Overexpression of miR-203 increases the sensitivity of NSCLC A549/H460 cell lines to cisplatin by targeting Dickkopf-1

Abstract

The number of new lung cancer cases diagnosed yearly is high, and the mortality rate has not substantially declined. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and adenocarcinoma accounts for the largest proportion of NSCLC. Currently, platinum-based combined chemotherapy, particularly cisplatin (DDP) is still the main form of treatment for advanced NSCLC. However, cisplatin resistance often occurs in patients who receive chemotherapy. Previous studies offer various explanations for how miRNAs affect cisplatin resistance, but the underlying mechanism remains largely unknown. The present study was designed to focus on miR-203 and Dickkopf-1 (DKK1), investigating the potential mechanisms involved in cisplatin resistance in tissues of lung adenocarcinoma and A549/H460 cell lines. In DDP-sensitive NSCLC samples, miR-203 was expressed at a higher level when compared with this level in DDP-insensitive samples, while DKK1 mRNA was expressed at a relatively low level as indicated by qRT-PCR. Dual luciferase reporter assay revealed that DKK1 is a target gene of miR-203 in A549 and H460 cells. Upregulation of miR-203 reduced the IC50 value of cisplatin in the A549 and H460 cells by inhibiting cell growth and promoting cell apoptosis. Similar effects of tumor inhibition and cisplatin sensitization were verified in vivo. Further research showed that both overexpression of miR-203 and knockdown of DKK1 increased the sensitization to DDP with a lower IC50 value. Upon DKK1 knockdown, overexpression of miR-203 had no added effects on the sensitivity of the cells. In addition, miR-203 was unable to sensitize cells with DKK1 that lacked the 3' untranslated region (3'UTR). We conclude that miR-203 targets the 3'UTR of DKK1, and increases cisplatin sensitivity in A549/H460 cell lines.

The Significance of MicroRNAs Expression in Regulation of Extracellular Matrix and Other Drug Resistant Genes in Drug Resistant Ovarian Cancer Cell Lines

“…In opposition to our results (upregulation in PAC and CIS resistant cell lines), Cheng R. et al showed that, in CIS-resistant NSCLC tumors, miR-203 was downregulated compared with CIS-sensitive tumors [57]. Ectopic expression of miR-203 in the NSCLC cell line increased CIS sensitivity and apoptosis [57]. Overexpression of miR-203 also reversed PAC-resistance in colorectal cancer [58].…”

The significance of microRNA genes expression in ovarian cancer cell lines resistant to cytotoxic drugs

“…In opposite to our result (upregulation in PAC and CIS resistant cell lines) Cheng R. et al shown that in CIS-resistant NSCLC tumours miR-203 was downregulated compare with CIS-sensitive tumours [63]. Ectopic expression of miR-203 in NSCLC cell line increases CIS sensitivity and apoptosis [63]. Overexpression of miR-203 also reversed PAC-resistance in colorectal cancer [64].…”

Relations between approved platinum drugs and non-coding RNAs in mesothelioma

“…Survivin-regulating miR-203 was also suppressed in MPM [75]. In NSCLC cells, miR-203 expression inhibited tumor cell growth, induced apoptosis, and increased the activity of cisplatin by suppression of DKK1 [76]. MiR-345 is highly expressed in malignant mesothelioma samples and its expression may contribute to enhanced cisplatin activity by suppression of the ABC-transporter MRP1, which was associated with multidrug resistance [[77], [78], [79]].…”