Hepatitis B virus X protein overcomes oncogenic RAS-induced senescence in human immortalized cells

Naoki Oishi, Khurts Shilagardi, Yasunari Nakamoto, Masao Honda, Shuichi Kaneko, Seishi Murakami

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


Chronic infection with hepatitis B virus (HBV) is a major risk factor for hepatocellular carcinoma. The HBV X protein (HBx) is thought to have oncogenic potential, although the molecular mechanism remains obscure. Pathological roles of HBx in the carcinogenic process have been examined using rodent systems and no report is available on the oncogenic roles of HBx in human cells in vitro. We therefore examined the effect of HBx on immortalization and transformation in human primary cells. We found that HBx could overcome active RAS-induced senescence in human immortalized cells and that these cells could form colonies in soft agar and tumors in nude mice. HBx alone, however, could contribute to neither immortalization nor transformation of these cells. In a population doubling analysis, an N-terminal truncated mutant of HBx, HBx-D1 (amino acids 51-154), which harbors the coactivation domain, could overcome active RAS-induced cellular senescence, but these cells failed to exhibit colonigenic and tumorigenic abilities, probably due to the low expression level of the protein. By scanning a HBx expression library of the clustered-alanine substitution mutants, the N-terminal domain was found to be critical for overcoming active RAS-induced senescence by stabilizing full-length HBx. These results strongly suggest that HBx can contribute to carcinogenesis by overcoming active oncogene-induced senescence.

Original languageEnglish (US)
Pages (from-to)1540-1548
Number of pages9
JournalCancer Science
Issue number10
StatePublished - Oct 2007
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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