miR‐495 Enhances the Sensitivity of Non‐Small Cell Lung Cancer Cells to Platinum by Modulation of Copper‐Transporting P‐type Adenosine Triphosphatase A (ATP7A)

Abstract

Copper-transporting P-type adenosine triphosphatase A (ATP7A) is associated with platinum drug resistance in non-small cell lung cancer (NSCLC). microRNAs (miRNAs) are a class of small non-coding RNA molecules that regulate gene expression at post-transcriptional level. In this study, the aim is to explore which miRNAs might participate in the platinum resistance by targeting ATP7A in NSCLC. Using real-time PCR-based miRNA expression profiling and bioinformatics, we selected miR-495 as a candidate miRNA. EGFP reporter assay, real-time PCR, and Western blot validated that ATP7A was a direct target for miR-495. The drug sensitivity assay indicated that miR-495 enhanced the cell response to cisplatin (CDDP) in NSCLC cells, while inhibition of miR-495 led to the opposite effects. Importantly, either overexpression or knockdown of ATP7A could override the effect of miR-495 on chemosensitivity. We also demonstrated that miR-495 increased the intracellular CDDP accumulation and overexpression of ATP7A can reduce the increased drug concentration induced by miR-495. Finally, we discovered that there was a converse relationship between miR-495 and ATP7A levels in NSCLC tissues sensitive or resistant to CDDP. In conclusion, our data demonstrate that miR-495 regulates the multi-drug resistance by modulation of ATP7A expression in NSCLC and suggest that miR-495 may serve as a potential biomarker for the treatment of multi-drug resistant NSCLC patients with high ATP7A levels.

MicroRNA‑495 suppresses cell proliferation and invasion of hepatocellular carcinoma by directly targeting insulin‑like growth factor receptor‑1

“…Lv et al found that restored miR-495 expression inhibits cell proliferation and motility and induces G0/G1 phase arrest in renal cell carcinoma (37). In lung cancer, miR-495 is involved in the regulation of cell proliferation, migration, epithelial-mesenchymal transition, chemosensitivity and chemoresistance (40,41,46). However, Tan et al indicated that miR-495 serves as an oncogene in bladder cancer through the regulation of cell proliferation and invasion (18).…”

“…The following target miR-495 genes have been identified: HMGN5 (19) in osteosarcoma; GFI1 (35) in medulloblastoma; Glut1 (42), MYB (43) and CDK6 (44) in glioma; FZD4 (36), Akt (45) and mTOR (45) in prostate cancer; SATB1 (37) in renal cell carcinoma; STAT-3 (38) and Bmi-1 (39) in breast cancer; epithelial and endothelial tyrosine kinase (40), MTA3 (41) and ATP7A (46) in lung cancer; and PTEN (18) in bladder cancer. In our study, IGF1R was demonstrated to be a direct functional downstream target of miR-495 in HCC.…”

Decreased Expression of miR216a Contributes to Non–Small-Cell Lung Cancer Progression

“…However, studies have shown that continuous infusion or multiple administrations of CDDP often results in the development of drug resistance, which often leads to treatment failure as demonstrated by tumor growth or tumor relapse (38,39). Recently, studies have established that miRNAs are also involved in the development of chemoresistance (40)(41)(42). Our data indicate that decreased miR216a expression contributes to CDDP resistance in NSCLC cells.…”

Embryonic stem cell-derived pancreatic endoderm transplant with MCT1-suppressing miR-495 attenuates type II diabetes in mice

“…In non-small cell lung cancer (NSCLC), hsa-miR-495 was found to inhibit the growth and migration of NSCLC by directly targeting MTA3 [37]. Moreover, hsa-miR-495 was also found to sensitize the NSCLC cells' response to drugs like cisplatin [38]. Jiang et al found hsa-miR-495 functions as a tumor suppressor in acute myeloid leukemia [39].…”