MiR-155 inhibits the sensitivity of lung cancer cells to cisplatin via negative regulation of Apaf-1 expression

Abstract

MicroRNA-155 (miR-155) overexpression is often found in malignancies including lung cancer. The objective of this study is to verify the hypothesis, based on the results of bioinformatics analysis, that miR-155 modulates cellular apoptosis and DNA damage through the regulation of Apaf-1 and is thus involved in the development and progression of lung cancer. First, we measured the expression of miR-155 and the Apaf-1 protein in lung cancer tissues. The results showed that expression of miR-155 was significantly higher in lung cancer tissues than in paracancerous and normal tissues; whereas Apaf-1 expression was lower in the lung cancerous tissues. We then established miR-155-silenced and Apaf-1-overexpressed A549 cell lines by transfection with pMAGic2.0-BIC-siRNA and pcDNA3.1-Apaf-1, respectively. These cell lines were then treated with cisplatin, and apoptosis and DNA damage were assessed, with non-transfected A549 cells used as negative controls. The results showed that, relative to controls, the silencing of miR-155 resulted in elevated expression of the Apaf-1 protein, whereas Apaf-1 mRNA levels remained unchanged. Both the silencing of miR-155 and the overexpression Apaf-1 greatly increased the sensitivity of A549 cells to cisplatin treatment, as evidenced by elevated rates of apoptosis and DNA damage. Furthermore, dual-transfection of A549 cells with miR-155 siRNA and Apaf-1 siRNA resulted in the attenuation of apoptosis and DNA damage. In conclusion, the inhibition of miR-155 can enhance the sensitivity of A549 cells to cisplatin treatment by modulation of cellular apoptosis and DNA damage through an Apaf-1-mediated pathway.

DNA damage responsive miR-33b-3p promoted lung cancer cells survival and cisplatin resistance by targeting p21WAF1/CIP1

“…28 miR-31 and miR-155 significantly inhibited the cisplatin sensitivity in non-small cell lung cancer cells by suppressing ABCB9 and Apaf-1, respectively, 29,30 while miR-451 elevated the cisplatin sensitivity of A549 cells. 31 Moreover, miR-98 sensitized cisplatin-resistant A549/DDP cells via upregulation of HMGA2.…”

microRNAs in Cancer Cell Response to Ionizing Radiation

“…miR-155 has been shown to target both APAF-1 and caspase 3 (141,162). miR-155 is up-regulated in several tumor types, including lung, breast, and pancreatic cancer (138,162) and, as mentioned earlier, has been shown to promote radiation resistance (5). Over-expression of miR-155 may result in a repression of APAF-1 and caspase 3, leading to an inhibition of FAS-R-mediated apoptosis.…”

MicroRNAs as Regulators of Cisplatin Resistance in Lung Cancer

“…Moreover, Let-7c directly interacts with the 3'UTR of Bcl-XL, which is an antiapoptotic protein, and down regulation of Let-7c increases the sensitivity of A549/DDP cells to DDP [55]. Down-regulation of miR-155 can reduce the expression of Bax and then enhance the sensitivity of A549 cells to CDDP treatment via modulating cellular apoptosis and DNA damage through an Apaf-1-mediated pathway [56]. Meanwhile, miR-503, miR-181a and has-miR-497 are also reported to modulate apoptosis via inhibiting Bcl-2 family protein expression [57,58].…”