HIF1 alpha/PD-L1 axis mediates hypoxia-induced cell apoptosis and tumor progression in follicular thyroid carcinoma

Background: Hypoxia-inducible factor 1 alpha (HIF-1 alpha) and programmed cell death-1 protein ligand 1 (PD-L1) are implicated in the metastasis and progression processes of multiple cancers. Hypoxia selectively elevates PD-L1 expression via HIF1 alpha activation in several solid tumors; however, the regulatory effect of HIF1 alpha on PD-L1 in the pathogenesis of follicular thyroid cancer (FTC) remains unclear. This study aims to investigate the regulatory effect of HIF1 alpha on PD-L1 and their potential roles in FTC pathogenesis. Methods: Spearman correlation analysis was performed to clarify the relationships between HIF1 alpha and PD-L1 expressions and the clinicopathologic characteristics. The expressions of HIF1 alpha and PD-L1 at mRNA and protein levels were analyzed by qRT-PCR and Western blot. Hypoxia induction and cell transfection were conducted in FTC cells. TUNEL and Annexin V staining were used to detect the cell apoptosis. FTC xenograft tumor models were generated to evaluate the roles of HIF1 alpha and PD-L1 in vivo. Results: Here, we found that the expressions of HIF1 alpha and PD-L1 were significantly increased in FTC tissues and were correlated with the FTC clinicopathologic features, such as the tumor size, T stage, TNM staging, and metastasis. In FTC cells, hypoxia-induced increased HIF1 alpha and PD-L1 expression. Knockdown of HIF1 alpha inhibits hypoxia-induced PD-L1 expression and cells apoptosis. Moreover, inhibition of HIF1 alpha or PD-L1 significantly delays tumor growth and metastasis in vivo. Conclusion: Hypoxia could promote FTC progression by upregulating HIF1 alpha and PD-L1, which could serve as the molecular targets for FTC treatment.