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Habibzadeh G, Mokhtari K, Heshmati M, Salimy S, Mei Z, Entezari M, Hashemi M, Fu J, Maghsoudloo M. Identification of lncRNA associated with the SERPINE1 gene in colorectal cancer through TGF-β pathway. Comput Biol Med 2025; 190:110037. [PMID: 40112564 DOI: 10.1016/j.compbiomed.2025.110037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Revised: 03/12/2025] [Accepted: 03/14/2025] [Indexed: 03/22/2025]
Abstract
Colorectal cancer (CRC) is a common cancer type which develops due to intricate molecular processes, the Transforming Growth Factor-beta (TGF-β) pathway a role in progression. This study investigates the immunological functions of SERPINE1 and its interaction with long non-coding RNA (lncRNA) LINC01705 within the TGF-β pathway, aiming to identify novel therapeutic targets for CRC. We hypothesized that LINC01705 modulates SERPINE1 expression, thereby influencing CRC progression and immune response. To test this hypothesis, we employed bioinformatics analysis of the TCGA-COAD dataset and experimental validation through RT-qPCR. Our findings revealed a significant upregulation of SERPINE1 in CRC, with nine interacting proteins involved in CRC-related processes identified through coexpression network analysis. Moreover, our findings revealed a high prevalence of mutations in SERPINE1, highlighting its potential as a target for immunotherapy. Additionally, we identified a strong correlation between LINC01705 and SERPINE1, with experimental validation confirming their concurrent upregulation in CRC tissues. These results highlight the importance of the SERPINE1/LINC01705 axis as a novel candidate that influence the TGF-β pathway, offering new insights into CRC pathogenesis and providing potential targets for diagnosis and immunotherapy.
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Affiliation(s)
- Ghazale Habibzadeh
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Khatere Mokhtari
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Masoomeh Heshmati
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Siamak Salimy
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Zhiqiang Mei
- Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Maliheh Entezari
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Junjiang Fu
- Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Mazaher Maghsoudloo
- Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou 646000, Sichuan, China.
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Gan L, Zheng L, Zou J, Luo P, Chen T, Zou J, Li W, Chen Q, Cheng L, Zhang F, Qian B. Critical roles of lncRNA-mediated autophagy in urologic malignancies. Front Pharmacol 2024; 15:1405199. [PMID: 38939836 PMCID: PMC11208713 DOI: 10.3389/fphar.2024.1405199] [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: 03/22/2024] [Accepted: 05/23/2024] [Indexed: 06/29/2024] Open
Abstract
Urologic oncology is a significant public health concern on a global scale. Recent research indicates that long chain non-coding RNAs (lncRNAs) and autophagy play crucial roles in various cancers, including urologic malignancies. This article provides a summary of the latest research findings, suggesting that lncRNA-mediated autophagy could either suppress or promote tumors in prostate, kidney, and bladder cancers. The intricate network involving different lncRNAs, target genes, and mediated signaling pathways plays a crucial role in urological malignancies by modulating the autophagic process. Dysregulated expression of lncRNAs can disrupt autophagy, leading to tumorigenesis, progression, and enhanced resistance to therapy. Consequently, targeting particular lncRNAs that control autophagy could serve as a dependable diagnostic tool and a promising prognostic biomarker in urologic oncology, while also holding potential as an effective therapeutic approach.
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Affiliation(s)
- Lifeng Gan
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Key Laboratory of Urology and Andrology of Ganzhou, Ganzhou, Jiangxi, China
| | - Liying Zheng
- Department of Graduate, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Junrong Zou
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Key Laboratory of Urology and Andrology of Ganzhou, Ganzhou, Jiangxi, China
| | - Peiyue Luo
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Key Laboratory of Urology and Andrology of Ganzhou, Ganzhou, Jiangxi, China
| | - Tao Chen
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Key Laboratory of Urology and Andrology of Ganzhou, Ganzhou, Jiangxi, China
| | - Jun Zou
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Key Laboratory of Urology and Andrology of Ganzhou, Ganzhou, Jiangxi, China
| | - Wei Li
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Key Laboratory of Urology and Andrology of Ganzhou, Ganzhou, Jiangxi, China
| | - Qi Chen
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Key Laboratory of Urology and Andrology of Ganzhou, Ganzhou, Jiangxi, China
| | - Le Cheng
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Key Laboratory of Urology and Andrology of Ganzhou, Ganzhou, Jiangxi, China
| | - Fangtao Zhang
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Key Laboratory of Urology and Andrology of Ganzhou, Ganzhou, Jiangxi, China
| | - Biao Qian
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Key Laboratory of Urology and Andrology of Ganzhou, Ganzhou, Jiangxi, China
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Liu S, Huttad L, He G, He W, Liu C, Cai D, Chen H, Qiu J. Long noncoding RNA HULC regulates the NF-κB pathway and represents a promising prognostic biomarker in liver cancer. Cancer Med 2023; 12:5124-5136. [PMID: 36213936 PMCID: PMC9972175 DOI: 10.1002/cam4.5263] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 04/13/2022] [Accepted: 04/24/2022] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND Long noncoding RNAs (lncRNAs) are involved in a diverse array of biological processes. While lncRNAs are commonly upregulated in hepatocellular carcinoma (HCC), the specific regulatory roles they play in this oncogenic context require further study and clarification. Although HULC (lncRNA highly upregulated in liver cancer) is involved in disease pathogenesis, its precise role in this context remains unclear. METHODS Here, we have explored the mechanistic relevance of HULC expression by assessing its expression in patient samples. The importance of this lncRNA in the onset and progression of HCC was investigated through in vitro approaches including Western blotting, quantitative PCR, Transwell assays, electron microscopy, wound healing assays, and real-time cell analysis (RTCA). Additionally, the in vivo functions of this lncRNA were assessed using an orthotopic HCC xenograft in nude mouse model system. RESULTS HULC was identified as a lncRNA that is highly upregulated in human liver tumors. In vitro, HULC was able to promote HCC malignancy, although its excess overexpression also led robust autophagic induction, promoting the increased expression of autophagy-associated genes including LC3 and Beclin-1. At a mechanistic level, HULC was able to promote the phosphorylation of p65 and IkBkB thus enhancing autophagy by increasing LC3II levels in a manner dependent upon the NF-κB pathway. HULC downregulation was also linked to impaired orthotopic HCC tumor growth in vivo. The link between HULC and autophagy may play a role in disease progression. CONCLUSIONS These results suggest that HULC is an oncogenic lncRNA, and may thus offer value as a prognostic biomarker and promoter of HCC development, in addition to being a potential therapeutic target in this cancer type.
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Affiliation(s)
- Shihai Liu
- Medical Animal Lab, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Lakshmi Huttad
- Asian Liver Center, Department of Surgery, School of Medicine, Stanford University, Stanford, California, USA
| | - Guifang He
- Medical Animal Lab, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Weitai He
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi'an, China
| | - Changchang Liu
- Medical Animal Lab, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Duo Cai
- Medical Animal Lab, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hao Chen
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, Biomedical Informatics & Genomics Center, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China.,Research Institute of Xi'an Jiaotong University, Hangzhou, Zhejiang, China
| | - Jing Qiu
- Department of Stomatology, Qingdao Municipal Hospital, Qingdao, China
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Li D, Wang R, Wu N, Yu Y. LncRNA HULC as a potential predictor of prognosis and clinicopathological features in patients with digestive system tumors: a meta-analysis. Aging (Albany NY) 2022; 14:1797-1811. [PMID: 35183058 PMCID: PMC8908940 DOI: 10.18632/aging.203903] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 02/02/2022] [Indexed: 11/25/2022]
Abstract
Objective: This meta-analysis aimed to evaluate the correlation between lncRNA HULC, prognosis and clinicopathological characteristics in patients with digestive system tumors. Methods: The relevant literatures were collected through PubMed, Web of Science and Embase up to February 2021. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to assess the prognostic value of HULC in patients with digestive system tumors. The clinicopathological characteristics of HULC in patients were estimated by odds ratios (ORs). Results: A total of 14 studies involving 1312 patients were included. The up-regulated expression level of HULC was associated with poorer overall survival (OS) in patients with digestive system tumors (HR = 1.83, 95% CI: 1.05-3.19, P = 0.033). Subgroup analysis showed that cancer type (pancreatic cancer or gastric cancer), residence region (China, Japan or Korea), and specimen (serum) significantly associated between HULC and OS. In addition, high HULC expression significantly increased the risk of high TNM stage (OR = 2.51, 95%CI: 1.36-4.62, P < 0.05), poor differentiation (OR = 1.38, 95%CI: 1.02-1.87, P < 0.05) and lymphatic node metastasis (LNM, OR = 4.93, 95% CI: 3.47-6.99, P < 0.05). Conclusions: High expression level of HULC is related to OS, TNM stage, differentiation and LNM. Therefore, HULC can be used as a new potential predictor for prognosis and clinicopathological features of patients with digestive system tumors.
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Affiliation(s)
- Duo Li
- Department of Gastroenterology, The First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei, China
| | - Rui Wang
- Department of Gastroenterology, The First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei, China
| | - Na Wu
- Department of Gastroenterology, The First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei, China
| | - Yongqiang Yu
- Department of Gastroenterology, The First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei, China
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Wang Z, Yang X, Gui S, Yang F, Cao Z, Cheng R, Xia X, Li C. The Roles and Mechanisms of lncRNAs in Liver Fibrosis. Front Pharmacol 2021; 12:779606. [PMID: 34899344 PMCID: PMC8652206 DOI: 10.3389/fphar.2021.779606] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Accepted: 11/02/2021] [Indexed: 12/12/2022] Open
Abstract
Long non-coding RNAs (lncRNAs) can potentially regulate all aspects of cellular activity including differentiation and development, metabolism, proliferation, apoptosis, and activation, and benefited from advances in transcriptomic and genomic research techniques and database management technologies, its functions and mechanisms in physiological and pathological states have been widely reported. Liver fibrosis is typically characterized by a reversible wound healing response, often accompanied by an excessive accumulation of extracellular matrix. In recent years, a range of lncRNAs have been investigated and found to be involved in several cellular-level regulatory processes as competing endogenous RNAs (ceRNAs) that play an important role in the development of liver fibrosis. A variety of lncRNAs have also been shown to contribute to the altered cell cycle, proliferation profile associated with the accelerated development of liver fibrosis. This review aims to discuss the functions and mechanisms of lncRNAs in the development and regression of liver fibrosis, to explore the major lncRNAs involved in the signaling pathways regulating liver fibrosis, to elucidate the mechanisms mediated by lncRNA dysregulation and to provide new diagnostic and therapeutic strategies for liver fibrosis.
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Affiliation(s)
- Zhifa Wang
- Department of Rehabilitation Medicine, Chaohu Hospital of Anhui Medical University, Hefei Anhui, China
| | - Xiaoke Yang
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Siyu Gui
- Department of Ophthalmology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Fan Yang
- The First Clinical Medical College, Anhui Medical University, Hefei, China
| | - Zhuo Cao
- The First Clinical Medical College, Anhui Medical University, Hefei, China
| | - Rong Cheng
- Department of Gastroenterology, Anhui Provincial Children's Hospital, Hefei, China
| | - Xiaowei Xia
- Department of Gastroenterology, Anhui Provincial Children's Hospital, Hefei, China
| | - Chuanying Li
- Department of Gastroenterology, Anhui Provincial Children's Hospital, Hefei, China
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Wang J, Zhong P, Hua H. The Clinical Prognostic Value of lncRNA SBF2-AS1 in Cancer Patients: A Meta-Analysis. Technol Cancer Res Treat 2021; 20:15330338211004915. [PMID: 33906548 PMCID: PMC8107676 DOI: 10.1177/15330338211004915] [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] [Indexed: 11/18/2022] Open
Abstract
Background: The mortality and recurrence of patients with cancer is of high prevalence. SET-binding factor 2 (SBF2) antisense RNA1 (lncRNA-SBF2-AS1) is a promising long non-coding RNA. There is increasing evidence that SBF2-AS1 is abnormally expressed in various tumors and is associated with cancer prognosis. However, the identification of the effect of lncRNA SBF2-AS1 in tumors remains necessary. Materials and Methods: Up to November 2, 2020, electronic databases, including PubMed, Cochrane Library, EMBASE, Medline, and Web of Science, were searched. The results were evaluated by pooled odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs). Results: A total of 11 literatures on cancer patients were included for the present meta-analysis. The combined results revealed that high expression of SBF2-AS1 was significantly associated with unfavorable overall survival (OS) (HR = 1.48, 95% CI: 1.34-1.62, P < 0.00001) in a variety of cancers. In additional, the increase in SBF2-AS1 expression was also correlated with tumor size ((larger vs. smaller) OR = 2.34, 95% CI: 1.47-3.70, P = 0.0003), advanced TNM stage ((III/IV vs. I/II) OR = 2.78, 95% CI: 1.75-4.41, P < 0.0001), lymph node metastasis ((Positive vs. Negative) OR = 3.06, 95% CI: 1.93-4.86, P < 0.00001), and histological grade ((poorly vs. well/moderately) OR = 2.58, 95% CI: 1.47-4.52, P = 0.001) in patients with cancer. Furthermore, The Cancer Genome Atlas (TCGA) dataset valuated that SBF2-AS1 was upregulated in a variety of tumors, and predicted the worse prognosis. Conclusions: Our results of this meta-analysis demonstrate that high SBF2-AS1 expression may become a potential target for predicting the prognosis of human cancers.
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Affiliation(s)
- Jie Wang
- Department of Hepatic-Biliary-Pancreatic Surgery, The 371971First People's Hospital of Neijiang, Neijiang, Sichuan, China
| | - Pingyong Zhong
- Department of Hepatic-Biliary-Pancreatic Surgery, The 371971First People's Hospital of Neijiang, Neijiang, Sichuan, China
| | - Hao Hua
- Department of Hepatic-Biliary-Pancreatic Surgery, The 371971First People's Hospital of Neijiang, Neijiang, Sichuan, China
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β-Elemene suppresses tumor growth of diffuse large B-cell lymphoma through regulating lncRNA HULC-mediated apoptotic pathway. Biosci Rep 2021; 40:222028. [PMID: 32010942 PMCID: PMC7012654 DOI: 10.1042/bsr20190804] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 01/23/2020] [Accepted: 01/28/2020] [Indexed: 01/04/2023] Open
Abstract
Background: Diffuse large B-cell lymphoma (DLBCL) is considered the most common aggressive subtype of lymphoma. A number of DLBCL patients fail to achieve a response to currently available therapies or develop resistance. β-Elemene is derived from herb Curcuma wenyujin, and exhibits anti-tumor activity in both solid and non-solid tumors through modulating several molecular signaling pathways. We aimed to explore the role of β-elemene in DLBCL treatment and elucidate the involved mechanism. Materials and methods: Cell viability, apoptosis and expressions of related proteins were assessed and in vivo study were performed to determine the tumor suppressive effect of β-elemene and explore the molecular mechanisms. Results: β-Elemene significantly suppressed the viability of DLBCL cells, and β-elemene down-regulated the lncRNA HULC expression and regulated key pro-apoptotic and anti-apoptotic proteins to induce significant apoptosis of DLBCL cells. HULC overexpression could decrease the β-elemene induced apoptosis, while HULC knockdown increased the apoptosis in DLBCL cells. In vivo study further confirmed that β-elemene could suppress the growth of DLBCL xenograft and regulate the HULC expression and the critical proteins of the apoptotic pathway. Conclusion: β-Elemene performs as a tumor suppressor and modulator of HULC-mediated apoptotic pathway in DLBCL and will be an alternative candidate for clinical application.
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Klein MI, Cannataro VL, Townsend JP, Newman S, Stern DF, Zhao H. Identifying modules of cooperating cancer drivers. Mol Syst Biol 2021; 17:e9810. [PMID: 33769711 PMCID: PMC7995435 DOI: 10.15252/msb.20209810] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 01/20/2021] [Accepted: 01/26/2021] [Indexed: 12/22/2022] Open
Abstract
Identifying cooperating modules of driver alterations can provide insights into cancer etiology and advance the development of effective personalized treatments. We present Cancer Rule Set Optimization (CRSO) for inferring the combinations of alterations that cooperate to drive tumor formation in individual patients. Application to 19 TCGA cancer types revealed a mean of 11 core driver combinations per cancer, comprising 2-6 alterations per combination and accounting for a mean of 70% of samples per cancer type. CRSO is distinct from methods based on statistical co-occurrence, which we demonstrate is a suboptimal criterion for investigating driver cooperation. CRSO identified well-studied driver combinations that were not detected by other approaches and nominated novel combinations that correlate with clinical outcomes in multiple cancer types. Novel synergies were identified in NRAS-mutant melanomas that may be therapeutically relevant. Core driver combinations involving NFE2L2 mutations were identified in four cancer types, supporting the therapeutic potential of NRF2 pathway inhibition. CRSO is available at https://github.com/mikekleinsgit/CRSO/.
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Affiliation(s)
- Michael I Klein
- Program in Computational Biology and BioinformaticsYale UniversityNew HavenCTUSA
- Bioinformatics R&DSema4StamfordCTUSA
| | - Vincent L Cannataro
- Department of BiologyEmmanuel CollegeBostonMAUSA
- Department of BiostatisticsYale School of Public HealthNew HavenCTUSA
| | - Jeffrey P Townsend
- Program in Computational Biology and BioinformaticsYale UniversityNew HavenCTUSA
- Department of BiostatisticsYale School of Public HealthNew HavenCTUSA
- Yale Cancer CenterYale UniversityNew HavenCTUSA
| | | | - David F Stern
- Yale Cancer CenterYale UniversityNew HavenCTUSA
- Department of PathologyYale School of MedicineNew HavenCTUSA
| | - Hongyu Zhao
- Program in Computational Biology and BioinformaticsYale UniversityNew HavenCTUSA
- Department of BiostatisticsYale School of Public HealthNew HavenCTUSA
- Yale Cancer CenterYale UniversityNew HavenCTUSA
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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: 29] [Impact Index Per Article: 7.3] [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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10
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Wang H, Feng Q, Wu Y, Feng L, Yuan H, Hou L, Wei P, Wang C, Wang J. Association of circulating long non-coding RNA HULC expression with disease risk, inflammatory cytokines, biochemical index levels, severity-assessed scores, and mortality of sepsis. J Clin Lab Anal 2020; 35:e23656. [PMID: 33314296 PMCID: PMC7957974 DOI: 10.1002/jcla.23656] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 10/29/2020] [Accepted: 11/05/2020] [Indexed: 12/13/2022] Open
Abstract
Background The present study aimed to explore the correlation of long non‐coding RNA highly up‐regulating in liver cancer (lncRNA HULC) with disease risk, inflammatory cytokines, biochemical indexes, disease severity, infective features, and 28‐day mortality of sepsis. Methods Totally 174 sepsis patients and 100 controls were enrolled. Peripheral blood samples were collected from sepsis patients after diagnosis and from controls at enrollment, respectively, and further for separation of peripheral blood mononuclear cell (PBMC) and serum samples. PBMC samples were for lncRNA HULC detection, and serum samples were for inflammatory cytokine detection. Results LncRNA HULC expression was increased in sepsis patients compared with controls. Moreover, lncRNA HULC was positively associated with TNF‐α, IL‐6, IL‐17, intercellular adhesion molecule 1, vascular cell adhesion molecule 1, serum creatinine, white blood cell, and C‐reactive protein in sepsis patients, but not in controls. Furthermore, in sepsis patients, lncRNA HULC expression was positively correlated with acute physiology and chronic health evaluation II score and sequential organ failure assessment score, but not correlated with primary infection sites or primary infection organisms; meanwhile, lncRNA HULC expression was increased in deaths compared with survivors; subsequent receiver operating characteristic curve indicated that lncRNA HULC presented good value in predicting increased 28‐day mortality (AUC: 0.785, 95% CI: 0.713–0.857), and its independent predictive value for mortality was also verified by multivariate analysis. Conclusion LncRNA HULC is correlated with higher disease risk, severity, and inflammation and serves as an independent factor for predicting increased mortality, suggesting its potential in promoting accuracy of prognostic prediction for sepsis management.
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Affiliation(s)
- Haiyan Wang
- Department of Critical Care Medicine, HanDan Central Hospital, Handan, China
| | - Qiang Feng
- Department of Cardiology, HanDan Central Hospital, Handan, China
| | - Yiping Wu
- Department of Neurology, HanDan Central Hospital, Handan, China
| | - Lingxiang Feng
- Department of Critical Care Medicine, HanDan Central Hospital, Handan, China
| | - Haiyan Yuan
- Department of Critical Care Medicine, HanDan Central Hospital, Handan, China
| | - Liyan Hou
- Department of Critical Care Medicine, HanDan Central Hospital, Handan, China
| | - Peixuan Wei
- Department of Critical Care Medicine, HanDan Central Hospital, Handan, China
| | - Chao Wang
- Department of Critical Care Medicine, HanDan Central Hospital, Handan, China
| | - Jingmei Wang
- Department of Critical Care Medicine, HanDan Central Hospital, Handan, China
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Li L, Zhu H, Li X, Ke Y, Yang S, Cheng Q. Long non-coding RNA HAGLROS facilitates the malignant phenotypes of NSCLC cells via repressing miR-100 and up-regulating SMARCA5. Biomed J 2020; 44:S305-S315. [PMID: 35307327 PMCID: PMC9068548 DOI: 10.1016/j.bj.2020.12.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Revised: 12/15/2020] [Accepted: 12/24/2020] [Indexed: 12/25/2022] Open
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Olivero CE, Dimitrova N. Identification and characterization of functional long noncoding RNAs in cancer. FASEB J 2020; 34:15630-15646. [PMID: 33058262 PMCID: PMC7756267 DOI: 10.1096/fj.202001951r] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 09/29/2020] [Accepted: 10/01/2020] [Indexed: 12/12/2022]
Abstract
Long noncoding RNAs (lncRNAs) have emerged as key regulators in a variety of cellular processes that influence disease states. In particular, many lncRNAs are genetically or epigenetically deregulated in cancer. However, whether lncRNA alterations are passengers acquired during cancer progression or can act as tumorigenic drivers is a topic of ongoing investigation. In this review, we examine the current methodologies underlying the identification of cancer-associated lncRNAs and highlight important considerations for evaluating their biological significance as cancer drivers.
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Affiliation(s)
- Christiane E. Olivero
- Department of Molecular, Cellular and Developmental BiologyYale UniversityNew HavenCTUSA
| | - Nadya Dimitrova
- Department of Molecular, Cellular and Developmental BiologyYale UniversityNew HavenCTUSA
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13
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Zhang H, Li S, Xu H, Sun L, Zhu Z, Yao Z. Interference of miR-107 with Atg12 is inhibited by HULC to promote metastasis of hepatocellular carcinoma. MedComm (Beijing) 2020; 1:165-177. [PMID: 34766115 PMCID: PMC8491224 DOI: 10.1002/mco2.25] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 06/10/2020] [Accepted: 06/11/2020] [Indexed: 01/13/2023] Open
Abstract
Highly upregulated in liver cancer (HULC) had a significant predictive effect on tumor growth and metastasis of hepatocellular carcinoma (HCC); however, the mechanisms of HULC on HCC still need to be clarified. We attempted to determine the roles of HULC and miR-107 in autophagy and invasion of HCC. HULC siRNA reduced the level of autophagy. The impact of HULC siRNA on invasion can be reversed by activating autophagy in HCC cell lines. Further studies on HULC and autophagy were conducted. An interacting sequence between HULC and miR-107, as well as miR-107 and Atg12, was predicted by software. The relationship of each pair of molecules was confirmed by luciferase reporter assays. The negative impacts of miR-107 on autophagy and invasion were proved in HCC cell lines. The inhibitor of miR-107-promoted invasion can also be reversed by Atg12 siRNA. The changes of miR-107, Atg12, epithelial-mesenchymal transition, and autophagy in transplanted tumors of mouse models also confirmed the results in HCC cell lines. Finally, we find that HULC acts as an endogenous sponge, which abolishes the binding of miR-107 on the Atg12 3'-UTR and promotes autophagy and metastasis of HCC.
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Affiliation(s)
- Haiming Zhang
- Liver Transplantation CenterNational Clinical Research Center for Digestive Diseases and Beijing Key Laboratory of Tolerance Induction and Organ Protection in TransplantationBeijing Friendship HospitalCapital Medical UniversityBeijingChina
| | - Shipeng Li
- Department of General SurgeryJiaozuo People's HospitalXinxiang Medical UniversityJiaozuoChina
| | - Haixu Xu
- Department of ImmunologyTianjin Key Laboratory of Cellular and Molecular ImmunologyTianjin Medical UniversityTianjinChina
| | - Liying Sun
- Liver Transplantation CenterNational Clinical Research Center for Digestive Diseases and Beijing Key Laboratory of Tolerance Induction and Organ Protection in TransplantationBeijing Friendship HospitalCapital Medical UniversityBeijingChina
| | - Zhijun Zhu
- Liver Transplantation CenterNational Clinical Research Center for Digestive Diseases and Beijing Key Laboratory of Tolerance Induction and Organ Protection in TransplantationBeijing Friendship HospitalCapital Medical UniversityBeijingChina
| | - Zhi Yao
- Department of ImmunologyTianjin Key Laboratory of Cellular and Molecular ImmunologyTianjin Medical UniversityTianjinChina
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Zhong Y, Zhao M, Yu Y, Li Q, Wang F, Wu P, Zhang W, Miao L. Prognostic value and therapeutic potential of the long noncoding RNA TP73-AS1 in cancers: A systematic review and meta-analysis. Sci Rep 2020; 10:9053. [PMID: 32493915 PMCID: PMC7271165 DOI: 10.1038/s41598-020-65726-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 04/30/2020] [Indexed: 12/26/2022] Open
Abstract
Studies published in recent years have demonstrated that abnormal long noncoding RNA (lncRNA) antisense RNA to TP73 gene (TP73-AS1) expression is markedly associated with tumorigenesis, cancer progression and the prognosis of cancer patients. We aimed to explore the prognostic value of TP73-AS1 in multiple cancers. We comprehensively searched PubMed, Embase, Web of Science and the Cochrane Library (up to February 21, 2019). Hazard ratios (HRs), odds ratios (ORs) and the corresponding 95% confidence intervals (95% CIs) were calculated to estimate the association of TP73-AS1 with survival and clinicopathological features. The potential targets and pathways of TP73-AS1 in multiple cancers were summarized. Nineteen studies that involved thirteen types of cancers and 1329 cancer patients were identified as eligible for this meta-analysis. The results showed that high TP73-AS1 expression was significantly correlated with shorter overall survival (OS) (HR = 1.962, 95% CI 1.630-2.362) and disease-free survival (DFS) (HR = 2.050, 95% CI 1.293-3.249). The summary HRs of OS were 2.101 (95% CI 1.516-2.911) for gastric cancer (GC) and 1.920 (95% CI 1.253-2.942) for osteosarcoma. Subgroup analysis of OS demonstrated that the differential expression of TP73-AS1 in cancer tissues was a potential source of heterogeneity. Furthermore, increased TP73-AS1 expression was markedly associated with larger tumor size (OR = 2.759, 95% CI 1.759-4.330), advanced histological grade (OR = 2.394, 95% CI 1.231-4.656), lymph node metastasis (OR = 2.687, 95% CI 1.211-5.962), distant metastasis (OR = 4.145, 95% CI 2.252-7.629) and advanced TNM stage (OR = 2.633, 95% CI 1.507-4.601). The results of Egger's test and sensitivity analysis verified the robustness of the original results. High TP73-AS1 expression can predict poor survival and poor clinicopathological features in cancer patients and TP73-AS1 might be a potential biomarker and therapeutic target.
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Affiliation(s)
- Yuan Zhong
- Medical Center for Digestive Diseases, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, China
| | - Meng Zhao
- Department of Cardiovascular Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, China
| | - Yang Yu
- Nantong Tumor Hospital, Nantong, 226300, China
| | - Quanpeng Li
- Medical Center for Digestive Diseases, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, China
| | - Fei Wang
- Medical Center for Digestive Diseases, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, China
| | - Peiyao Wu
- Medical Center for Digestive Diseases, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, China
| | - Wen Zhang
- Medical Center for Digestive Diseases, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, China
| | - Lin Miao
- Medical Center for Digestive Diseases, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, China.
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15
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Long noncoding RNA LINC00460 conduces to tumor growth and metastasis of hepatocellular carcinoma through miR-342-3p-dependent AGR2 up-regulation. Aging (Albany NY) 2020; 12:10544-10555. [PMID: 32493835 PMCID: PMC7346032 DOI: 10.18632/aging.103278] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 04/28/2020] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common malignant tumor in the world. It ranks third among cancer-induced deaths worldwide and has the characteristics of high metastasis and high recurrence rate. Long non-coding RNA (LncRNA) LINC00460 is significantly up-regulated in multiple types of cancers and is closely related to the progression of tumors. However, effects of LINC00460 and corresponding regulatory path in HCC are still poorly investigated. In our study, we found that expression of LINC00460 was up-regulated in HCC tissues and cell lines compared with the control. Then we revealed that knockdown of LINC00460 suppressed cell proliferation and cell mobility and induced cell apoptosis in HCC cells. Further study demonstrated that knockdown of LINC00460 suppressed the progression of HCC by elevating the expression of microRNA (miRNA, miR)-342-3p. Besides that, metastasis marker, Anterior gradient homolog 2 (AGR2) was found to be a target of miR-342-3p and overexpression of AGR2 promoted the progression of HCC. Finally, the in vivo experiments further verified the anti-tumor effects of LINC00460 / miR-342-3p / AGR2 axis in HCC. The LINC00460 / miR-342-3p / AGR2 axis exerts anti-tumor effect in HCC in vitro and in vivo, consolidating and expanding the research about targeted gene therapy for early diagnosis and treatment of HCC.
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16
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Highly upregulated in liver cancer (HULC): An update on its role in carcinogenesis. J Cell Physiol 2020; 235:9071-9079. [DOI: 10.1002/jcp.29765] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 04/25/2020] [Indexed: 12/13/2022]
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17
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Ou ZL, Luo Z, Lu YB. Long non-coding RNA HULC as a diagnostic and prognostic marker of pancreatic cancer. World J Gastroenterol 2019; 25:6728-6742. [PMID: 31857775 PMCID: PMC6920662 DOI: 10.3748/wjg.v25.i46.6728] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 11/18/2019] [Accepted: 11/29/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Long non-coding RNA (lncRNA) is abnormally expressed in various malignant tumors. In recent years, it has been found that IncRNA HULC is increasingly expressed in pancreatic cancer tissues and is involved in the development and progression of pancreatic cancer. However, the clinical value of serum HULC in pancreatic cancer remains unclear, and there are few studies on how HULC regulates the biological function of pancreatic cancer cells.
AIM To determine the value of lncRNA HULC in the diagnosis and prognosis of pancreatic cancer, and its possible biological potential.
METHODS Sixty patients with pancreatic cancer and sixty patients with benign pancreatic diseases admitted to Xiangya Hospital, Central South University were assigned to the pancreatic cancer group and the benign disease group, respectively, and another 60 healthy subjects were enrolled as the normal group during the same period. HULC-siRNA and NC-siRNA were transfected into pancreatic cancer cells. Quantitative real-time polymerase chain reaction was performed to determine the expression of HULC in tissues, serum, and cells. Western Blot was carried out to determine the expression of β-catenin, c-myc, and cyclin D1 in cells, and the cell counting kit-8, flow cytometry, and Transwell assay were conducted to determine the proliferation, apoptosis and invasion of cells.
RESULTS Highly expressed in the tissues and serum of pancreatic cancer patients, HULC showed good clinical value in distinguishing between patients with pancreatic cancer, patients with benign pancreatic diseases and healthy subjects. HULC was related to pathological parameters including tumor size, T staging, M staging and vascular invasion, and the area-under-the-curve for evaluating these four parameters was 0.844, 0.834, 0.928 and 0.818, respectively. Patients with low expression of HULC had a significantly higher 3-year overall survival (OS) and 5-year OS than those with high expression. T staging, M staging, vascular invasion, and HULC were independent prognostic factors affecting the 3-year OS of patients with pancreatic cancer. Inhibition of HULC expression prevented the proliferation and invasion of pancreatic cancer cells, promoted apoptosis, and inhibited the expression of Wnt/β-catenin signaling pathway-related proteins, β-catenin, c-myc, and cyclin D1. The Wnt/β-catenin signaling pathway agonist (LiCl) restored proliferation, apoptosis, and invasion of pancreatic cancer cells with inhibited expression of HULC.
CONCLUSION HULC is an effective marker for the diagnosis and prognosis of pancreatic cancer, which may affect the biological function of pancreatic cancer cells through the Wnt/β-catenin signaling pathway.
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Affiliation(s)
- Zheng-Lin Ou
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Zhen Luo
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Ye-Bin Lu
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
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18
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The Value of lncRNA GHET1 as a Prognostic Factor for Survival of Chinese Cancer Outcome: A Meta-Analysis. DISEASE MARKERS 2019; 2019:5824190. [PMID: 31885739 PMCID: PMC6914916 DOI: 10.1155/2019/5824190] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 09/06/2019] [Accepted: 10/30/2019] [Indexed: 12/30/2022]
Abstract
Aim There is increasing evidence that high expression levels of the gastric carcinoma highly expressed transcript 1 (GHET1), a long noncoding RNA (lncRNA), are associated with cancer prognosis and may be used as a valuable biomarker for cancer patients. The purpose of this meta-analysis was to analyze existing data to reveal potential clinical applications of GHET1 for cancer prognosis and tumor progression. All of these studies included in this meta-analysis were collected through a variety of retrieval strategies; and the enrolled articles were qualified via the meta-analysis of enrolled studies in epidemiology (MOOSE) and the preferred reporting items for systematic reviews and meta-analyses (PRISMA) checklists. Materials and Methods The literature collection was performed by a comprehensive search through electronic databases for studies published on or before March 10, 2019. These included the Cochrane library, PubMed, Embase, Web of Science, Springer, Science Direct, and three Chinese databases: CNKI, Weipu, and Wanfang. Seven studies that met the specified criteria were analyzed in the present research. Results The combined results indicate that an elevated GHET1 expression level is significantly associated with poor overall survival (OS) (HR = 2.40, 95% CI: 1.87–3.08, p < 0.001) and tumor progression (III/IV vs. I/II: HR = 1.80, 95% CI: 1.48–2.18, p < 0.001) in multiple cancers. The elevated GHET1 expression was also associated with lymph node metastasis (LNM) (HR = 2.44, 95% CI: 1.86–3.20, p < 0.001) in Chinese cancer patients. Conclusions. The present findings indicate that an increased GHET1 expression level is associated with poor OS, tumor progression, and LNM in patients with multiple tumors and may serve as a useful prognostic biomarker in Chinese cancer patients.
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Dong B, Chen X, Zhang Y, Zhu C, Dong Q. The prognostic value of lncRNA SNHG1 in cancer patients: a meta-analysis. BMC Cancer 2019; 19:780. [PMID: 31391030 PMCID: PMC6686246 DOI: 10.1186/s12885-019-5987-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Accepted: 07/29/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Increasing evidence revealed that high expression level of lncRNA SNHG1 was associated with the unfavorable prognosis of cancer and maybe used as a valuable biomarker for cancer patients. The present meta->analysis is to analyze existing data to reveal potential clinical application of SNHG1 on cancer prognosis and tumor progression. All of the included studies were collected through a variety of retrieval strategies. And the articles were qualified by MOOSE and PRISMA checklists. METHODS Up to Mar 20, 2018, literature collection was performed by comprehensive search through electronic databases, including the Cochrane library, PubMed, Embase, Web of science, Springer, Science direct, and three Chinese databases: CNKI, Weipu, and Wanfang. We analyzed 14 studies that met the criteria, and concluded that the increased SHNG1 level was correlated with poor OS and tumor progression. RESULTS The combined results indicated that elevated SNHG1 expression level was significantly associated with poor OS (HR = 2.06, 95% CI: 1.69-2.52, P < 0.01) and PFS (HR = 2.78, 95% CI: 1.69-4.55, P < 0.01) in various cancers. Moreover, the promoted SNHG1 expression was also associated with tumor progression ((III/IV vs. I/II: HR = 1.89, 95% CI: 1.53-2.34, P < 0.01). In stratified analyses, a significantly unfavorable association of elevated lncRNA SNHG1 and OS was observed in both digestive system (HR = 2.04, 95% CI: 1.56-2.68, P < 0.01) and non-digestive system (HR = 2.09, 95% CI: 1.55-2.83, P < 0.01) cancer patients. CONCLUSIONS The present analysis indicated that the increased SNHG1 is associated with poor OS in patients with general tumors and may be served as a useful prognostic biomarker.
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Affiliation(s)
- Bingzi Dong
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, 266003 China
| | - Xian Chen
- Department of Clinical Laboratory, The Affiliated Hospital of Qingdao University, Qingdao, 266003 China
| | - Yunyuan Zhang
- Department of Clinical Laboratory, The Affiliated Hospital of Qingdao University, Qingdao, 266003 China
| | - Chengzhan Zhu
- Department of Clinical Laboratory, The Affiliated Hospital of Qingdao University, Qingdao, 266003 China
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, 266003 China
- Shandong Key Laboratory of Digital Medicine and Computer Assisted Surgery, The Affiliated Hospital of QingDao University, Qingdao, 266003 China
| | - Qian Dong
- Department of Pediatric Surgery, The Affiliated Hospital of Qingdao University, Qingdao, 266003 China
- Shandong Key Laboratory of Digital Medicine and Computer Assisted Surgery, The Affiliated Hospital of QingDao University, Qingdao, 266003 China
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20
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Islam Khan MZ, Tam SY, Law HKW. Autophagy-Modulating Long Non-coding RNAs (LncRNAs) and Their Molecular Events in Cancer. Front Genet 2019; 9:750. [PMID: 30693021 PMCID: PMC6340191 DOI: 10.3389/fgene.2018.00750] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Accepted: 12/31/2018] [Indexed: 12/11/2022] Open
Abstract
Cancer is a global threat of health. Cancer incidence and death is also increasing continuously because of poor understanding of diseases. Although, traditional treatments (surgery, radiotherapy, and chemotherapy) are effective against primary tumors, death rate is increasing because of metastasis development where traditional treatments have failed. Autophagy is a conserved regulatory process of eliminating proteins and damaged organelles. Numerous research revealed that autophagy has dual sword mechanisms including cancer progressions and suppressions. In most of the cases, it maintains homeostasis of cancer microenvironment by providing nutritional supplement under starvation and hypoxic conditions. Over the past few decades, stunning research evidence disclosed significant roles of long non-coding RNAs (lncRNAs) in the regulation of autophagy. LncRNAs are RNA containing more than 200 nucleotides, which have no protein-coding ability but they are found to be expressed in most of the cancers. It is also proved that, autophagy-modulating lncRNAs have significant impacts on pro-survival or pro-death roles in cancers. In this review, we highlighted the recently identified autophagy-modulating lncRNAs, their signaling transduction in cancer and mechanism in cancer. This review will explore newly emerging knowledge of cancer genetics and it may provide novel targets for cancer therapy.
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Affiliation(s)
| | | | - Helen Ka Wai Law
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hong Kong, Hong Kong
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21
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Yan X, Zhu Y, Li F, Shi W, Wang J, Wang Q, Zhang Q, Chai L, Li M. The value of long noncoding RNA CASC2 as a biomarker of prognosis in carcinomas: a meta-analysis. J Cancer 2018; 9:3824-3830. [PMID: 30410584 PMCID: PMC6218775 DOI: 10.7150/jca.26458] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Accepted: 08/26/2018] [Indexed: 12/13/2022] Open
Abstract
Lnc RNA Cancer Susceptibility Candidate 2(CASC2) has been shown to be aberrantly expressed in multiple types of cancer and might serve as a prognosis biomarker. The present meta-analysis was conducted to investigate whether the expression of CASC2 was associated with prognosis or clinicopathological features in correlative cancers. A total of 11 studies with 765 cancer patients were included by searching the electronic databases, the results found a significant association between high expression of CASC2 and longer OS in cancer patients (HR=0.43, 95% CI: 0.33-0.55, P =0.000).In addition, a significant correlation was observed between high level of CASC2 and earlier TNM stage(OR = 0.30, 95% CI =0.21-0.43, P < 0.001), smaller tumor size(OR = 0.28, 95% CI =0.12-0.66, P =0.004), better tumor differentiation(OR = 0.42, 95% CI =0.27-0.66, P =0.0002). In conclusion, CASC2 can serve as a novel marker predicting the prognosis and clinicopathological features in various cancers.
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Affiliation(s)
- Xin Yan
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Yanting Zhu
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Fangwei Li
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Wenhua Shi
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Jian Wang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Qingting Wang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Qianqian Zhang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Limin Chai
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Manxiang Li
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
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22
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Zhuang C, Zheng L, Wang P. Prognostic role of long non-coding RNA HNF1A-AS1 in Chinese cancer patients: a meta-analysis. Onco Targets Ther 2018; 11:5325-5332. [PMID: 30214238 PMCID: PMC6126479 DOI: 10.2147/ott.s163575] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background Long non-coding RNAs (LncRNAs) play important roles in tumorigenesis and progression. Recent studies have demonstrated that LncRNA HNF1A antisense RNA 1 (HNF1A-AS1) is aberrantly expressed in several types of cancers and is associated with poor outcomes. This meta-analysis was conducted to investigate the relationship between HNF1A-AS1 expression and clinical outcomes in cancer patients. Methods We searched PubMed, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), and Wan Fang databases (updated until December 31, 2017) for literature. A total of eight studies with 789 cancer patients were finally included in the present meta-analysis. Results The results showed that high expression of HNF1A-AS1 significantly predicted poor overall survival (HR=3.10, 95% CI: 1.58-6.11, P=0.001), which was further validated using The Cancer Genome Atlas (TCGA) dataset. Moreover, high HNF1A-AS1 expression was also associated with advanced TNM stage (OR=3.32, 95% CI: 2.28-4.83, P<0.001), lymph node metastasis (OR=3.08, 95% CI: 1.95-4.85, P<0.001), and distant metastasis (OR=5.53, 95% CI: 1.94-15.77, P=0.001). Conclusion Our results suggested that elevated HNF1A-AS1 was associated with poor clinical outcomes and might serve as a potential prognostic biomarker of cancer.
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Affiliation(s)
- Chunbo Zhuang
- Department of Clinical Laboratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Lei Zheng
- Department of Clinical Laboratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Pei Wang
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China,
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23
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Jiang H, Huang G, Zhao N, Zhang T, Jiang M, He Y, Zhou X, Jiang X. Long non-coding RNA TPT1-AS1 promotes cell growth and metastasis in cervical cancer via acting AS a sponge for miR-324-5p. J Exp Clin Cancer Res 2018; 37:169. [PMID: 30045766 PMCID: PMC6060520 DOI: 10.1186/s13046-018-0846-8] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Accepted: 07/16/2018] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Increasing studies confirmed that abnormal lncRNAs expression play a critical role in cervical cancer (CC) development and progression. LncRNA TPT1-AS1, a novel lncRNA, its role and underlying mechanisms involved in CC remain largely unknown. METHODS Colony formation, EdU and Transwell assays were used to determine colony formation, proliferation, migration and invasion in vitro. The subcutaneous tumor model and tail vein injection lung metastasis model were performed to check tumor growth and metastasis in vivo. Luciferase activity and RIP experiment were carried out to determine the interaction between miR-324-5p and TPT1-AS1. RESULTS We demonstrated for the first time that TPT1-AS1 expression was up-regulated in CC tissues and cell lines. High TPT1-AS1 was significantly correlated with adverse prognostic characteristics and poor survival. TPT1-AS1 overexpression and knockdown experiments revealed that TPT1-AS1 promoted cell colony formation, proliferation, migration, invasion and EMT progression of CC cells in vitro and in vivo. The underlying mechanism indicated that TPT1-AS1 functioned as an endogenous sponge for miR-324-5p in CC cells. Gain- and loss- experiment confirmed that miR-324-5p inhibited cell colony formation, proliferation, migration, invasion and EMT progression of CC cells, and mediated the biological effects of TPT1-AS1. Further investigations confirmed that SP1 was a direct target of miR-324-5p and mediated the effects of TPT1-AS1 and miR-324-5p in CC. CONCLUSIONS We demonstrated for the first time that TPT1-AS1 as an oncogenic lncRNA in CC progression and as a potential target for CC cure.
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Affiliation(s)
- Hui Jiang
- Department of Abdominal Oncology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510700 China
- Department of Gynaecology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510700 China
| | - Guanqun Huang
- Department of General Surgery, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510700 China
| | - Nianzhang Zhao
- Department of Anesthesia, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510700 China
| | - Ting Zhang
- Department of Gynaecology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510700 China
| | - Mengni Jiang
- Department of Gynaecology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510700 China
| | - Yueming He
- Department of Gynaecology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510700 China
| | - Xinke Zhou
- Department of Abdominal Oncology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510700 China
| | - Xianhan Jiang
- Department of Abdominal Oncology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510700 China
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Liu X, Ming X, Jing W, Luo P, Li N, Zhu M, Yu M, Liang C, Tu J. Long non-coding RNA XIST predicts worse prognosis in digestive system tumors: a systemic review and meta-analysis. Biosci Rep 2018; 38:BSR20180169. [PMID: 29752340 PMCID: PMC6013696 DOI: 10.1042/bsr20180169] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Revised: 05/09/2018] [Accepted: 05/09/2018] [Indexed: 02/07/2023] Open
Abstract
Increasing studies are indicating that long non-coding RNA (lncRNA) X-inactive specific transcript (XIST) is associated with the prognosis of cancer patients. However, the results have been disputed. Therefore, we aimed to further explore the prognostic value and clinical significance of XIST in various types of cancers. Then, we focussed our research on the comparison of the predictive value of XIST between digestive system tumors and non-digestive system tumors. We performed a systematic search by looking up PubMed, Embase, Cochrane Library, Web of Science, and Medline (up to 3 January 2018). Fifteen studies which matched our inclusion criteria with a total of 920 patients for overall survival and 867 patients for clinicopathological characteristics were included in this meta-analysis. Pooled hazard ratios (HR) and odds ratios (ORs) with their corresponding 95% confidence intervals (95% CIs) were calculated to summarize the effects. Our results suggested that high expression levels of XIST were associated with unfavorable overall survival in cancer patients (pooled HR = 1.81, 95% CI: 1.45-2.26). Additionally, we found that XIST was more valuable in digestive system tumors (pooled HR = 2.24, 95% CI: 1.73-2.92) than in non-digestive system tumors (pooled HR = 1.22, 95% CI: 0.60-2.45). Furthermore, elevated expression levels of XIST were connected with distant metastasis and tumor stage. XIST was correlated with poor prognosis, which suggested that XIST might serve as a novel predictive biomarker for cancer patients, especially for patients of digestive system tumors.
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Affiliation(s)
- Xuefang Liu
- Department of Laboratory Medicine, Clinical Laboratory Medicine and Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Xinliang Ming
- Department of Laboratory Medicine, Clinical Laboratory Medicine and Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Wei Jing
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Key Laboratory of Laboratory Medicine of Henan, Zhengzhou 450000, China
| | - Ping Luo
- Department of Laboratory Medicine, Clinical Laboratory Medicine and Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Nandi Li
- Department of Laboratory Medicine, Clinical Laboratory Medicine and Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Man Zhu
- Department of Laboratory Medicine, Clinical Laboratory Medicine and Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Mingxia Yu
- Department of Laboratory Medicine, Clinical Laboratory Medicine and Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Chunzi Liang
- Department of Laboratory Medicine, Clinical Laboratory Medicine and Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Jiancheng Tu
- Department of Laboratory Medicine, Clinical Laboratory Medicine and Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
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The association of lncRNA-HULC polymorphisms with hepatocellular cancer risk and prognosis. Gene 2018; 670:148-154. [PMID: 29803923 DOI: 10.1016/j.gene.2018.05.096] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 05/10/2018] [Accepted: 05/23/2018] [Indexed: 02/09/2023]
Abstract
BACKGROUND Genetic polymorphisms in lncRNA HULC may affect the susceptibility and clinical outcome of cancer. We aimed to investigate the association of HULC tagSNPs with the risk and prognosis of hepatocellular cancer, as well as the influence of the SNPs on lncRNA expression level. METHODS A total of 1338 samples were recruited in the risk study. Among them, 351 HCC patients were involved in the prognosis study. SNP genotyping was performed using KASP method and lncRNA expression was detected by Real-time PCR. RESULTS We found a promoter SNP, rs1041279, was associated with a 1.41-fold increased HCC risk (P = 0.032). In the stratified analysis, rs1041279 had greater ORs for the increased HCC risk in the male subgroup (P = 0.014, OR = 1.54). Furthermore, multi-logistic regression analysis revealed a two-way interaction effect of smoking-rs2038540 SNP on HCC risk (OR = 4.20). And MDR analysis consistently demonstrated a SNP-environmental interaction among smoking-drinking-rs2038540 SNP as the best model for predicting HCC risk (P = 0.0107). In our study, no significant association was found between HULC SNPs and the overall survival (P > 0.05), and no significant effect was observed of rs1041279 SNP on lncRNA-HULC expression (P > 0.05). CONCLUSION lncRNA-HULC rs1041279 SNP and the interaction of rs2038540 SNP with environmental factors could enhance HCC risk.
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Mu S, Ai L, Fan F, Sun C, Hu Y. Prognostic and clinicopathological significance of long noncoding RNA HOXA11-AS expression in human solid tumors: a meta-analysis. Cancer Cell Int 2018; 18:1. [PMID: 29308050 PMCID: PMC5751829 DOI: 10.1186/s12935-017-0498-3] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Accepted: 12/18/2017] [Indexed: 01/05/2023] Open
Abstract
Background Recent studies have emphasized the important prognostic role of long noncoding RNAs (lncRNAs) in various types of cancers. Here we conducted a meta-analysis to investigate whether lncRNA HOXA11-AS can be served as a prognostic biomarker in human cancers. Patients/methods We systematically searched PubMed, Embase, ISI Web of Science, and SCOPUS for relevant studies, to investigate the prognostic significance of HOXA11-AS expression in cancer patients. Odds ratios (ORs) or hazards ratios (HRs) with corresponding 95% confidence intervals (CIs) are pooled to estimate the association between HOXA11-AS expression and clinicopathological parameters or survival of cancer patients. Results A total of eight eligible studies with 1320 cancer patients were enrolled in our meta-analysis. The results revealed that increased expression level of HOXA11-AS was significantly associated with clinicopathological parameters including more lymph node metastasis (OR = 2.06, 95% CI 1.31–3.25), advanced tumor stage (OR = 4.22, 95% CI 2.60–6.85), as well as poor tumor differentiation (OR = 2.49, 95 CI 1.47–4.20), but not correlated with age (p = 0.101) or gender (p = 0.845). In addition, cancer patients with high HOXA11-AS are prognosed to have shorter OS (pooled HR = 1.86, 95% CI 1.39–2.48) and PFS (pooled HR = 2.47, 95% CI 1.29–4.75). Conclusions HOXA11-AS overexpression might be a convinced unfavorable prognostic factor that helps the clinical decision-making process.
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Affiliation(s)
- Shidai Mu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 China
| | - Lisha Ai
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 China
| | - Fengjuan Fan
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 China
| | - Chunyan Sun
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 China
| | - Yu Hu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 China
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Clinicopathological and Prognostic Role of Long Noncoding RNA Linc00152 in Various Human Neoplasms: Evidence from Meta-Analysis. BIOMED RESEARCH INTERNATIONAL 2017; 2017:6010721. [PMID: 29285514 PMCID: PMC5733223 DOI: 10.1155/2017/6010721] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/26/2017] [Revised: 09/24/2017] [Accepted: 10/01/2017] [Indexed: 02/06/2023]
Abstract
Recent researches have demonstrated that long noncoding RNA linc00152 was aberrantly upregulated in multiple tumor types. High expression of linc00152 was associated with poor outcomes in cancer patients. Therefore, we conducted this meta-analysis to evaluate its potential value as a prognostic predictor in various human neoplasms. Eligible studies were searched through several electronic databases including PubMed, Embase, Web of Science, and the Cochrane Library. Eight original studies including 752 cancer patients were ultimately enrolled. Statistical analysis suggested that overexpression of linc00152 was significantly correlated with unfavorable overall survival (OS) (HR = 2.05, 95% CI: 1.59–2.64) and disease-free/progression-free survival (DFS/PFS) (HR = 3.52, 95% CI: 1.82–6.79) in cancer patients. In addition, a significant correlation was observed between aberrant linc000152 expression and lymph node metastasis (LNM) (OR = 2.49, 95% CI: 1.57–3.94) but not in vessel invasion (VI) (OR = 1.02, 95% CI: 0.54–1.93) and distant metastasis (DM) (OR = 0.600, 95% CI: 0.213–1.689). Our meta-analysis demonstrated that high linc00152 expression significantly predicted inferior OS and DFS/PFS in multiple neoplasms, as well as advanced LNM and VI. Linc00152 may serve as a potential indicator in predicting poor outcomes and metastases of diverse cancers.
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lncRNA HULC promotes the growth of hepatocellular carcinoma cells via stabilizing COX-2 protein. Biochem Biophys Res Commun 2017. [PMID: 28634076 DOI: 10.1016/j.bbrc.2017.06.103] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Highly upregulated in liver cancer (HULC), a lncRNA overexpressed in hepatocellular carcinoma (HCC), has been demonstrated to be involved in the carcinogenesis and progression of HCC. However, the mechanisms of HULC promoting the abnormal growth of HCC cells are still not well elucidated. In the present study, we for the first time demonstrated that HULC promoted the growth of HCC cells through elevating COX-2 protein. Moreover, the study of the corresponding mechanism by which HULC upregulated COX-2 showed that HULC enhanced the level of ubiquitin-specific peptidase 22 (USP22), which decreased ubiquitin-mediated degradation of COX-2 protein by removing the conjugated polyubiquitin chains from COX-2 and finally stabilized COX2 protein. In addition, knockdown of USP22 or COX-2 attenuated HULC-mediated abnormal growth of HCC cells. In conclusion, our results demonstrated that "USP22/COX-2" axis played an important role in HULC promoting growth of HCC cells. The identification of this novel pathway may pave a road for developing new potential anti-HCC strategies.
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