Abstract
Tyrosine kinase inhibitor resistance is a key factor affecting the prognosis of patients with advanced hepatocellular carcinoma (HCC). Previously, our group demonstrated that HCC patients with high stomatin-like protein 2 (STOML2) expression were poorly sensitive to systemic therapy. Whether STOML2 is involved in sorafenib resistance is unclear. Recent mechanistic studies have demonstrated that selective activation of ferroptosis pathways is expected to restore sorafenib sensitivity. The aim of the present study was to investigate the STOML2-ferroptosis axis and its contribution to sorafenib resistance. In this study, STOML2 expression was detected in tissue microarrays from patients with primary HCC and in human cell lines. Functional proliferative clone formation assay was used to study the biological function of STOML2. Ferroptosis was detected by flow cytometry, cellular lipid peroxidation and the malondialdehyde (MDA) test. Western blotting and qPCR assays were used to verify the STOML2-AKT-solute carrier family 7 membrane 11 (SLC7A11) axis and to explore the possible mechanism of the combination of LY294002 (an AKT inhibitor) in patients with advanced HCC. The results indicated that patients with poor efficacy demonstrated higher expression of STOML2 compared with that in samples derived from patients with good efficacy. Knockdown of STOML2 expression inhibited colony formation and IC50 in HCC cell lines treated with sorafenib. High STOML2 expression was negatively correlated with ferroptosis as shown by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis. STOML2 inhibited ferroptosis by activating the AKT-SLC7A11 axis, which promoted increased intracellular antioxidant capacity. The AKT inhibitor LY294002 exhibited synergistic antitumor effects with sorafenib in HCC. In conclusion, the present study demonstrated that STOML2 could enhance the AKT-SLC7A11-mediated antioxidant capacity in HCC, inhibit ferroptosis and reduce the sensitivity of HCC to sorafenib, providing a theoretical basis for the combination of LY294002 and sorafenib.