Abstract 2274: Genomic and transcriptomic analyses of chemical hepatocarcinogenesis aggravated by loss of oncoproteins in hepatocytes

Abstract Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death without effective treatment. Oncogenic drivers, including PTPN11/Shp2, Ikkβ kinase (IKK), c-Met and β-catenin, as well as tumor microenvironment as illustrated by a carcinogen or diethylnitrosamine (DEN)-treated models, have combined contribution to cancer progression that have distinct prevalence in human HCC progression. We previously found that disruption of Ras/Erk by Shp2 deletion combined with deletion of NF-κB unexpectedly dysregulated circadian clock genes which leads to further cancer progression. Except for this, limited reports investigated how various other oncogenic genes aberration would incorporate with DEN to induce HCC. Further, no reports investigated the dynamic evolution of transcriptomic aberration incorporating genetic changes and the differential functional pathways involved in DEN plus oncogene triggered-HCC progression. Thus, we here sought to investigate the context-dependent contribution of PTPN11/Shp2, IKK, c-Met and β-catenin to HCC using hepatocyte-specific deletion models (SKO, IKO, MKO, BKO) combined with DEN treatment. Exome sequencing and RNAseq were used to identify dynamic changes of the genomic and transcriptomic variations of HCC development under the influence of both genetic deletion and DEN-treatment. We found that upregulated epithelial-mesenchymal transition (EMT), cancer metastasis/migration and downregulated fatty-acid and cholesterol metabolism were highly involved across models. Macrophages together with genes including Spi1, Clec7a, and microRNA networks including miR-122 and miR-155 etc. were also deregulated. Specifically, upregulated IL2-STAT5 signaling in DEN-SKO liver tissues, upregulated myogenesis, KRAS signaling and EMT as well as apoptosis in DEN-MKO, downregulated xenobiotic metabolism and bile acid metabolism in DEN-IKO and -BKO were identified to be distinct to oncogenic deletion in relation with HCC development. Citation Format: Xinyi Wang, Jiemeng Zhang, Yingluo Liu, Shuo Zhang, Yan Liang, Min Zong, Xiaoxue Lin, Michael Karin, Gensheng Feng. Genomic and transcriptomic analyses of chemical hepatocarcinogenesis aggravated by loss of oncoproteins in hepatocytes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2274.