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Link et al. Roles of p53 in extrinsic factor-induced liver carcinogenesis

for the HCV viral proteins. [77,110,111] Specifically, HCV risk factors for liver cancer have become preventable
core, NS3, and NS5 proteins have been implicated or treatable, efficient therapeutic strategies are still
in HCC development in both p53-dependent and limited. Hence, understanding the role of p53 in the
-independent manners. [112] molecular pathogenesis of HCC and restoring p53
activity in tumors would significantly help accelerate
Transgenic mice expressing the HCV core protein the development of new therapies for this therapy-
indeed spontaneously develop HCC, without the resistant disease.
background of cirrhosis. [113,114] HCV core protein also
increases ROS, inhibits Fas- and TNF-mediated Acknowledgments
apoptosis, and upregulates the Wnt-β-catenin We thank Atul Ranjan for editing the manuscript and
pathway. [115-117] Importantly, the core protein inhibits helpful discussion.
p53 activity by altering its subcellular localization to
the perinuclear region and nuclear granular structures, Authors’ contributions
as well as its post-translational modifications such as Collection of literature data: T. Link, T. Iwakuma
phosphorylation and acetylation of p53 in HeLa and Design, writing and revision of the paper: T. Link, T.
HepG2 cell lines [Figure 1B]. [118] Moreover, the core Iwakuma
protein upregulates SIRT1, a deacetylation enzyme
for p53, leading to impaired p53-dependent apoptosis Financial support and sponsorship
in HepG2 cells [Figure 1B]. [119] Thus, HCV core
protein likely causes HCC in both p53-dependent and This project is supported by NIH 1-R01-CA174735-03
-independent manners. (to T. Iwakuma) grant.

A non-structural HCV protein, NS3, is another HCV Conflicts of interest
protein that can transform human hepatocytes with an There are no conflicts of interest.
increase in cyclooxygenase-2 and activation of mitogen-
activated protein kinase. [120-122] NS3 also complexes Patient consent
with p53 in HeLa and NIH3T3 cells [123,124] and inhibit Not applicable.
p53’s transcriptional activity in NIH3T3 and Huh7 cells
[Figure 1B]. [124,125] Moreover, NIH3T3 cells transformed Ethics approval
by overexpression of NS3 can form tumors in mice. [126] Not applicable.
However, it remains unclear whether transformation by
NS3 is p53-dependent or not. REFERENCES

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100 Hepatoma Research ¦ Volume 3 ¦ June 6, 2017