STC2 mediates hypoxia-induced immunosuppression and tumorigenesis in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with a poor prognosis and limited therapeutic options. There is a pressing need to identify novel prognostic biomarkers and therapeutic targets, particularly among secreted proteins which play critical roles in tumor progression and the tumor microenvironment.

We conducted an integrated bioinformatic analysis of transcriptomic data from TCGA-LIHC and GEO datasets to identify dysregulated secretory proteins and construct a prognostic model. The top candidate, STC2, was selected for functional validation. Immune cell infiltration was analyzed using ESTIMATE and CIBERSORT algorithms. The functional role of STC2 was investigated through in vitro assays including siRNA knockdown, overexpression, cell proliferation, colony formation, and wound healing. Mechanisms of transcriptional regulation were assessed by chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays.

We established a robust risk-scoring model based on a signature of secretory proteins, which identified STC2 as a key prognostic determinant. High STC2 expression was linked to an immunosuppressive tumor microenvironment characterized by enriched macrophage infiltration. Furthermore, STC2 expression was significantly upregulated in HCC tissues and strongly associated with advanced tumor stage, metastasis, and reduced patient survival. Mechanistically, we demonstrated that the transcription factor HIF-1α directly binds to the STC2 promoter and activates its transcription. Functional studies confirmed that STC2 drives HCC cell proliferation, clonogenicity, and migration. Transcriptomic profiling further indicated that STC2 is involved in activating the PI3K-Akt and HIF-1α signaling pathways. Moreover, STC2 is highly expressed in tumor regions and is associated with M2-type macrophage polarization in TME.

Our study unveils STC2 as a pivotal hypoxia-induced oncogene in HCC, directly transcriptionally activated by HIF-1α. STC2 fosters tumor progression by enhancing malignant phenotypes and sculpting an immune-suppressive microenvironment, positioning it as a promising prognostic biomarker and an attractive therapeutic target for HCC.