SLC26A2 as a key regulator and therapeutic target in hepatocellular carcinoma: evidence from pan-cancer and mechanistic studies.

内容摘要

Hepatocellular carcinoma (HCC) faces a critical shortage of prognostic biomarkers and therapeutic targets. While solute carrier family 26 member 2 (SLC26A2) is known to be involved in skeletal disorders and even tumors, its specific role in HCC pathogenesis remains undefined. We utilized public databases to conduct a comprehensive analysis of SLC26A2 across 33 different cancer types. Additionally, we performed in vitro and in vivo experiments to investigate the functional role of SLC26A2 in the biological behavior of HCC and to explore its mechanistic pathways. A pan‑cancer analysis revealed significant variability in SLC26A2 mRNA and protein levels, with prognostic implications across cancers. In HCC, SLC26A2 was identified as an independent risk factor for poor overall survival (HR = 1.539, 95% CI 1.084-2.186, p = 0.016) and correlated with higher pathological grade. Functional assays showed that silencing SLC26A2 inhibited HCC cell proliferation, migration, and invasion, while promoting apoptosis; conversely, overexpression led to opposite outcomes. Notably, silencing SLC26A2 significantly increased intracellular ROS, which was linked to subsequent modulation of the JNK/ERK/p38 MAPK signaling pathway-an effect suggested to be reversible by the antioxidant N‑acetylcysteine. In vivo studies demonstrated that silencing SLC26A2 suppressed subcutaneous tumor growth in an HCC xenograft model. Additionally, bioinformatics analysis predicted a competing endogenous RNA regulatory axis comprising the SNHG3/LINC00662-hsa-miR‑122‑5p-SLC26A2. Our study identifies SLC26A2 as a clinically relevant biomarker and candidate therapeutic target in HCC. Mechanistically, SLC26A2 modulates JNK/ERK/p38 MAPK activity in a manner involving ROS signaling. While its biological roles extend beyond HCC, the clinical implications are most pronounced in this malignancy.