miR-135a-5p-mediated downregulation of protein tyrosine phosphatase receptor delta is a candidate driver of HCV-associated hepatocarcinogenesis

Renne, Nicolaas Van; Suarez, Armando Andres Roca; Duong, François H. T.; Gondeau, Claire; Calabrese, Diego; Fontaine, Nelly; Ababsa, Amina; Bandiera, Simonetta; Croonenborghs, Tom; Pochet, Nathalie; Blasi, Vito De; Pessaux, Patrick; Piardi, Tullio; Sommacale, Danièle; Ono, Atsushi; Chayama, Kazuaki; Fujita, Masashi; Nakagawa, Hidewaki; Hoshida, Yujin; Zeisel, Mirjam B.; Heim, Markus H.; Baumert, Thomas F.; Lupberger, Joachim

doi:10.1136/gutjnl-2016-312270

Cited by 65 publications

(68 citation statements)

References 50 publications

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“…Other miRNAs, including miR-155, miR-146a-5p, miR-135a-5p and miR-373, were shown to either promote or inhibit HCV-associated hepatocarcinogenesis. (45)(46)(47)(48) Our study highlighted how intratumoral introduction of synthetic miR-181c inhibits tumor progression in a HCC xenograft tumor model. Recent introduction of direct-acting antivirals (DAAs) with the combinations of virus replication inhibitors may achieve a decrease in virus titer to a sustained virological response in HCV-infected patients.…”

Section: Discussionmentioning

confidence: 88%

Hepatitis C Virus Mediated Inhibition of miR‐181c Activates ATM Signaling and Promotes Hepatocyte Growth

Patra¹,

Meyer²,

Ray³

et al. 2019

Hepatology

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Background and Aims Hepatitis C virus (HCV) infection promotes hepatocyte growth and progress to hepatocellular carcinoma. We previously observed that HCV infection of hepatocytes transcriptionally down‐regulates miR‐181c expression through CCAAT/enhancer binding protein β (C/EBP‐β). Here, we examined the role of miR‐181c in the regulation of cell cycle progression in relation to HCV infection. In silico analysis suggested that ataxia‐telangiectasia mutated (ATM) protein, a protein kinase, is a direct target of miR‐181c. ATM is a central mediator of response for cellular DNA double‐strand break. Approach and Results Our results demonstrated that ATM expression is higher in HCV‐infected hepatocytes and chronic HCV‐infected liver biopsy specimens. We have shown a direct interaction of miR‐181c with the 3′ untranslated region of ATM, and the presence of ATM in miR‐181c‐associated RNA‐induced silencing complex. Exogenous expression of miR‐181c inhibited ATM expression and activation of its downstream molecules, Chk2 and Akt. On the other hand, introduction of anti‐miR‐181c restored ATM and phosphorylated Akt. Furthermore, introduction of miR‐181c significantly inhibited phospho–cyclin‐dependent kinase 2 (CDK2) and cyclin‐A expression, arresting cell cycle progression, whereas overexpression of miR‐181c promoted apoptosis of HCV‐infected hepatocytes and can be inhibited by overexpression of ATM from a clone lacking miR‐181c binding sites. In addition, miR‐181c significantly regressed tumor growth in the xenograft human hepatocellular carcinoma mouse model. Conclusions Together, our results suggest that HCV infection suppresses miR‐181c in hepatocytes, resulting in ATM activation and apoptosis inhibition for promotion of cell cycle progression. The results provide mechanistic insight into understanding the role of miR‐181c in HCV‐associated hepatocyte growth promotion, and may have the potential for therapeutic intervention.

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Section: Discussionmentioning

confidence: 88%

Hepatitis C Virus Mediated Inhibition of miR‐181c Activates ATM Signaling and Promotes Hepatocyte Growth

Patra¹,

Meyer²,

Ray³

et al. 2019

Hepatology

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“…Third, RNA-Seq has a better accuracy and repeatability [9][10][11][12]. Advances in RNA-Seq have enabled the examination of HCC at high resolution [13][14][15][16][17].…”

Section: Discussionmentioning

confidence: 99%

Whole transcriptome analysis of chemically induced hepatocellular carcinoma using RNA‐sequencing analysis

et al. 2019

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RNA‐sequencing (RNA‐Seq) is a useful method to explore the molecular events in cells and tissues at the transcriptional level. However, comprehensive transcriptome analysis of hepatocarcinogenesis and progression is lacking. In this study, we aimed to characterize a dimethylnitrosamine (DEN) and carbon tetrachloride (CCl4; DEN+CCl4)‐induced hepatocellular carcinoma (HCC) mouse model by RNA‐Seq. In total, 2033 genes were up‐regulated and 841 genes were down‐regulated after DEN and CCl4 stimulation. The differentially expressed genes were highly enriched for the Gene Ontology terms oxoacid metabolic process, carboxylic acid metabolic process, and organic acid metabolic process. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the top five significantly overrepresented pathways were metabolic pathways, chemical carcinogenesis, steroid hormone biosynthesis, retinol metabolism and metabolism of xenobiotics by cytochrome P450. Moreover, a protein‐protein interaction network analysis indicated that Rous sarcoma oncogene (Src) may play a key role in DEN+CCl4‐induced HCC. These results provide a comprehensive overview of transcriptome events in DEN+CCl4‐induced HCC.

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“…Increasingly, dysregulated miRNAs are being found in virus-infected cells, which results in interference with several immune-related signaling pathways, and exert their functions in many pathophysiological processes, such as the JAK-STAT signaling pathway (SOCS3, STAT3, IFN), cytokine-cytokine receptor interaction (IL-6, IFN-␥), and T-cell receptor signaling pathways (IL-10) (34). miR-135a-5p is a negative regulator of STAT3 phosphatase PTPRD and is upregulated in HCV-infected hepatocytes, leading to enhanced STAT3 transcription (49). Some miRNAs, including miR-124, miR-20, and miR-29a, have been reported to be altered in RABV-infected mouse brain and neurons and have been predicted to contribute to immune modulation (34,35,50).…”

Section: Discussionmentioning

confidence: 99%

Pentagalloylglucose Inhibits the Replication of Rabies Virus via Mediation of the miR-455/SOCS3/STAT3/IL-6 Pathway

Zhang

et al. 2019

J Virol

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Our previous study showed that pentagalloylglucose (PGG), a naturally occurring hydrolyzable phenolic tannin, possesses significant anti-rabies virus (RABV) activity. In BHK-21 cells, RABV induced the overactivation of signal transducer and activator of transcription 3 (STAT3) by suppressing the expression of suppressor of cytokine signaling 3 (SOCS3). Inhibition of STAT3 by niclosamide, small interfering RNA, or exogenous expression of SOCS3 all significantly suppressed the replication of RABV. Additionally, RABV-induced upregulation of microRNA 455-5p (miR-455-5p) downregulated SOCS3 by directly binding to the 3′ untranslated region (UTR) of SOCS3. Importantly, PGG effectively reversed the expression of miR-455-5p and its following SOCS3/STAT3 signaling pathway. Finally, activated STAT3 elicited the expression of interleukin-6 (IL-6), thereby contributing to RABV-associated encephalomyelitis; however, PGG restored the level of IL-6 in vitro and in vivo in a SOCS3/STAT3-dependent manner. Altogether, these data identify a new miR-455-5p/SOCS3/STAT3 signaling pathway that contributes to viral replication and IL-6 production in RABV-infected cells, with PGG exerting its antiviral effect by inhibiting the production of miR-455-5p and the activation of STAT3. IMPORTANCE Rabies virus causes lethal encephalitis in mammals and poses a serious public health threat in many parts of the world. Numerous strategies have been explored to combat rabies; however, their efficacy has always been unsatisfactory. We previously reported a new drug, PGG, which possesses a potent inhibitory activity on RABV replication. Herein, we describe the underlying mechanisms by which PGG exerts its anti-RABV activity. Our results show that RABV induces overactivation of STAT3 in BHK-21 cells, which facilitates viral replication. Importantly, PGG effectively inhibits the activity of STAT3 by disrupting the expression of miR-455-5p and increases the level of SOCS3 by directly targeting the 3′ UTR of SOCS3. Furthermore, the downregulated STAT3 inhibits the production of IL-6, thereby contributing to a reduction in the inflammatory response in vivo. Our study indicates that PGG effectively inhibits the replication of RABV by the miR-455-5p/SOCS3/STAT3/IL-6-dependent pathway.

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miR-135a-5p-mediated downregulation of protein tyrosine phosphatase receptor delta is a candidate driver of HCV-associated hepatocarcinogenesis

Cited by 65 publications

References 50 publications

Hepatitis C Virus Mediated Inhibition of miR‐181c Activates ATM Signaling and Promotes Hepatocyte Growth

Hepatitis C Virus Mediated Inhibition of miR‐181c Activates ATM Signaling and Promotes Hepatocyte Growth

Whole transcriptome analysis of chemically induced hepatocellular carcinoma using RNA‐sequencing analysis

Pentagalloylglucose Inhibits the Replication of Rabies Virus via Mediation of the miR-455/SOCS3/STAT3/IL-6 Pathway

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