An Liu1, Yonggui Zhou2, Tian Zhao1, Xu Tang3, Binbin Zhou4, Jia Xu5. 1. Department of Chemistry and Chemical Engineering, Hunan Institute of Science and Technology, Yueyang, 414006, People's Republic of China. 2. Department of Gastrointestinal Surgery, The First People's Hospital of Yueyang, Yueyang, 414000, People's Republic of China. 3. Department of Intensive Care, The Second People's Hospital of Yueyang, Yueyang, 414006, People's Republic of China. muhaiqi2015@126.com. 4. Department of Chemistry and Chemical Engineering, Hunan Institute of Science and Technology, Yueyang, 414006, People's Republic of China. 442628565@qq.com. 5. Department of Gastrointestinal Surgery, The First People's Hospital of Yueyang, Yueyang, 414000, People's Republic of China. misshartha@qq.com.
Abstract
OBJECTIVES: Gemcitabine (Gem) is one of the most commonly used chemotherapeutic drugs in treating patients with pancreatic ductal adenocarcinoma (PDAC). Acquired drug resistance against Gem presents a major clinical challenge in the chemotherapy of PDAC. It has been shown that miRNA-3662 is lowly expressed and implicated with quantities of biological processes in cancer. However, whether miRNA-3662 regulates chemoresistance in PDAC remains largely unknown. MATERIALS AND METHODS: The level of miRNA-3662 in PDAC tissues was determined by real-time qPCR (RT-qPCR). Functional experiments were used to investigate the biological role of miRNA-3662 on Gem resistance of PDAC in vitro and in vivo. Fluorescence in situ hybridization (FISH), RT-qPCR, western blotting, bioinformatics analysis and luciferase reporter assay were employed to determine the precise regulation mechanisms. RESULTS: In this study, it was investigated that miRNA-3662 was down-regulated in PDAC clinical samples as well as cell lines. Functional assays revealed that miRNA-3662 was sufficient to inhibit Gem resistance in PDAC cells both in vitro and in vivo. Mechanistically, hypoxia-inducible factor 1ɑ (HIF-1ɑ) was one of the transcriptional target of miRNA-3662 and was up-regulated in PDAC samples. Importantly, genetic promoting of HIF-1ɑ largely compromised miR-3662-mediated chemosensitive effects. In addition, miR-3662 could impair the aerobic glycolysis in PDAC cells. CONCLUSIONS: This study sheds light on miRNA-3662 inhibits PDAC cell chemoresistance and aerobic glycolysis through a negative feedback loop with HIF-1ɑ. Therefore, the co-delivery of miR-3662 and Gem could be served as a promising therapeutic regimen for PDAC patients.
OBJECTIVES:Gemcitabine (Gem) is one of the most commonly used chemotherapeutic drugs in treating patients with pancreatic ductal adenocarcinoma (PDAC). Acquired drug resistance against Gem presents a major clinical challenge in the chemotherapy of PDAC. It has been shown that miRNA-3662 is lowly expressed and implicated with quantities of biological processes in cancer. However, whether miRNA-3662 regulates chemoresistance in PDAC remains largely unknown. MATERIALS AND METHODS: The level of miRNA-3662 in PDAC tissues was determined by real-time qPCR (RT-qPCR). Functional experiments were used to investigate the biological role of miRNA-3662 on Gem resistance of PDAC in vitro and in vivo. Fluorescence in situ hybridization (FISH), RT-qPCR, western blotting, bioinformatics analysis and luciferase reporter assay were employed to determine the precise regulation mechanisms. RESULTS: In this study, it was investigated that miRNA-3662 was down-regulated in PDAC clinical samples as well as cell lines. Functional assays revealed that miRNA-3662 was sufficient to inhibit Gem resistance in PDAC cells both in vitro and in vivo. Mechanistically, hypoxia-inducible factor 1ɑ (HIF-1ɑ) was one of the transcriptional target of miRNA-3662 and was up-regulated in PDAC samples. Importantly, genetic promoting of HIF-1ɑ largely compromised miR-3662-mediated chemosensitive effects. In addition, miR-3662 could impair the aerobic glycolysis in PDAC cells. CONCLUSIONS: This study sheds light on miRNA-3662 inhibits PDAC cell chemoresistance and aerobic glycolysis through a negative feedback loop with HIF-1ɑ. Therefore, the co-delivery of miR-3662 and Gem could be served as a promising therapeutic regimen for PDACpatients.
Authors: Annie Riera Leal; Pablo César Ortiz-Lazareno; Luis Felipe Jave-Suárez; Adrián Ramírez De Arellano; Adriana Aguilar-Lemarroy; Yveth Marlene Ortiz-García; Carlos Alfredo Barrón-Gallardo; Raúl Solís-Martínez; Sonia Luquin De Anda; José Francisco Muñoz-Valle; Ana Laura Pereira-Suárez Journal: Int J Oncol Date: 2019-11-14 Impact factor: 5.650