Hif-1 Alpha Is Necessary For Activation And Tumour-Promotion Effect Of Cancer-Associated Fibroblasts In Lung Cancer

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