Abstract 1569: Keratin X promotes cell metastasis and sorafenib resistance via the AMPKα/Snail axis in hepatocellular carcinoma

Abstract

Abstract A great majority of liver cancers are developed from cirrhotic livers. The key molecules involved in cirrhosis-mediated hepatocarcinogenesis have not been clearly defined. Understanding the oncogenic pathways and their associations with cancer growth, metastasis and drug resistance may help scientists devise new effective therapeutic agents. In the present study, we identified the intermediate filament-forming protein keratin X (KRTX) as a key factor in cirrhosis-mediated hepatocarcinogenesis. KRTX was highly expressed in HCC tissues and correlated with poor survival outcomes. Experimental verification revealed that overexpression of KRTX enhanced cell growth, tumor cell metastasis, glycolysis and sorafenib resistance. Conversely, knockdown of KRTX led to opposite effects. Mechanistically, KRTX inhibited AMPKα phosphorylation, thereby enhancing Snail protein stability. Additionally, TGFβ1 positively regulated KRTX expression, resulting in a KRTX/AMPKα (Thr172)/Snail axis-mediated increase in cell motility. Treating with 2-deoxyglucose reversed the KRTX-induced metastasis and sorafenib resistance. In clinic, KRTX expression is positively correlated with Snail overexpression and high KRTX/Snail expression had poor prognosis in HCC patients. Our data revealed a signaling pathway from TGFβ1, KRTX, through p-AMPKα (Thr172) to Snail. Targeting KRTX and its pathway may be effective for treating patients with metastatic HCC. Citation Format: Yang-Hsiang Lin, Chau-Ting Yeh. Keratin X promotes cell metastasis and sorafenib resistance via the AMPKα/Snail axis in hepatocellular carcinoma [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 1569.