MicroRNA-19b Downregulates NR3C1 and Enhances Oxaliplatin Chemoresistance in Colon Cancer via the PI3K/AKT/mTOR Pathway

Zhongbo Han; Chao Zhang; Qingfeng Wang; Liang Li; Meng Wang; Xi Li; Chunxia Yang

doi:10.1177/11795549211012666

MicroRNA-19b Downregulates NR3C1 and Enhances Oxaliplatin Chemoresistance in Colon Cancer via the PI3K/AKT/mTOR Pathway

Clin Med Insights Oncol. 2021 May 5:15:11795549211012666. doi: 10.1177/11795549211012666. eCollection 2021.

Authors

Zhongbo Han¹, Chao Zhang¹, Qingfeng Wang¹, Liang Li¹, Meng Wang¹, Xi Li², Chunxia Yang¹

Affiliations

¹ Department of Gastrointestinal Surgery, Zibo Central Hospital, Shandong University, Zibo, China.
² Department of Gastrointestinal Surgery, Zibo Central Hospital, Binzhou Medical University, Zibo, China.

Abstract

Background: Identifying the genes and signaling pathways related to chemoresistance might facilitate the development of novel therapeutic strategies for colon cancer. In this study, we aimed to investigate the biological functions and underlying mechanisms of action of miR-19b and NR3C1, as well as their effects on chemosensitivity to oxaliplatin and prognosis of colon cancer patients.

Methods: Reverse transcription-polymerase chain reaction (RT-PCR), Western blotting, and immunohistochemical staining were used to analyze the expression of miR-19b and NR3C1. Dual firefly luciferase reporter gene analysis was used to identify miR-19b target genes. Associations of miR-19b and NR3C1 with survival were estimated by the Kaplan-Meier method and Cox regression analyses. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometric analysis were used to measure cell viability, cytotoxicity, cell cycle phase, and apoptosis, respectively. The effect of miR-19b on cell proliferation was investigated in vivo.

Results: The miR-19b was overexpressed and NR3C1 was decreased in colon cancer tissue and cell lines (SW480 and DLD-1). The miR-19b inhibition and NR3C1 overexpression inhibited cell proliferation, and induced G1/S cell cycle blockade, apoptosis, and chemosensitivity to oxaliplatin in vitro. The miR-19b inhibition suppressed subcutaneous tumorigenesis in vivo. Increased miR-19b and decreased NR3C1 in colon cancer were correlated with poor prognosis. In addition, our results confirmed NR3C1 was directly targeted by miR-19b. Thus, miR-19b might inhibit apoptosis and enhance oxaliplatin chemoresistance via the PI3K/AKT/mTOR pathway.

Conclusions: Our study revealed that miR-19b promotes cell survival and chemoresistance to oxaliplatin via the PI3K/AKT/mTOR pathway by downregulating NR3C1 in colon cancer. miR-19b and NR3C1 might be potential intervention targets for chemoresistance of colon cancer.

Keywords: Colon cancer; NR3C1; PI3K/AKT/mTOR pathway; chemoresistance; microRNA-19b.