HIF-1α is necessary for activation and tumour-promotion effect of cancer-associated fibroblasts in lung cancer.

Abstract

Cancer‐associated fibroblasts (CAFs) activation is crucial for the establishment of a tumour promoting microenvironment, but our understanding of CAFs activation is still limited. In this study, we found that hypoxia‐inducible factor‐1α (HIF‐1α) was highly expressed in CAFs of human lung cancer tissues and mouse spontaneous lung tumour. Accordingly, enhancing the expression of HIF‐1α in fibroblasts via hypoxia induced the conversion of normal fibroblasts into CAFs. HIF‐1α‐specific inhibitor or HIF‐1α knockout (KO) significantly attenuated CAFs activation, which was manifested by the decreased expression of COL1A2 and α‐SMA. In vivo, during tumour formation, the expression of Ki‐67 and proliferating cell nuclear antigen (PCNA) in the tumour tissue with HIF‐1α KO fibroblasts was significantly lower than that of normal fibroblasts. Moreover, HIF‐1α in fibroblasts could activate the NF‐κB signalling pathway and enhance a subsequent secretion of CCL5, thus promoting the tumour growth. In conclusion, our results suggest that HIF‐1α is essential for the activation and tumour‐promotion function of CAFs in lung cancer (LC). And targeting HIF‐1α expression on CAFs may be a promising strategy for LC therapy.