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

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.

MicroRNA-19b Plays a Key Role in 5-Fluorouracil Resistance and Predicts Tumor Progression in Locally Advanced Rectal Cancer Patients

“…Our observations would suggest that this miR could also have both a clinical and therapeutic impact in metastatic CRC (mCRC), since 5-FU is widely used within the adjuvant therapy in the clinical management of these patients. Moreover, miR-19b has been reported to mediate oxaliplatin resistance through a direct regulation of SMAD4 and NR3C1 [ 39 , 48 ]. In concordance with these findings, it has also been described in the role of exosomal miR-19b secretion modulating oxaliplatin sensitivity in CRC cells [ 49 ].…”

Downregulated antisense lncRNA ENTPD3-AS1 contributes to the development of lung adenocarcinoma

“…NR3C1 expression is upregulated in breast cancer, and the inhibition of NR3C1 decreases the migration and invasion of breast cancer cells [28]. In contrast, NR3C1 is greatly downregulated in colon cancer, and miR-19b strengthens oxaliplatin resistance and colon cancer malignant progression by targeting NR3C1 [29]. Caratti et al revealed that GR, the product of NR3C1 gene, was present in cytoplasmic KRAS-containing complexes and inhibited the activation of wild-type and oncogenic KRAS in mouse embryonic fibroblasts and human lung cancer A549 cells [30].…”

Midkine: A Cancer Biomarker Candidate and Innovative Therapeutic Approaches

“…NR3C1, a member of the nuclear hormone receptor superfamily, encodes the glucocorticoid receptor (133). After binding to glucocorticoids, NR3C1 transfers from the cytoplasm to the nucleus and function as a transcription factor (134). In human cell lines, NR3C1/GR binds to the proximal RANKL promoter region, promoting RANKL transcription (135).…”