Effects of nuclear CD276 on CD36-mediated lipid metabolism reprogramming on TKI resistance in hepatoma..

Abstract

e16174 Background: The clinical benefit of tyrosine kinase inhibitors (TKIs)-based systemic therapy for advanced hepatocellular carcinoma (HCC) is limited due to drug resistance. Fatty acid metabolism reprogramming drive initiation and progression of tumors, and targeted drugs against aberrant tumor metabolism have emerged as a promising option to combat tumor progression. CD276 is an immunoregulatory protein and plays an oncogenic role in multiple tumor types. Here, we uncover that lipid metabolic reshaping mediated by CD276 endows HCC with malignancy and resistance to TKIs. Methods: Molecular screening and bioinformatics analysis were performed in HCC based on data from The Cancer Genome Atlas (TCGA) database. Liver cancer tissues were utilized for analysis of CD276 expression for association with clinicopathological factors from patients by immunohistochemistry assay. Manipulation of CD276 expression, the liver cancer cell proliferation, tolerance to TKIs were assessed using cell viability CCK-8, colony formation assay, flow cytometry. Furthermore, the metabolomics analysis, oil red o staining, fatty acid and lipid droplets fluorescence probe were conducted for measuring lipid metabolism. The mass spectrometry (MS), western blot, qRT-PCR, luciferase reporter assay, chromatin immunoprecipitation (ChIP) assays, co-immunoprecipitation (CO-IP) and other biological methods were performed to explore and verify related downstream targets and pathways. Various cell line models and animal models were constructed to perform biological functional experiments. Results: In this study, we founded that CD276 highly expressed in TKI-resistant tumor tissue, which is associated with an unfavorable outcome, and demonstrated its role in promoting malignancy and TKIs resistance by influencing lipid metabolism in vitro and in vivo. Mechanistically, TKIs facilitated nuclear translocation of CD276, nuclear CD276 recruited p-STAT3 and enhanced its binding to the promoter of CD36. The lipid remodeling was activated by upregulated CD36, Causing proliferation and desensitization to TKIs in liver cancer cells. Therapeutically, Sulfosuccinimidyl oleate sodium (SSO), an inhibitor of CD36, was found to impede its fatty acid uptake and thereby attenuating tumor lipid metabolic process, offering potential benefits for patients with TKIs resistant liver cell cancer. Conclusions: Our findings highlight CD276 as a novel biomarker to predict poor prognosis and TKIs resistance in HCC. We reveal an unexpected non-canonical function of CD276 in promoting reshaping lipid metabolism, providing an effective strategy to sensitizing TKIs through targeting aberrant fatty acid remolding.