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Interactions between specific driver genes shape the signaling pathway landscape and direct the treatment of hepatocellular carcinoma

ABSTRACT: Hepatocellular carcinoma (HCC) is one of the most lethal malignancies, whose initiation and development are driven by alterations in driver genes. In this study, we identified four driver genes (TP53, PTEN, CTNNB1, and KRAS) that exhibit a high frequency of somatic mutations or copy number variations (CNVs) in patients with HCC. Four different spontaneous HCC mouse models were constructed to screen for changes in various kinase signaling pathways. The Trp53mut+Ptenmut tumor upregulated mTOR and noncanonical NF-κB signaling, which was shown to be strongly inhibited by rapamycin (an mTOR inhibitor) in vitro or in vivo. JAK-STAT signaling was activated in the Ctnnb1mut+Ptenmut tumor, the proliferation of which was strongly inhibited by napabucasin (a STAT3 inhibitor). MTOR, cytoskeleton, and AMPK signaling were upregulated while rapamycin and ezrin inhibitors exerted potent anti-proliferative effects in the Ptenmut+KrasG12D tumor. JAK-STAT, MAPK, and cytoskeleton signaling were activated in the Tp53mut+KrasG12D tumor and the combination of sorafenib and napabucasin led to the complete inhibition of tumor growth in vivo. In patients with HCC that had the same molecular classification as our mouse models, the downstream signaling pathway landscapes associated with genomic alterations were identical. Our research provides novel targeted therapeutic options for the clinical treatment of HCC, based on the presence of specific genetic alterations within the tumor.

ORGANISM(S): Mus musculus

PROVIDER: GSE208279 | GEO | 2022/07/19

REPOSITORIES: GEO

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Liver epithelial cell-specific loss of mTOR aggravates tumor development in a murine model of nonalcoholic steatohepatitis related hepatocellular carcinoma

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2023-11-15 | PXD039944 | Pride

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MicroRNAs mediate rapamycin resistance in a myogenic tumor cell line

2013-02-08 | GSE19916 | GEO

Gene expression data from rapamycin resistant and sensitive cell lines

2013-02-08 | GSE19885 | GEO

MicroRNAs mediate rapamycin resistance in a myogenic tumor cell line

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2013-02-08 | E-GEOD-19916 | biostudies-arrayexpress

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