p53 haploinsufficiency and increased mTOR signalling define a subset of aggressive hepatocellular carcinoma

Luo，Yuan Deng1; Fang，Lei1; Yu，Hong Qiang1; Zhang，Jie1; Lin，Xiao Tong1; Liu，Xiao Yu2; Wu，Di1; Li，Gui Xi1; Huang，Deng1; Zhang，Yu Jun1; Chen，Shu1; Jiang，Yan1; Shuai，Ling1; He，Yu1; Zhang，Lei Da1; Bie，Ping3; Xie，Chuan Ming1

2020

10.1016/j.jhep.2020.07.036

JOURNAL OF HEPATOLOGY   影响因子和分区

0168-8278

1600-0641

Background & Aims: p53 mutations occur frequently in human HCC. Activation of the mammalian target of rapamycin (mTOR) pathway is also associated with HCC. However, it is still unknown whether these changes together initiate HCC and can be targeted as a potential therapeutic strategy. Methods: We generated mouse models in which mTOR was hyperactivated by loss of tuberous sclerosis complex 1 (Tsc1) with or without p53 haplodeficiency. Primary cells were isolated from mouse livers. Oncogenic signalling was assessed in vitro and in vivo, with or without targeted inhibition of a single molecule or multiple molecules. Transcriptional profiling was used to identify biomarkers predictive of HCC. Human HCC materials were used to corroborate the findings from mouse models. Results: p53 haploinsufficiency facilitates mTOR signalling via the PTEN/PI3K/Akt axis, promoting HCC tumorigenesis and lung metastasis. Inhibition of PI3K/Akt reduced mTOR activity, which effectively enhanced the anticancer effort of an mTOR inhibitor. ATP-binding cassette subfamily C member 4 (Abcc4) was found to be responsible for p53 haploinsufficiency- and Tsc1 loss-driven HCC tumorigenesis. Moreover, in clinical HCC samples, Abcc4 was specifically identified an aggressive subtype. The mTOR inhibitor rapamycin significantly reduced hepatocarcinogenesis triggered by Tsc1 loss and p53 haploinsufficiency in vivo, as well as the biomarker Abcc4. Conclusions: Our data advance the current understanding of the activation of the PTEN/PI3K/Akt/mTOR axis and its downstream target Abcc4 in hepatocarcinogenesis driven by p53 reduction and Tsc1 loss. Targeting mTOR, an unexpected vulnerability in p53 (haplo)deficiency HCC, can be exploited therapeutically to treat Abcc4-positive patients with HCC. Lay summary: Tsc1 loss facilitates the p53 (haplo)insufficiency-mediated activation of the PTEN/Akt/mTOR axis, leading to the elevated expression of Abcc4 to drive HCC tumorigenesis and metastasis in mice. Inhibition of mTOR protects against p53 haploinsufficiency and Tsc1 loss-triggered tumour-promoting activity, providing a new approach for treating an aggressive subtype of HCC exhibiting high Abcc4 expression.

Abcc4 Hepatocellular carcinoma p53 PI3K/Akt Poor survival PTEN Rapamycin Sapanisertib Tsc1/mTOR

SCI

英语

其他

CLINICAL MEDICINE

2-s2.0-85095798082

Scopus

1.Key Laboratory of Hepatobiliary and Pancreatic Surgery,Institute of Hepatobiliary Surgery,Southwest Hospital,Third Military Medical University (Army Medical University),Chongqing,China
2.School of Medicine,Southern University of Science and Technology,Shenzhen,China
3.Department of Hepatobiliary and Pancreatic Surgery,The Third Affiliated Hospital of Chongqing Medical University (General Hospital),Chongqing,China

Luo，Yuan Deng,Fang，Lei,Yu，Hong Qiang,et al. p53 haploinsufficiency and increased mTOR signalling define a subset of aggressive hepatocellular carcinoma[J]. JOURNAL OF HEPATOLOGY,2020.

Luo，Yuan Deng.,Fang，Lei.,Yu，Hong Qiang.,Zhang，Jie.,Lin，Xiao Tong.,...&Xie，Chuan Ming.(2020).p53 haploinsufficiency and increased mTOR signalling define a subset of aggressive hepatocellular carcinoma.JOURNAL OF HEPATOLOGY.

Luo，Yuan Deng,et al."p53 haploinsufficiency and increased mTOR signalling define a subset of aggressive hepatocellular carcinoma".JOURNAL OF HEPATOLOGY (2020).