LOX-1 and Its Splicing Variant LOX-1Δ4 Differently Influence Hepatocellular Carcinoma Cell Progression and...

Hepatocellular carcinoma (HCC) is a leading cause among cancer-related deaths. HCC progression is linked to alteration of lipid metabolism. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), a receptor for oxidized low-density lipoproteins (ox-LDLs), and its splicing isoform LOX-1Δ4 have been recently identified and linked to tumor aggressiveness, but their role in HCC carcinogenesis is largely unexplored. The present study is aimed at investigating and comparing the role of LOX-1 and its splicing variant LOX-1Δ4 in HCC progression and chemoresistance.

We performed in vivo evaluation of LOX-1 expression on HCC tissue samples by immunohistochemistry and in vitro transfection studies on HCC cell line HepG2 to verify the involvement of LOX-1 and its variant LOX-1Δ4 expression in cell proliferation and chemoresistance.

Total LOX-1 expression correlated with higher tumor grade in HCC tissue samples. LOX-1Δ4 transfection significantly increased proliferation, enhanced doxorubicin resistance, upregulated p21^Cip1/Waf1, p27^Kip1, and Cyclin D1, and downregulated p53 expression. LOX-1Δ4 also increased acetyl-histone H4 expression, suggesting DNA acetylation-driven transcription. Both LOX-1 and LOX-1Δ4 transfections were associated with increased p62 and vimentin expression, alongside decreased LC3B-II levels, with LOX-1Δ4 exhibiting a more marked modulation of LC3B.

LOX-1Δ4 isoform appears to exert a more pronounced influence than full-length LOX-1 on HCC progression-related features in vitro. LOX-1Δ4 appears to impact nonviral HCC progression more than LOX-1 in vitro. These preliminary findings suggest this axis as a potential future therapeutic target, though in vivo validation remains essential.