Hypoxia-induced upregulation of HIF1A-AS3 promotes MSC transition to cancer-associated fibroblasts and confers drug resistance in gastric cancer

Abstract

Chemotherapy resistance is a major cause of poor prognosis in gastric cancer patients and tumor microenvironment plays a critical role in conferring chemotherapy resistance. As a dominant source of tumor stromal cells, mesenchymal stem cells (MSCs) exert pro-oncogenic activities when reprogrammed to a cancer-associated fibroblast (CAF) phenotype. The precise mechanisms for MSC reprogramming and their subsequent role in chemotherapy resistance have not been fully understood. Herein, we reported that HIF1A-AS3, a lncRNA that was highly expressed in tumor-promoting MSCs, was upregulated in tumor tissues and serum of gastric cancer patients and associated with poor prognosis. The upregulation of HIF1A-AS3 reprogramed MSCs to acquire the CAF phenotype, which consequently enhanced the resistance of gastric cancer cells to oxaliplatin. Mechanistically, hypoxia related transcription factor HIF-1α induced high expression of HIF1A-AS3 in MSCs. Then, HIF1A-AS3 competitively sponged miR-142-3p and miR-24-3p, leading to the upregulation of PROX1 (prospero-related homeobox protein 1) gene expression. This further promoted the nuclear translocation of β-catenin and the activation of β-catenin signaling pathway in MSCs, which critically regulated their transition to CAFs. Finally, targeted inhibition of HIF1A-AS3 in hypoxia-MSCs through exosome-mediated siRNA delivery significantly suppressed gastric cancer growth and improved chemosensitivity in mouse tumor models. Conclusively, hypoxia-induced HIF1A-AS3 upregulation reprograms MSCs to CAFs through the miR-142-3p/miR-24-3p/PROX1/β-catenin axis, thereby promoting chemotherapy resistance in gastric cancer, which uncovers a new molecular mechanism for MSCs transition to CAFs in gastric cancer and provides a new target for the diagnosis and targeted therapy of gastric cancer.

Keywords: Chemotherapy resistance; Gastric cancer; Hypoxia; LncRNA; Mesenchymal stem cells; Tumor microenvironment.