HIF-1 promotes pancreatic ductal adenocarcinoma invasion and metastasis by activating transcription of the actin-bundling protein fascin

Abstract

Early onset of invasive and metastatic progression of pancreatic ductal adenocarcinoma (PDAC) makes it one of the most lethal human cancers. In this study, we investigated the role of the pro-metastatic actin bundling protein fascin in PDAC progression. Expression levels of fascin were higher in cancer tissues than in normal tissues and fascin overexpression correlated with PDAC differentiation and prognosis. Fascin overexpression promoted PDAC cells migration and invasion by elevating MMP-2 expression via PKC and ERK. Importantly, our results showed that hypoxia-induced fascin overexpression in PDAC cells by promoting HIF-1 binding to the fascin promoter and transactivating fascin mRNA transcription. Intriguingly, HIF-1alpha expression levels in PDAC patient specimens correlated with fascin expression. Moreover, immunohistochemical staining of consecutive sections demonstrated HIF-1alpha and fascin colocalization in PDAC specimens, suggesting that hypoxia and HIF-1alpha were responsible for fascin overexpression in PDAC. When ectopically expressed, fascin rescued PDAC cell invasion after HIF-1alpha silencing. Our results demonstrated that fascin is a direct target gene of HIF-1. Further, they suggested that the hypoxic tumor microenvironment might promote invasion and metastasis of PDAC via fascin overexpression, highlighting fascin as a target to block PDAC progression.