miR-15b regulates cisplatin resistance and metastasis by targeting PEBP4 in human lung adenocarcinoma cells

Abstract

MicroRNAs (miRNAs) have been identified as important posttranscriptional regulators involved in various biological and pathological processes of cells, but their association with tumor chemoresistance has not been fully understood. We detected miR-15b expression in two lung adenocarcinoma cell lines, A549 and A549/CDDP, and then investigated the effects of miR-15b on the metastasis and the chemosensitivity of cancer cells, using both gain- and loss-of-function studies. The correlation between miR-15b level and chemoresistance was further investigated in clinical lung adenocarcinoma specimens. miR-15b was significantly upregulated in cisplatin-resistant lung adenocarcinoma A549/CDDP cells compared with parental A549 cells. miR-15b regulates epithelial-mesenchymal transition (EMT) and cisplatin resistance in vitro and modulates response of lung adenocarcinoma cells to cisplatin in vivo. Further studies identified phosphatidylethanolamine-binding protein 4 (PEBP4) as a direct and functional target of miR-15b. Small-interfering RNA-mediated PEBP4 knockdown revealed similar effects as that of ectopic miR-15b expression, whereas overexpression of PEBP4 attenuated the function of miR-15b in lung adenocarcinoma cells. Increased miR-15b expression was also detected in tumor tissues sampled from lung adenocarcinoma patients treated with cisplatin-based chemotherapy and was proved to be correlated with low expression of PEBP4, decreased sensitivity to cisplatin and poor prognosis. Our results suggest that upregulation of miR-15b could suppress PEBP4 expression and in turn contribute to chemoresistance of lung adenocarcinoma cells to cisplatin.

Pharmacokinetics and Bioavailability of Annatto δ-tocotrienol in Healthy Fed Subjects

“…miR-199a, miR-204, miR-205, miR-22 and miR-342) tested in this study were associated with various types of cancers, and were down-regulated by δ-tocotrienol treatment, except miR-15b and miR-17-5p, which were up-regulated by the tocotrienol treatment. miR-15b was significantly up-regulated in cisplatin-resistant lung adenocarcinoma A549/CDDP cells compared with parental A549 cells [42]. miR-17-5p, on the other hand, was a key regulator of the GI/s phase cell cycle transition, and acted as an oncogene and a tumor suppressor in different cellular contexts [43].…”

The Network of Non-coding RNAs in Cancer Drug Resistance

“…In gastric cancer, miR-20a negatively regulates cylindromatosis (CYLD) expression, thus inducing cisplatin resistance (287). miR-15b had a dual role in oral tongue squamous cell carcinoma (TSCC) and lung adenocarcinoma; through the regulation of TRIM14 it was implicated in the reversion of cisplatin resistance in TSCC (288), while it decreased sensitivity to cisplatin by targeting PEBP4 in lung adenocarcinoma (289). Similarly, Chen et al discovered the involvement of miR-136 as a tumor suppressor, which targeted E2F1 gene and reversed cisplatin resistance in glioma cells (290).…”

MicroRNAs as Regulators of Cisplatin Resistance in Lung Cancer

“…These functions of miR-17, 20a, 20b may be caused at least in part via inhibition of TGF beta signal pathway, because those miRNAs are shown to directly target and repress TGFbeta receptor 2 (TGF beta R2) which is an important component of TGF beta signal pathway [36]. In another report, both miR-15b and miR-34a can regulate EMT and the response of lung adenocarcinoma cells to CDDP both in vitro and in vivo by targeting PEBP4 [37,38]. Also, miR-27a can regulate EMT via direct and functional targeting Raf-1 kinase inhibitory protein (RKIP), which then affects the sensitivity of lung adenocarcinoma cells to CDDP both in vitro and in vivo [39].…”