Hepatocellular Carcinoma LINC01116 Outcompetes T Cells for Linoleic Acid and Accelerates Tumor Progression

Abstract

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer with a highly immunosuppressive tumor microenvironment and a typical pattern of disturbances in hepatic lipid metabolism. Long non‐coding RNAs are shown to play an important role in the regulation of gene expression, but much remains unknown between tumor microenvironment and lipid metabolism as a bridging molecule. Here, long intergenic nonprotein coding RNA 01116 (LINC01116) acts as this molecular which is frequently upregulated in HCC patients and associated with HCC progression in vitro and in vivo is identified. Mechanistically, LINC01116 stabilizes EWS RNA‐binding protein 1 (EWSR1) by preventing RAD18 E3 Ubiquitin Protein Ligase (RAD18) ‐mediated ubiquitination. The enhanced EWSR1 protein upregulates peroxisome proliferator activated receptor alpha (PPARA) and fatty acid binding protein1 (FABP1) expression, a long‐chain fatty acid (LCFA) transporter, and thus cancer cells outcompete T cells for LCFAs, especially linoleic acid, for seeding their own growth, leading to T cell malfunction and HCC malignant progression. In a preclinical animal model, the blockade of LINC01116 leads to enhanced efficacy of anti‐PD1 treatment accompanied by increased cytotoxic T cell and decreased exhausted T cell infiltration. Collectively, LINC01116 is an immunometabolic lncRNA and the LINC01116‐EWSR1‐PPARA‐FABP1 axis may be targetable for cancer immunotherapy.

The switch triggering the invasion process: Lipid metabolism in the metastasis of hepatocellular carcinoma

“…[41] FABP5, another pivotal FABP mediating FA transport, was found not only to modulate the IL6/STAT3/VEGFA pathway in HCC cells, but also to regulate the tube formation, viability, and migration of human umbilical vein endothelial cells, indicating a potential angiogenic role of FABP5 in HCC. [42] Moreover, Ma et al [43] demonstrated that long intergenic noncoding RNA 01116 (LINC01116) blocks the ubiquitin-proteasome pathway to stabilize EWS RNA-binding protein 1 (EWSR1). Subsequently, EWSR1 acts as an m6A reader to regulate the stability of peroxisome proliferator-activated receptor-α (PPARα), increasing the expression of FABP1 to enhance FA intake, which facilitates the metastasis and growth of HCC.…”

“…Antisense oligonucleotides targeting LINC01116 improved the curative effect of anti-PD-1 therapy in a mouse model, regulating antitumor immunity and inducing tumor regression of HCC. [43] Simvastatin, an inhibitor of cholesterol synthesis, intensifies the efficacy of PD-L1 antibodies to synergistically resist HCC metastasis and proliferation when applied via LSEC-targeted nano-delivery. [114] ICIs and mTKIs are most momentous drugs of systemic therapy.…”