Department of Chemistry and Chemical Engineering, Hunan Institute of Science and Technology, Yueyang, 414006, People's Republic of China.
Department of Gastrointestinal Surgery, The First People's Hospital of Yueyang, Yueyang, 414000, People's Republic of China.
Cancer Chemother Pharmacol. 2021 Aug;88(2):343-357. doi: 10.1007/s00280-021-04289-z. Epub 2021 May 15.
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.
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.
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.
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.
吉西他滨（Gem）是治疗胰腺导管腺癌（PDAC）患者最常用的化疗药物之一。对 Gem 的获得性耐药性是 PDAC 化疗的主要临床挑战。已经表明，miRNA-3662 表达水平低，与癌症中的大量生物学过程有关。然而，miRNA-3662 是否调节 PDAC 的化疗耐药性在很大程度上尚不清楚。
通过实时 qPCR（RT-qPCR）测定 PDAC 组织中的 miRNA-3662 水平。体外和体内功能实验用于研究 miRNA-3662 对 PDAC 对 Gem 耐药性的生物学作用。荧光原位杂交（FISH）、RT-qPCR、western blot、生物信息学分析和荧光素酶报告基因检测用于确定精确的调控机制。
在这项研究中，研究了 miRNA-3662 在 PDAC 临床样本和细胞系中下调。功能测定表明，miRNA-3662 在体外和体内均足以抑制 PDAC 细胞的 Gem 耐药性。在机制上，缺氧诱导因子 1ɑ（HIF-1ɑ）是 miRNA-3662 的转录靶标之一，在 PDAC 样本中上调。重要的是，遗传促进 HIF-1ɑ 大大削弱了 miR-3662 介导的化疗敏感性效应。此外，miRNA-3662 可以破坏 PDAC 细胞的有氧糖酵解。
本研究表明，miRNA-3662 通过与 HIF-1ɑ 的负反馈环抑制 PDAC 细胞的化疗耐药性和有氧糖酵解。因此，miR-3662 和 Gem 的共同递送可以作为 PDAC 患者有前途的治疗方案。
