Nuclear PTEN and p53 suppress stress-induced liver cancer through distinct mechanisms

Takashi Kato, Daisuke Murata, Robert A. Anders, Hiromi Sesaki, Miho Iijima

Research output: Contribution to journalArticlepeer-review

Abstract

PTEN and p53 are highly mutated in many cancers. These two tumor suppressors have critical functions in the nucleus, such as DNA repair, cell cycle progression, and genome maintenance. However, the in vivo functional relationship of nuclear PTEN and p53 is unknown. Here, we analyzed the liver of mice in which nuclear PTEN and p53 are individually or simultaneously depleted. We found that nuclear PTEN loss greatly upregulates p53 expression upon oxidative stress, while the loss of p53 potentiates stress-induced accumulation of PTEN in the nucleus. Next, we examined oxidative stress-induced DNA damage in hepatocytes, and found that nuclear PTEN loss aggravated the damage while p53 loss did not. Notably, mice lacking nuclear PTEN had increased hepatocellular carcinoma under oxidative stress, while mice lacking p53 in hepatocytes had accelerated hepatocellular carcinoma and intrahepatic cholangiocarcinoma. The formation of cholangiocarcinoma appears to involve the transformation of hepatocytes into cholangiocarcinoma. Simultaneous loss of nuclear PTEN and p53 exacerbated both types of liver cancers. These data suggest that nuclear PTEN and p53 suppress liver cancers through distinct mechanisms.

Original languageEnglish (US)
Pages (from-to)83-90
Number of pages8
JournalBiochemical and Biophysical Research Communications
Volume549
DOIs
StatePublished - Apr 16 2021

Keywords

  • Cholangiocarcinoma
  • DNA damage
  • Hepatocellular carcinoma
  • Liver cancer
  • Nuclear PTEN
  • p53

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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