{"doi":"10.1038/s41419-023-05958-y","title":"Loss of TP53 cooperates with c-MET overexpression to drive hepatocarcinogenesis","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.","journal":"Cell Death and Disease","year":2023,"id":333995,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":22,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9555,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":865109,"name":"Guofei Cui","orcid":"0009-0005-5624-0403","position":1,"is_corresponding":false},{"id":634648,"name":"Hongwei Xu","orcid":"0009-0000-9490-7196","position":2,"is_corresponding":false},{"id":1062346,"name":"Joanne Chun","orcid":null,"position":3,"is_corresponding":false},{"id":1061918,"name":"Doris Yang","orcid":"0000-0002-5188-2571","position":4,"is_corresponding":false},{"id":105893,"name":"Zheng Zhang","orcid":"0000-0003-1470-6998","position":5,"is_corresponding":false},{"id":1061919,"name":"Lihui Yang","orcid":"0000-0001-6542-7484","position":6,"is_corresponding":false},{"id":278052,"name":"Jingxiao Wang","orcid":"0000-0002-7799-781X","position":7,"is_corresponding":false},{"id":1062347,"name":"Meijuan Wan","orcid":null,"position":8,"is_corresponding":false},{"id":270014,"name":"Diego F. Calvisi","orcid":"0000-0002-6038-8567","position":9,"is_corresponding":false},{"id":450691,"name":"Shumei Lin","orcid":null,"position":10,"is_corresponding":false},{"id":1360,"name":"Xin Chen","orcid":"0000-0002-9588-0164","position":11,"is_corresponding":false},{"id":302531,"name":"Haichuan Wang","orcid":"0000-0002-6886-5698","position":12,"is_corresponding":false},{"id":278051,"name":"Yi Zhou","orcid":"0000-0001-9024-7514","position":0,"is_corresponding":true}],"reference_count":35,"raw_metadata":null,"created_at":"2026-07-19T01:09:44.297718Z","pmid":"37500626","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}