Hypoxia-elicited exosomes promote the chemoresistance of pancreatic cancer cells by transferring lncROR via Hippo signaling

Abstract

Abstract Recent studies have found that hypoxia contributes to tumor progression and drug resistance via inducing exosomes secretion. However, the underlying mechanism of this resistance in pancreatic cancer remains to be explored. In this study, we explored the effect and molecular mechanisms of hypoxia-induced tumor-derived exosomes (Hexo) on stemness and gemcitabine (GEM) resistance in pancreatic cancer cells. Firstly, we discovered that hypoxia could promote the stemness and induce gemcitabine resistance in pancreatic cancer cells. Subsequently, we proved that exosomes secreted by pancreatic cancer cells under normoxic or hypoxic conditions can be transfected into tumor cells. And then, Hexo was demonstrated to promote the proliferation, stemness and Gem resistance of pancreatic cancer cells, as well as inhibit the apoptosis and the cell cycle arrest induced by gemcitabine. Finally, it was verified that Hexo could inactivate the Hippo/YAP pathway of pancreatic cancer cells by transferring exosomal lncROR. In summary, hypoxic tumor microenvironment could promote the stemness and induce gemcitabine resistance in pancreatic cancer cells. Mechanically, Hexo enhanced the stemness to promote chemoresistance of pancreatic cancer cells by transferring lncROR via Hippo signaling. Thus, exosomal lncROR may serve as a candidate target for pancreatic cancer chemotherapy.