WW domain binding protein 5 induces multidrug resistance of small cell lung cancer under the regulation of miR-335 through the Hippo pathway.
WW domain binding protein 5 induces multidrug resistance of small cell lung cancer under the regulation of miR-335 through the Hippo pathway.
复制标题
WW结构域结合蛋白5在miR-335的调控下通过Hippo通路诱导小细胞肺癌多药耐药
DOI：
10.1038/bjc.2016.186
复制
发表时间：
2016-07-12
影响因子：
8.8
通讯作者：
Guo L
中科院分区：
文献类型：
--
作者：
Tang R;Lei Y;Hu B;Yang J;Fang S;Wang Q;Li M;Guo L
背景：我们的前期研究表明，WW结构域结合蛋白5（WBP 5）在耐药细胞中的表达与其亲本细胞相比显著升高。方法：采用免疫组化方法检测62例小细胞肺癌（SCLC）患者标本中WBP 5的表达。进一步建立稳定的WBP 5过表达和WBP 5低表达细胞，以评估WBP 5在耐药性、凋亡和肿瘤生长中的作用。结果：WBP 5的表达与SCLC患者的生存期显著相关，而WBP 5的表达与SCLC患者的生存期显著相关。上调WBP 5可诱导多药耐药（MDR）并减少细胞凋亡，而下调WBP 5可增强药物敏感性并增加细胞凋亡。我们还发现miR-335通过靶向WBP 5的3′ UTR负调控WBP 5的MDR。此外，WBP 5可以降低YAP 1在丝氨酸127处的磷酸化并诱导YAP 1的核积累。结论：WW结构域结合蛋白5在miR-335的调控下，通过Hippo通路调节多药耐药。WW结构域结合蛋白5可能是一个预后预测因子，也可能是一个潜在的干预MDR的靶点。
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.