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

Hepatology ◽  
2019 ◽  
Vol 71 (3) ◽  
pp. 780-793 ◽  
Author(s):  
Tapas Patra ◽  
Keith Meyer ◽  
Ratna B. Ray ◽  
Ranjit Ray

2009 ◽  
Vol 83 (19) ◽  
pp. 9663-9671 ◽  
Author(s):  
Arup Banerjee ◽  
Kousuke Saito ◽  
Keith Meyer ◽  
Sutapa Banerjee ◽  
Malika Ait-Goughoulte ◽  
...  

ABSTRACT Hepatitis C virus (HCV) often causes chronic infection and may lead to hepatocellular carcinoma (HCC). We have shown previously that HCV core protein has pleiotropic functions, including transcriptional regulation of a number of cellular genes, although the mechanism for gene regulation remains unclear. In this study, a mammalian two-hybrid screen identified a novel binding partner, HS1-associated protein X-1 (HAX-1), for HCV core protein from a human liver cDNA library. An association between HAX-1 and HCV core protein was further verified by confocal microscopy and coimmunoprecipitation in HepG2 cells expressing HCV core or full-length (FL) gene. Both HCV core protein and a chemotherapeutic agent for HCC, 5-flouorouracil (5-FU), are known to modulate p53. We examined here whether an association between core and HAX-1 has any functional relevance to p53 modulation in 5-FU-treated cells. For this, the role of HAX-1 on 5-FU treatment was examined in HepG2 cells expressing HCV core or FL gene using cell proliferation, p53 expression, and caspase activation analysis. Cells expressing HCV-core or FL gene were more susceptible to 5-FU-induced growth inhibition than control cells, whereas cell survival was enhanced after suppression of HAX-1 by small interfering RNA. Further, 5-FU-mediated p53 expression was reduced with concurrent HAX-1 suppression in core- or polyprotein-expressing cells compared to control HepG2 cells, and caspase-2 and -7 activities were diminished. On the other hand, HCV core protein did not play a detectable role in 5-FU-mediated caspase-7 activation in the absence of functional p53 in Hep3B or Huh-7 cells. These observations underscore an association between HCV core and HAX-1, which promotes 5-FU mediated p53-dependent caspase-7 activation and hepatocyte growth inhibition.







2018 ◽  
Vol 92 (20) ◽  
Author(s):  
Subhayan Sur ◽  
Reina Sasaki ◽  
Pradip Devhare ◽  
Robert Steele ◽  
Ranjit Ray ◽  
...  

ABSTRACT Chronic hepatitis C virus (HCV) infection may lead to end-stage liver disease, including hepatocellular carcinoma (HCC). We have shown previously that microRNA-373 (miR-373) is upregulated in HCV-infected human liver biopsy specimens. To gain insight into the role of miR-373 in HCV-mediated pathogenesis, we investigated its interacting partner for hepatocyte growth regulation. Transcriptome sequencing (RNA-seq) data revealed that Wee1 is associated with miR-373 and is a direct target. Interestingly, higher expression of Wee1 was noted in HCV-infected hepatocytes than in uninfected hepatocytes, suggesting that other factors may block miR-373-mediated Wee1 inhibition. We subsequently found an association between the long noncoding RNA NORAD (LINC00657) and miR-373, and we demonstrated that NORAD binds to miR-373 and Wee1 independently. However, the high level of Wee1 expression in HCV-infected hepatocytes suggested that miR-373 forms a complex with NORAD. Depletion of miR-373 or the inhibitor Wee1 reduces the growth of Huh7.5 cells harboring the HCV genome as well as reducing Wee1 expression. Taken together, our data demonstrate a novel mechanism of hepatocyte growth promotion during HCV infection involving a miR-373–NORAD–Wee1 axis, which may be a target for future therapy against HCV-associated HCC. IMPORTANCE The mechanism of HCV-mediated liver pathogenesis is poorly understood. In this study, we observed that HCV infection upregulates miR-373 and Wee1, a pivotal player in the G2 checkpoint in the cell cycle, although Wee1 is a direct target for miR-373. Subsequent investigation demonstrated that miR-373 forms a complex with the long noncoding RNA NORAD, resulting in the release of their common target, Wee1, in HCV-infected cells, which, in turn, favors uncontrolled cell growth. Our study suggested a previously unknown mechanism for hepatocyte growth promotion following HCV infection, and this pathway can be targeted for future therapy against HCV-mediated liver pathogenesis.



1998 ◽  
Vol 10 (2) ◽  
pp. 164-166 ◽  
Author(s):  
T. Rampino ◽  
C. Libetta ◽  
A. Mazzone ◽  
M. Gregorini ◽  
G. Soccio ◽  
...  


2006 ◽  
Vol 44 ◽  
pp. S163
Author(s):  
E. Marín-Serrano ◽  
J.A. Girón-González ◽  
M. Tejada-Cabrera ◽  
C. Rodríguez-Ramos ◽  
E. Díaz-García ◽  
...  


2010 ◽  
Vol 82 (5) ◽  
pp. 763-767 ◽  
Author(s):  
Guillermina Barril ◽  
Javier Bartolomé ◽  
Paloma Sanz ◽  
Emmanuela Buoncristiani ◽  
Juan Antonio Traver ◽  
...  


1999 ◽  
Vol 56 (6) ◽  
pp. 2286-2291 ◽  
Author(s):  
Teresa Rampino ◽  
Eloisa Arbustini ◽  
Marilena Gregorini ◽  
Paola Guallini ◽  
Carmelo Libetta ◽  
...  


Hepatology ◽  
2005 ◽  
Vol 41 (5) ◽  
pp. 1096-1105 ◽  
Author(s):  
Takayoshi Fukutomi ◽  
Yonghong Zhou ◽  
Shigenobu Kawai ◽  
Hidetoshi Eguchi ◽  
Jack R. Wands ◽  
...  


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