Multifaceted role of E-cadherin in hepatitis C virus infection and pathogenesis

Hepatitis C virus (HCV) is a major global cause of liver disease, including cirrhosis and hepatocellular carcinoma (HCC). Although direct-acting antivirals (DAAs) can cure the majority of infected patients, their high cost prevents access to treatment for the majority of patients worldwide. Moreover, not all patient groups respond to therapy and some patients fail therapy as a result of DAA resistance (1). There is accumulating evidence that viral cure does not eliminate the risk for progressive liver disease once fibrosis has been established (2). Indeed, HCC risk persists following viral cure, particularly among cirrhotic and elderly patients (2). The mechanisms of HCV-induced hepatocarcinogenesis as well as its progression to advanced and metastatic disease, however, are still only partially understood. Most importantly, efficient strategies to treat HCV-associated HCC are limited and urgently needed. In PNAS, Li et al. (3) uncover E-cadherin (E-Cad), a major adherens junction protein, as a novel HCV host factor that not only further advances our understanding of the first steps of HCV infection but also identifies tight junctions as a pathogenic link between viral cell entry and hepatocellular carcinoma. HCV infects hepatocytes via a complex, multistep process requiring an expanding list of host factors, including cluster of differentiation 81 (CD81), scavenger receptor class B type I (SR-BI), and the tight-junction proteins claudin-1 (CLDN1) and occludin (OCLN) (4). However, the HCV entry pathway is still not fully understood. In particular, the precise mechanisms that regulate the cellular entry factors and orchestrate the multistep entry process still need to be elucidated. In this study, the authors elucidate a novel regulatory mechanism for a postbinding HCV entry step, thus contributing another piece to the overall HCV entry puzzle and providing a new link between a viral entry step and the pathogenesis of hepatocellular cancer. Using classical gene silencing and antibody … [↵][1]1To whom correspondence should be addressed. Email: Thomas.Baumert{at}unistra.fr. [1]: #xref-corresp-1-1