LncRNA HIF1A-AS1 Promotes Gemcitabine Resistance of Pancreatic Cancer by Enhancing Glycolysis through Modulating the AKT/YB1/HIF1α Pathway
| Autor: | Yong Zhao, Kang Huang, Fan Wang, Chunyou Wang, Jiang Tang, Ding Chen, Ping Hu, Fengyu Xu, Qing-Yong Chen, Gang Zhao, Yuhang Hu, Zhu Zeng, Yi Niu, Mengqi Huang, Chi He |
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| Rok vydání: | 2021 |
| Předmět: |
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 |
| Zdroj: | Cancer research. 81(22) |
| ISSN: | 1538-7445 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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