WW domain binding protein 5 induces multidrug resistance of small cell lung cancer under the regulation of miR-335 through the Hippo pathway

Abstract

Background:Our previous study indicated that WW domain binding protein 5 (WBP5) expression was elevated significantly in a drug-resistant cell compared with its parental cell. Nevertheless, its functional role and underlying mechanisms remain unknown.Methods:In this study, WBP5 was examined in 62 small cell lung cancer (SCLC) patient samples by immunohistochemical technique. Stable WBP5-overexpressed and WBP5-underexpressed cells were further established to assess the role of WBP5 in drug resistance, apoptosis and tumour growth. We also conducted western blot to detect the expression of MST2 and YAP1 and their phosphorylated protein.Results:The results revealed that WBP5 expression was significantly associated with the shorter survival time in SCLC patients. Upregulation of WBP5 induced multidrug resistance (MDR) and decreased apoptosis, whereas downregulation of WBP5 enhanced drug sensitivity and increased apoptosis. We also found that miR-335 negatively regulated the MDR of WBP5 by targeting its 3′UTR. Furthermore, WBP5 can lower YAP1 phosphorylation at Serine 127 and induce nuclear accumulation of YAP1. Inhibition of YAP1 by Verteporfin could blunt the MDR phenotype of WBP5.Conclusions:WW domain binding protein 5 can modulate MDR through the Hippo pathway under the regulation of miR-335. WW domain binding protein 5 may be a prognostic predictor and a potential target for interfering with MDR in SCLC.

Defined factors to reactivate cell cycle activity in adult mouse cardiomyocytes

“…Although Bex1 and Tceal8 did not increase nuclear Yap, it is possible that the cellular context could play a role in the outcome of Hippo signaling (92,93), as neonatal cardiomyocytes are quite different from adult cardiomyocytes (Table S1). Furthermore, miRNA signaling has been shown to control Tceal family proteins in the context of Yap signaling (91).…”

Identification of H2O2 induced oxidative stress associated microRNAs in HLE-B3 cells and their clinical relevance to the progression of age-related nuclear cataract

“…Opinions about the role of miR-335-3p in tumor progression are controversial. Some believed that miR-335-3p is an oncogene for its effect on induction of multidrug resistance [ 39 ] and cancer-associated fibroblasts [ 40 ], while others viewed miR-335-3p as a tumor suppressor [ 41 , 42 ]. This difference could be explained by the diversity of miRNA’s function.…”

The long noncoding RNA HOTAIR activates the Hippo pathway by directly binding to SAV1 in renal cell carcinoma

“…YAP1 is a key transcription factor that controls the transcription of several oncogenes including EGFR and SOX9 [ 35 , 36 ]. Recent studies showed that the Hippo pathway modulates cancer invasion, metastasis, drug resistance, and the maintenance of cancer cell stemness [ 33 , 37 – 41 ]. The Hippo pathway is therefore a potential drug target in cancer therapy.…”