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.

Loss of TP53 cooperates with c-MET overexpression to drive hepatocarcinogenesis / Zhou, Yi; Cui, Guofei; Xu, Hongwei; Chun, Joanne; Yang, Doris; Zhang, Zheng; Yang, Lihui; Wang, Jingxiao; Wan, Meijuan; Calvisi, Diego F; Lin, Shumei; Chen, Xin; Wang, Haichuan. - In: CELL DEATH & DISEASE. - ISSN 2041-4889. - 14:7(2023), p. 476. [10.1038/s41419-023-05958-y]

Loss of TP53 cooperates with c-MET overexpression to drive hepatocarcinogenesis

Calvisi, Diego F
Conceptualization
;
2023-01-01

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.
2023
Loss of TP53 cooperates with c-MET overexpression to drive hepatocarcinogenesis / Zhou, Yi; Cui, Guofei; Xu, Hongwei; Chun, Joanne; Yang, Doris; Zhang, Zheng; Yang, Lihui; Wang, Jingxiao; Wan, Meijuan; Calvisi, Diego F; Lin, Shumei; Chen, Xin; Wang, Haichuan. - In: CELL DEATH & DISEASE. - ISSN 2041-4889. - 14:7(2023), p. 476. [10.1038/s41419-023-05958-y]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11388/324292
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