MiR-146a-5p inhibits cell proliferation and cell cycle progression in NSCLC cell lines by targeting CCND1 and CCND2

Abstract

Previous studies have indicated that miR-146a-5p acts as an oncogene in several types of cancer, yet a tumor suppressor gene in others. In non-small cell lung cancer (NSCLC), one report showed that it was downregulated and played the role of tumor suppressor. However, another study showed that miR-146a-5p was overexpressed in the serum of NSCLC patients compared to healthy controls. Therefore, it is obvious that further study of the function of miR-146a-5p in NSCLC is necessary to fully understand its importance. Herein, we have verified that miR- 146a- 5p acts as a tumor suppressor in NSCLC. Our data revealed that the expression level of miR-146a-5p was significantly decreased in several human NSCLC cell lines, and also less abundant in human NSCLC tissues, when compared with controls. Moreover, we observed that miR-146a-5p could suppress cell proliferation, both in vitro and in vivo. Our results also showed that miR-146a-5p directly targeted the 3′-UTR of CCND1 and CCND2 mRNAs as well as decreased their expression at both mRNA and protein levels, causing cell cycle arrest at the G0/G1 phase. Furthermore, siRNA-mediated downregulation of CCND1 or CCND2 yielded the same effects on proliferation and cell cycle arrest as miR-146a-5p upregulation did in the NSCLC cell lines. We confirmed that the expression of miR-146a-5p had negative relationship with CCND1 or CCND2. Besides, we also found that miR-146a-5p could inhibit tumor growth in xengroft mouse models, and CCND1 and CCND2 were downregulated in miR-146a-5p overexpressed xengroft tumor tissues. In summary, our results demonstrated that miR-146a-5p could suppress the proliferation and cell cycle progression in NSCLC cells by inhibiting the expression of CCND1 and CCND2.

Effect of miR-146a-5p on proliferation and metastasis of triple-negative breast cancer via regulation of SOX5

“…miR-146a-5p functions as a tumor suppressor in various types of cancer, including hepatocellular carcinoma, esophageal squamous cell carcinoma, NSCLC and prostate cancer (20)(21)(22)(23). However, the role of miR-146a-5p in the development of TNBC remains unclear.…”

“…Wang et al (21) revealed that miR-146a-5p promoted esophageal squamous cell carcinoma progression by regulating epithelial-mesenchymal transition (EMT) via targeting Notch2. Furthermore, miR-146a-5p has been confirmed to inhibit non-small cell lung cancer (NSCLC) cell proliferation and cell cycle progression (22). Another study indicated that miR-146a-5p could promote prostate cancer cell apoptosis by targeting ROCK1 (23).…”

Aryl hydrocarbon receptor (AhR)-dependent regulation of pulmonary miRNA by chronic cigarette smoke exposure

“…miR-146a is a potent suppressor of inflammation4243, including the suppression of cigarette smoke-induced COX-2 in vitro 23. As such, miR-146a may play an important role in inflammation-associated diseases such COPD2444, lung cancer4546 and CVD47. There is evidence that miR-146a is transiently induced by inflammatory stimuli, including smoke exposure, where there is a rapid rise followed by a return to basal levels with 24 hours or so4048.…”

miR‐146a‐5p: Expression, regulation, and functions in cancer

“…Clinically, patients with low miR‐146a expression in their lung tumors tended to have advanced stage cancer and metastases, while patients with high miR‐146a levels demonstrated longer progression‐free survival (Chen et al, ). Cell cycle progression is also slowed by miR‐146a, in part by specifically targeting cyclins D1/2 (Li et al, ) and cyclin J (Shi et al, ). These in vitro results were replicated in a xenograft mouse model, where implanted cells overexpressing miR‐146a formed smaller tumors (Li et al, ).…”