Year: 2023
Type: article
Abstract: Hepatocellular carcinoma (HCC) is a deadly malignancy with high genetic heterogeneity. TP53 mutation and c-MET activation are frequent events in human HCCs. Here, we discovered that the simultaneous mutations in TP53 and activation of c-MET occur in ~20% of human HCCs, and these patients show a poor prognosis. Importantly, we found that concomitant deletion of Trp53 and overexpression of c-MET (c-MET/sgp53) in the mouse liver led to HCC formation in vivo. Consistent with human HCCs, RNAseq showed that c-MET/sgp53 mouse HCCs were characterized by activated c-MET and Ras/MAPK cascades and increased tumor cell proliferation. Subsequently, a stably passaged cell line derived from a c-MET/sgp53 HCC and corresponding subcutaneous xenografts were generated. Also, in silico analysis suggested that the MEK inhibitor trametinib has a higher inhibition score in TP53 null human HCC cell lines, which was validated experimentally. We consistently found that trametinib effectively inhibited the growth of c-MET/sgp53 HCC cells and xenografts, supporting the possible usefulness of this drug for treating human HCCs with TP53-null mutations. Altogether, our study demonstrates that loss of TP53 cooperates with c-MET to drive hepatocarcinogenesis in vivo. The c-MET/sgp53 mouse model and derived HCC cell lines represent novel and useful preclinical tools to study hepatocarcinogenesis in the TP53 null background.
Source: Cell Death and Disease
Institutions: University of California, San Francisco, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Cancer Center of Hawaii, University of Hawaii Cancer Center, Sichuan University, West China Hospital of Sichuan University, Beijing University of Chinese Medicine, University of Regensburg, First Hospital of Xi'an
Language: English
Subfield: Hepatology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,490
Funders: Foundation for the National Institutes of Health, National Natural Science Foundation of China, National Institutes of Health, University of California, San Francisco, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, Liver Center, University of California, San Francisco
OpenAlex ID: W4385297820