
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Lin J, Fan X, Chen J, Xie X, Yu H. Small interfering RNA-mediated knockdown of KRT80 suppresses colorectal cancer proliferation. Exp Ther Med 2020; 20:176. [PMID: 33101466 PMCID: PMC7579811 DOI: 10.3892/etm.2020.9306] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Accepted: 04/17/2020] [Indexed: 02/05/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer in the world and its development is associated with oncogenic dysfunction. Therefore, the present study aimed to identify differentially expressed genes (DEGs) in CRC tissues and to determine the role of keratin 80 (KRT80) in CRC cell proliferation. DEGs were initially screened in 32 paired CRC tissues and matched adjacent normal tissues from RNA-Seq datasets in The Cancer Genome Atlas database using the limma package in R software. In total, 2,114 DEGs were identified, of which KRT80 was discovered to be the most upregulated in CRC tissues. Moreover, increased KRT80 expression levels were confirmed in tissues collected from 50 patients with CRC using reverse transcription-quantitative PCR, and its increased expression levels were significantly associated with increased lymph node and distant metastasis and a higher pathological stage. Furthermore, KRT80 knockdown using siRNA decreased the viability and proliferation of CRC cells. Finally, pathway analysis revealed that the proteins co-expressed with KRT80 in CRC were enriched in the cell cycle, DNA replication, immune system, metabolism of protein and RNA, signal transduction and other cellular processes. Among them, the cell cycle and DNA replication pathways contained the highest number of the proteins identified. In conclusion, the findings of the present study suggested that KRT80 may be overexpressed in CRC tissues. Furthermore, KRT80 may be involved in the proliferation of CRC cells, which is likely through its ability to regulate the cell cycle and DNA replication pathways, thus it may serve as a potential therapeutic target for patients with CRC.
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Affiliation(s)
- Jiatian Lin
- Department of Minimally Invasive Intervention, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Xiaoqin Fan
- Department of Otolaryngology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Junhui Chen
- Department of Minimally Invasive Intervention, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Xina Xie
- Guangdong Key Laboratory of Systems and Synthetic Biology for Urogenital Tumors, Institute of Translational Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong 518035, P.R. China
- Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - Hongjian Yu
- Department of Minimally Invasive Intervention, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
- Correspondence to: Dr Hongjian Yu, Department of Minimally Invasive Intervention, Peking University Shenzhen Hospital, 1120 Lianhua Road, Shenzhen, Guangdong 518036, P.R. China
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Comprehensive analysis of prognostic biomarkers in lung adenocarcinoma based on aberrant lncRNA-miRNA-mRNA networks and Cox regression models. Biosci Rep 2020; 40:221898. [PMID: 31950990 PMCID: PMC6997105 DOI: 10.1042/bsr20191554] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 12/04/2019] [Accepted: 01/07/2020] [Indexed: 12/14/2022] Open
Abstract
Lung adenocarcinoma (LUAD) is the leading cause of cancer-related death worldwide, and its underlying mechanism remains unclear. Accumulating evidence has highlighted that long non-coding RNA (lncRNA) acts as competitive endogenous RNA (ceRNA) and plays an important role in the occurrence and development of LUAD. Here, we comprehensively analyzed and provided an overview of the lncRNAs, miRNAs, and mRNAs associated with LUAD from The Cancer Genome Atlas (TCGA) database. Then, differentially expressed lncRNAs (DElncRNA), miRNAs (DEmiRNA), and mRNAs (DEmRNA) were used to construct a lncRNA–miRNA–mRNA regulatory network according to interaction information from miRcode, TargetScan, miRTarBase, and miRDB. Finally, the RNAs of the network were analyzed for survival and submitted for Cox regression analysis to construct prognostic indicators. A total of 1123 DElncRNAs, 95 DEmiRNAs, and 2296 DEmRNAs were identified (|log2FoldChange| (FC) > 2 and false discovery rate (FDR) or adjusted P value < 0.01). The ceRNA network was established based on this and included 102 lncRNAs, 19 miRNAs, and 33 mRNAs. The DEmRNAs in the ceRNA network were found to be enriched in various cancer-related biological processes and pathways. We detected 22 lncRNAs, 12 mRNAs, and 1 miRNA in the ceRNA network that were significantly associated with the overall survival of patients with LUAD (P < 0.05). We established three prognostic prediction models and calculated the area under the 1,3,5-year curve (AUC) values of lncRNA, mRNA, and miRNA, respectively. Among them, the prognostic index (PI) of lncRNA showed good predictive ability which was 0.737, 0.702 and 0.671 respectively, and eight lncRNAs can be used as candidate prognostic biomarkers for LUAD. In conclusion, our study provides a new perspective on the prognosis and diagnosis of LUAD on a genome-wide basis, and develops independent prognostic biomarkers for LUAD.
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Gupta M, Chandan K, Sarwat M. Role of microRNA and Long Non-Coding RNA in Hepatocellular Carcinoma. Curr Pharm Des 2020; 26:415-428. [PMID: 31939724 PMCID: PMC7403690 DOI: 10.2174/1381612826666200115093835] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Accepted: 12/04/2019] [Indexed: 02/08/2023]
Abstract
Hepatocellular carcinoma (HCC) accounts for about 80-90% of all liver cancers and is found to be the third most common cause of cancer mortality in the Asia-Pacific region. Risk factors include hepatitis B and C virus, cirrhosis, aflatoxin-contaminated food, alcohol, and diabetes. Surgically removing the tumor tissue seems effective but a high chance of recurrence has led to an urgent need to develop novel molecules for the treatment of HCC. Clinical management with sorafenib is found to be effective but it is only able to prolong survival for a few months. Various side effects like gastrointestinal and abdominal pain, hypertension, and hemorrhage are also associated with sorafenib, which calls for the unmet need of effective therapies against HCC. Similarly, the genetic mechanisms behind the occurrence of HCC are still unknown and need to be expounded further for developing newer candidates. Since unearthing the concept of these variants, transcriptomics has revealed the role of non-coding RNAs (ncRNAs) in many cellular, physiological and pathobiological processes. They are also found to be widely associated and abundantly expressed in a variety of cancer. Aberrant expression and mutations are closely related to tumorigenesis and metastasis and hence are classified as novel biomarkers and therapeutic targets for the treatment of cancer, including HCC. Herein, this review summarises the relationship between ncRNAs and hepatocellular carcinoma.
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Affiliation(s)
- Meenakshi Gupta
- Amity Institute of Pharmacy, Amity University, Noida-201313, Uttar Pradesh, India
| | - Kumari Chandan
- Amity Institute of Pharmacy, Amity University, Noida-201313, Uttar Pradesh, India
| | - Maryam Sarwat
- Amity Institute of Pharmacy, Amity University, Noida-201313, Uttar Pradesh, India
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Wang Z, Wang Q, Xu G, Meng N, Huang X, Jiang Z, Chen C, Zhang Y, Chen J, Li A, Li N, Zou X, Zhou J, Ding Q, Wang S. The long noncoding RNA CRAL reverses cisplatin resistance via the miR-505/CYLD/AKT axis in human gastric cancer cells. RNA Biol 2020; 17:1576-1589. [PMID: 31885317 PMCID: PMC7567514 DOI: 10.1080/15476286.2019.1709296] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 12/10/2019] [Accepted: 12/12/2019] [Indexed: 12/24/2022] Open
Abstract
Emerging evidence has suggested that long noncoding RNAs (lncRNAs) play an essential role in the tumorigenesis of multiple types of cancer including gastric cancer (GC). However, the potential biological roles and regulatory mechanisms of lncRNA in response to cisplatin, which may be involved in cisplatin resistance, have not been fully elucidated. In this study, we identified a novel lncRNA, cisplatin resistance-associated lncRNA (CRAL), that was downregulated in cisplatin-resistant GC cells, impaired cisplatin-induced DNA damage and cell apoptosis and thus contributed to cisplatin resistance in GC cells. Furthermore, the results indicated that CRAL mainly resided in the cytoplasm and could sponge endogenous miR-505 to upregulate cylindromatosis (CYLD) expression, which further suppressed AKT activation and led to an increase in the sensitivity of gastric cancer cells to cisplatin in vitro and in preclinical models. Moreover, a specific small molecule inhibitor of AKT activation, MK2206, effectively reversed the cisplatin resistance in GC caused by CRAL deficiency. In conclusion, we provide the first evidence that a novel lncRNA, CRAL, could function as a competing endogenous RNA (ceRNA) to reverse GC cisplatin resistance via the miR-505/CYLD/AKT axis, which suggests that CRAL could be considered a potential predictive biomarker and therapeutic target for cisplatin resistance in gastric cancer.
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Affiliation(s)
- Zhangding Wang
- Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People’s Republic of China
- Department of Molecular Cell Biology and Toxicology, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China
| | - Qiang Wang
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People’s Republic of China
| | - Guifang Xu
- Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People’s Republic of China
| | - Na Meng
- Department of Medical Records and Statistics, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People’s Republic of China
| | - Xinli Huang
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People’s Republic of China
| | - Zerun Jiang
- Department of Molecular Cell Biology and Toxicology, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China
| | - Chen Chen
- Department of Molecular Cell Biology and Toxicology, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China
| | - Yan Zhang
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People’s Republic of China
| | - Junjie Chen
- Department of Molecular Cell Biology and Toxicology, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China
| | - Aiping Li
- Department of Molecular Cell Biology and Toxicology, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China
| | - Nan Li
- Department of Gastroenterology, Zhongda Hospital Affiliated to Southeast University, Nanjing, Jiangsu Province, People’s Republic of China
| | - Xiaoping Zou
- Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People’s Republic of China
| | - Jianwei Zhou
- Department of Molecular Cell Biology and Toxicology, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China
| | - Qingqing Ding
- Department of Geriatric Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China
| | - Shouyu Wang
- Department of Molecular Cell Biology and Toxicology, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People’s Republic of China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China
- Jiangsu Key Laboratory of Molecular Medicine, Nanjing University Medical School, Nanjing, Jiangsu Province, People’s Republic of China
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Fei L, Sun G, You Q. miR-642a-5p partially mediates the effects of lipopolysaccharide on human pulmonary microvascular endothelial cells via eEF2. FEBS Open Bio 2020; 10:2294-2304. [PMID: 32881411 PMCID: PMC7609801 DOI: 10.1002/2211-5463.12969] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 08/08/2020] [Accepted: 08/27/2020] [Indexed: 11/29/2022] Open
Abstract
Inhalation or systemic administration of lipopolysaccharide (LPS) can induce acute pulmonary inflammation and lung injury. The pulmonary vasculature is composed of pulmonary microvascular endothelial cells (PMVECs), which form a semiselective membrane for gas exchange. The miRNA miR‐642a‐5p has previously been reported to be up‐regulated in patients with acute respiratory distress syndrome; thus, here, we examined whether this miRNA is involved in the effects of LPS on PMVECs. The levels of miR‐642a‐5p and mRNA encoding eukaryotic elongation factor 2 (eEF2) were detected by quantitative RT‐PCR. Moesin and eEF2 protein levels were tested by western blot assay. Dual‐luciferase reporter assay was used to examine the relationship between miR‐642a‐5p and eEF2. Cell viability was assessed using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay, and cell permeability was analyzed using the transendothelial electrical resistance assay. We report that miR‐642a‐5p levels are significantly up‐regulated in LPS‐stimulated PMVECs, and miR‐642a‐5p contributes to LPS‐induced hyperpermeability and apoptosis of PMVECs. LPS treatment results in down‐regulation of eEF2 in PMVECs. Overexpression of eEF2, a direct target of miR‐642a‐5p, inhibited the effect of LPS on PMVECs. miR‐642a‐5p promoted LPS‐induced hyperpermeability and apoptosis by targeting eEF2. Thus, miR‐642a‐5p and eEF2 may serve as potential targets for acute lung injury/acute respiratory distress syndrome diagnosis or treatment.
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Affiliation(s)
- Liming Fei
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Gengyun Sun
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Qinghai You
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China
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Lu Y, Hou K, Li M, Wu X, Yuan S. Exosome-Delivered LncHEIH Promotes Gastric Cancer Progression by Upregulating EZH2 and Stimulating Methylation of the GSDME Promoter. Front Cell Dev Biol 2020; 8:571297. [PMID: 33163491 PMCID: PMC7591465 DOI: 10.3389/fcell.2020.571297] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 09/22/2020] [Indexed: 12/20/2022] Open
Abstract
Gastric cancer is the third leading cause of cancer-related deaths worldwide and is characterized by poor survival and high recurrence rates. Long non-coding RNAs (lncRNAs) have gained considerable attention in recent years as prognostic markers and gene regulators in various cancers. Here, we found that lncHEIH was upregulated in gastric cancer tissues and cell lines and positively correlated with high expression levels of EZH2. Mechanistically, the lncHEIH-EZH2 axis could promote the progression of gastric cancer. In addition, lncHEIH encapsulated in exosomes was released by gastric cancer cells and then absorbed by normal gastric cells. The uptake of lncHEIH resulted in the upregulation of EZH2, which inhibited the expression of the tumor suppressor GSDME by methylation of the GSDME promoter, promoting the malignant transformation of normal gastric cells. Overall, lncHEIH promotes gastric cancer progression by upregulating the expression of EZH2 and reducing the expression of GSDME in normal cells to induce malignant cell proliferation and migration, indicating its potential as a target in gastric cancer therapy.
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Affiliation(s)
- Yan Lu
- Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, Key Laboratory of Gene Engineering of the Ministry of Education, College of Life Sciences, Sun Yat-sen University, Guangzhou, China
- Department of Gastrointestinal Surgery, The 8th Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, China
| | - Kaiqing Hou
- Department of Gastrointestinal Surgery, Haikou City People’s Hospital, Haikou, China
| | - Mengsen Li
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, China
| | - Xiaobin Wu
- Department of Gastrointestinal Surgery, The 8th Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Shaochun Yuan
- Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, Key Laboratory of Gene Engineering of the Ministry of Education, College of Life Sciences, Sun Yat-sen University, Guangzhou, China
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Xu G, Xu WY, Xiao Y, Jin B, Du SD, Mao YL, Zhang ZT. The emerging roles of non-coding competing endogenous RNA in hepatocellular carcinoma. Cancer Cell Int 2020; 20:496. [PMID: 33061848 PMCID: PMC7552539 DOI: 10.1186/s12935-020-01581-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 09/28/2020] [Indexed: 01/17/2023] Open
Abstract
Accumulating evidence has emerged revealing that noncoding RNAs (ncRNAs) play essential roles in the occurrence and development of hepatocellular carcinoma (HCC). However, the complicated regulatory interactions among various ncRNAs in the development of HCC are not entirely understood. The newly discovered mechanism of competing endogenous RNAs (ceRNAs) uncovered regulatory interactions among different varieties of RNAs. In recent years, a growing number of studies have suggested that ncRNAs, including long ncRNAs, circular RNAs and pseudogenes, play major roles in the biological functions of the ceRNA network in HCC. These ncRNAs can share microRNA response elements to affect microRNA affinity with target RNAs, thus regulating gene expression at the transcriptional level and both physiological and pathological processes. The ncRNAs that function as ceRNAs are involved in diverse biological processes in HCC cells, such as tumor cell proliferation, epithelial-mesenchymal transition, invasion, metastasis and chemoresistance. Based on these findings, ncRNAs that act as ceRNAs may be promising candidates for clinical diagnosis and treatments. In this review, we discuss the mechanisms and research methods of ceRNA networks. We also reviewed the recent advances in studying the roles of ncRNAs as ceRNAs in HCC and highlight possible directions and possibilities of ceRNAs as diagnostic biomarkers or therapeutic targets. Finally, the limitations, gaps in knowledge and opportunities for future research are also discussed.
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Affiliation(s)
- Gang Xu
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital and Chinese Academy of Medical Sciences, 1# Shuaifuyuan, Wangfujing, Dong-Cheng District, Beijing, 100730 China
| | - Wei-Yu Xu
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Cancer Invasion and Metastasis Research & National Clinical Research Center for Digestive Diseases, No. 95 Yong-An Road, Xi-Cheng District, Beijing, 100050 People's Republic of China
| | - Yao Xiao
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital and Chinese Academy of Medical Sciences, 1# Shuaifuyuan, Wangfujing, Dong-Cheng District, Beijing, 100730 China
| | - Bao Jin
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital and Chinese Academy of Medical Sciences, 1# Shuaifuyuan, Wangfujing, Dong-Cheng District, Beijing, 100730 China
| | - Shun-Da Du
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital and Chinese Academy of Medical Sciences, 1# Shuaifuyuan, Wangfujing, Dong-Cheng District, Beijing, 100730 China
| | - Yi-Lei Mao
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital and Chinese Academy of Medical Sciences, 1# Shuaifuyuan, Wangfujing, Dong-Cheng District, Beijing, 100730 China
| | - Zhong-Tao Zhang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Cancer Invasion and Metastasis Research & National Clinical Research Center for Digestive Diseases, No. 95 Yong-An Road, Xi-Cheng District, Beijing, 100050 People's Republic of China
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