Deregulation of lncRNA-AC078883.3 and microRNA-19a is involved in the development of chemoresistance to cisplatin via modulating signaling pathway of PTEN/AKT

Abstract

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer death worldwide. As a platinum-based chemotherapeutic drug, cisplatin has been used in the NSCLC treatment for over 30 years, and its effects are impaired by drug resistance. This study aimed to investigate the potential role of lncRNA-AC078883.3 in the development of chemoresistance against cisplatin. Real-time PCR, Western blot analysis, Immunohistochemistry (IHC) assay, bioinformatic analysis, and luciferase assay were collaboratively used to establish the lncRNA-AC078883.3/miR-19a/PTEN/AKT pathway. Also, the effect of cisplatin on cell proliferation was observed via an MTT assay. Furthermore, Cox regression and Kaplan-Meier analyses were used to study whether lncRNA-AC078883.3 is involved in the survival of NSCLC. Compared with the Cisplatin-Sensitive group, the Cisplatin-Resistance group exhibited lower levels of lncRNA-AC078883.3 and PTEN and higher levels of miR-19a and p-Akt. The growth rate of A549 and H460 cells and the IC ₅₀ of DPP in the Cisplatin-Resistance group were higher than those in the Cisplatin-S group. miR-19a contains a putative binding site of lncRNA-AC078883.3, which enabled the luciferase activity of wild-type lncRNA-AC078883.3 to be reduced by miR-19a. In addition, by directly targeting PTEN 3'-untranslated region (UTR), miR-19a repressed the luciferase activity of wild-type PTEN 3'-UTR. The median OS of patients with reduced lncRNA-AC078883.3 expression was longer than that of patients with higher lncRNA-AC078883.3 expression. Finally, compared with low lncRNA-AC078883.3-expression patients, the high lncRNA-AC078883.3-expression patients were associated with lower miR-19a expression and higher PTEN expression. Therefore, we suggested for the first time that the low expression of lncRNA-AC078883.3 contributed to the development of chemoresistance against cisplatin.

Keywords: PTEN; chemoresistance; lncRNA-AC078883.3; miR-19a; non-small cell lung cancer.