DNA damage responsive miR-33b-3p promoted lung cancer cells survival and cisplatin resistance by targeting p21^WAF1/CIP1

Abstract

Cisplatin is the most potent and widespread used chemotherapy drug for lung cancer treatment. However, the development of resistance to cisplatin is a major obstacle in clinical therapy. The principal mechanism of cisplatin is the induction of DNA damage, thus the capability of DNA damage response (DDR) is a key factor that influences the cisplatin sensitivity of cancer cells. Recent advances have demonstrated that miRNAs (microRNAs) exerted critical roles in DNA damage response; nonetheless, the association between DNA damage responsive miRNAs and cisplatin resistance and its underlying molecular mechanism still require further investigation. The present study has attempted to identify differentially expressed miRNAs in cisplatin induced DNA damage response in lung cancer cells, and probe into the effects of the misexpressed miRNAs on cisplatin sensitivity. Deep sequencing showed that miR-33b-3p was dramatically down-regulated in cisplatin-induced DNA damage response in A549 cells; and ectopic expression of miR33b-3p endowed the lung cancer cells with enhanced survival and decreased gH2A.X expression level under cisplatin treatment. Consistently, silencing of miR-33b-3p in the cisplatin-resistant A549/DDP cells evidently sensitized the cells to cisplatin. Furthermore, we identified CDKN1A (p21) as a functional target of miR-33b-3p, a critical regulator of G1/S checkpoint, which potentially mediated the protection effects of miR-33b-3p against cisplatin. In aggregate, our results suggested that miR-33b-3p modulated the cisplatin sensitivity of cancer cells might probably through impairing the DNA damage response. And the knowledge of the drug resistance conferred by miR-33b-3p has great clinical implications for improving the efficacy of chemotherapies for treating lung cancers.

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

“…Various studies indicate that BCL2associated athanogene-1 (BAG-1) (30,34,35) may promote sensitivity to chemotherapy in NSCLC patients. DNA damage and DNA repair-associated genes and factors have been identified as being involved in DDP resistance (36)(37)(38). Spindle and kinetochore-associated complex subunit 1 (SKA1) is considered to regulate the ERK1/2 and the Akt-mediated signaling pathways in NSCLC cells (39).…”

Identification of novel gene expression signature in lung adenocarcinoma by using next-generation sequencing data and bioinformatics analysis

“…We focused on microRNAs with predictable putative targets - BTNL9, FMO2, IL33, CPED1, and PDK4. Among these microRNAs, elevated expression of hsa-miR-183-5p [ 74 ], hsa-miR-33b-5p [ 75 ], hsa-miR-429 [ 76 ], hsa-miR-182-5p [ 77 ], and hsa-miR-130b-5p [ 78 ] have been associated with tumorigenesis in lung cancer. The function of hsa-miR-542-3p is unclear.…”

Identification of key candidate targets and pathways for the targeted treatment of leukemia stem cells of chronic myelogenous leukemia using bioinformatics analysis

“…MiR‐500a‐5p was identified as an oxidative stress miRNA whose activity may define breast cancer progression and survival (Degli Esposti et al, ). MiR‐33b‐3p regulated cisplatin sensitivity in cancer cells, possibly by impairing the DNA damage response (Xu et al, ). MiR‐122‐5p inhibited the migration and invasion of gastric cancer cells by inhibiting DUSP4 (Xu et al, ).…”