Zhou, Yi and Cui, Guofei and Xu, Hongwei and Chun, Joanne and Yang, Doris and Zhang, Zheng and Yang, Lihui and Wang, Jingxiao and Wan, Meijuan and Calvisi, Diego F. and Lin, Shumei and Chen, Xin and Wang, Haichuan (2023) Loss of <i>TP53</i> cooperates with c-MET overexpression to drive hepatocarcinogenesis. CELL DEATH & DISEASE, 14 (7): 476. ISSN 2041-4889,
Full text not available from this repository. (Request a copy)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 similar to 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | P53; EXPRESSION; MUTATION; MOUSE; MICE; PROTOONCOGENE; AFLATOXIN; SUBSET; GENES; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 30 Jan 2024 12:15 |
| Last Modified: | 30 Jan 2024 12:15 |
| URI: | https://pred.uni-regensburg.de/id/eprint/60782 |
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