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 …
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