Research Papers:

Dual oncogenic and tumor suppressor roles of the promyelocytic leukemia gene in hepatocarcinogenesis associated with hepatitis B virus surface antigen

Yih-Lin Chung _ and Mei-Ling Wu

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Oncotarget. 2016; 7:28393-28407. https://doi.org/10.18632/oncotarget.8613

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Yih-Lin Chung1, and Mei-Ling Wu2

1Department of Radiation Oncology, Koo Foundation Sun-Yat-Sen Cancer Center, Taipei, Taiwan

2Department of Pathology and Laboratory Medicine, Koo Foundation Sun-Yat-Sen Cancer Center, Taipei, Taiwan

Correspondence to:

Yih-Lin Chung, email: [email protected]

Keywords: hepatitis B virus, hepatocarcinogenesis, PML, tumor suppressor, oncogene

Received: November 05, 2015     Accepted: March 18, 2016     Published: April 6, 2016


Proteasome-mediated degradation of promyelocytic leukemia tumor suppressor (PML) is upregulated in many viral infections and cancers. We previously showed that PML knockdown promotes early-onset hepatocellular carcinoma (HCC) in hepatitis B virus surface antigen (HBsAg)-transgenic mice. Here we report the effects of PML restoration on late-onset HBsAg-induced HCC. We compared protein expression patterns, genetic mutations and the effects of pharmacologically targeting PML in wild-type, PML-/-, PML+/+HBsAgtg/o and PML-/-HBsAgtg/o mice. PML-/- mice exhibited somatic mutations in DNA repair genes and developed severe steatosis and proliferative disorders, but not HCC. PML-/-HBsAgtg/o mice exhibited early mutations in cancer driver genes and developed hyperplasia, fatty livers and indolent adipose-like HCC. In PML+/+HBsAg-transgenic mice, HBsAg expression declined over time, and HBsAg-associated PML suppression was concomitantly relieved. Nevertheless, these mice accumulated mutations in genes contributing to oxidative stress pathways and developed aggressive late-onset angiogenic trabecular HCC. PML inhibition using non-toxic doses of arsenic trioxide selectively killed long-term HBsAg-affected liver cells in PML+/+HBsAgtg/o mice with falling HBsAg and rising PML levels, but not normal liver cells or early-onset HCC cells in PML-/-HBsAgtg/0 mice. These findings suggest dual roles for PML as a tumor-suppressor lost in early-onset HBsAg-induced hepatocarcinogenesis and as an oncogenic promoter in late-onset HBsAg-related HCC progression.

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