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LncRNA HIF1A-AS1 Promotes Gemcitabine Resistance of Pancreatic Cancer by Enhancing Glycolysis through Modulating the AKT/YB1/HIF1α Pathway
- Source :
- Cancer research. 81(22)
- Publication Year :
- 2021
-
Abstract
- 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 HIF1α (HIF1A-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 HIF1α 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 1 (YB1), which promoted phosphorylation of YB1 (pYB1). Meanwhile, HIF1A-AS1 recruited pYB1 to HIF1α mRNA that consequently promoted translation of HIF1α. Furthermore, HIF1α promoted HIF1A-AS1 transcription by directly binding to the HIF1α response element in the promoter area of HIF1A-AS1 to form a positive feedback. Consistently, both HIF1A-AS1 and HIF1α were upregulated in pancreatic cancer tissues and associated with poor overall survival. Together, our results underline a reciprocal loop of HIF1A-AS1 and HIF1α that contributes to GEM resistance of pancreatic cancer and indicate that HIF1A-AS1 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 HIF1α promotes gemcitabine resistance of pancreatic cancer, which provides an applicable therapeutic target.
- Subjects :
- Male
Cancer Research
Antimetabolites, Antineoplastic
Mice, Nude
Apoptosis
medicine.disease_cause
Deoxycytidine
Mice
Downregulation and upregulation
Pancreatic cancer
medicine
Biomarkers, Tumor
Tumor Cells, Cultured
Animals
Humans
Neoplasm Invasiveness
Protein kinase B
Cell Proliferation
Mice, Inbred BALB C
Chemistry
Kinase
medicine.disease
Hypoxia-Inducible Factor 1, alpha Subunit
Prognosis
Xenograft Model Antitumor Assays
Gemcitabine
Gene Expression Regulation, Neoplastic
Pancreatic Neoplasms
Survival Rate
HIF1A
Oncology
Drug Resistance, Neoplasm
Cancer research
Phosphorylation
RNA, Long Noncoding
Y-Box-Binding Protein 1
Carcinogenesis
Glycolysis
Proto-Oncogene Proteins c-akt
medicine.drug
Subjects
Details
- ISSN :
- 15387445
- Volume :
- 81
- Issue :
- 22
- Database :
- OpenAIRE
- Journal :
- Cancer research
- Accession number :
- edsair.doi.dedup.....5caadf31929f43afef19b6584f71c049