LncRNA HIF1A-AS1 Promotes Gemcitabine Resistance of Pancreatic Cancer by Enhancing Glycolysis through Modulating the AKT/YB1/HIF1α Pathway

Gemcitabine (GEM) resistance is a major challenge for chemotherapy of pancreatic cancer. Previous studies have reported on the role of long noncoding RNA (lncRNA) in tumorigenesis of pancreatic cancer, however, the involvement of lncRNA in the development of GEM resistance of pancreatic cancer remains unclear. In the present study, we demonstrated that the antisense RNA1 of HIF1 alpha (HIFIA-AS1) was significantly elevated in the GEM-resistant pancreatic cancer cells. Gain- and lost-of-function experiments validated that HIF1A-AS1 promoted GEM resistance of pancreatic cancer cells both in vitro and vivo. We further revealed that HIF1A-AS1 upregulated HIF1A expression and thus promoted glycolysis to enhance GEM resistance of pancreatic cancer cells. Mechanistically, HIF1A-AS1 facilitated the interaction between serine/threonine kinase AKT and Y-box-binding protein I (YB1), which promoted phosphorylation of YB1 (pYB1). Meanwhile, HIF1A-AS1 recruited pYB1 to HIFI a mRNA that consequently promoted translation of HIF1 alpha. Furthermore, HIF1 alpha promoted HIF1A-AS1 transcription by directly binding to the HIF1 alpha response element in the promoter area of HIF1A-AS1 to form a positive feedback. Consistently, both HIF1A-AS1 and HIF1 alpha were upregulated in pancreatic cancer tissues and associated with poor overall survival. Together, our results underline a reciprocal loop of HIF1A-AS1 and HIF1 alpha that contributes to GEM resistance of pancreatic cancer and indicate that HIF1A-ASI might serve as a novel therapeutic target for GEM resistance of pancreatic cancer. Significance: These findings show that a reciprocal feedback of HIF1A-AS1 and HIF1 alpha promotes gemcitabine resistance of pancreatic cancer, which provides an applicable therapeutic target.

Automated summary

The reciprocal feedback loop between HIF1A-AS1 and HIF1 alpha promotes gemcitabine resistance in pancreatic cancer, highlighting a potential therapeutic target.