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Repression of YAP by NCTD disrupts NSCLC progression.

ABSTRACT: The efficacy of available lung cancer therapeutic interference is significantly limited by various resistance mechanisms to those drugs. Activation of the oncogene YAP underlying the initiation, progression, and metastasis of lung cancer associates with poor prognosis and confers drug resistance against targeted therapy. In this study, we evaluated the specificity of norcantharidin (NCTD) in repressing YAP to inhibit non-small cell lung carcinoma (NSCLC) progression. Our study revealed that YAP signal pathways were aberrantly activated in lung cancer tissues and cells which rendered more proliferative and invasive phenotypes to human lung cancer cells. We confirmed that NCTD specifically repressed YAP signaling pathway to interfere the YAP-mediated non-small cell lung carcinoma progression and metastasis via arresting cell cycle, enhancing apoptosis and inducing senescence. We also found NCTD-mediated repression of YAP decreased epithelial-to-mesenchymal transition (EMT) and reduced the motile and invasive cellular phenotype in vitro via enhancing E-cadherin and decreasing fibronectin/vimentin. Mechanistic investigations revealed that NCTD transcriptionally downregulated YAP and post-translationally modulated the subcellular redistribution of YAP between nucleus and cytoplasm. Collectively, our results indicated that NCTD is a novel therapeutic drug candidate for NSCLC which specifically and sensitively target YAP signal pathway.

SUBMITTER: Guo J

PROVIDER: S-EPMC5356801 | biostudies-other | 2017 Jan

REPOSITORIES: biostudies-other

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Repression of YAP by NCTD disrupts NSCLC progression.

Guo Jiwei J Wu Yan Y Yang Lijuan L Du Jing J Gong Kaikai K Chen Weiwei W Dai Juanjuan J Li XueLin X Xi Sichuan S

Oncotarget 20170101 2

The efficacy of available lung cancer therapeutic interference is significantly limited by various resistance mechanisms to those drugs. Activation of the oncogene YAP underlying the initiation, progression, and metastasis of lung cancer associates with poor prognosis and confers drug resistance against targeted therapy. In this study, we evaluated the specificity of norcantharidin (NCTD) in repressing YAP to inhibit non-small cell lung carcinoma (NSCLC) progression. Our study revealed that YAP ...[more]

PMID: 27903989

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Project description:BACKGROUND:Recent evidence indicates that metformin inhibits mammalian cancer growth and metastasis through the regulation of microRNAs. Metformin regulates miR-381 stability, which plays a vital role in tumor progression. Moreover, increased YAP expression and activity induce non-small cell lung cancer (NSCLC) tumor growth and metastasis. However, the molecular mechanism underpinning how metformin-induced upregulation of miR-381 directly targets YAP or its interactions with the epithelial-mesenchymal transition (EMT) marker protein Snail in NSCLC is still unknown. METHODS:Levels of RNA and protein were analyzed using qPCR, western blotting and immunofluorescence staining. Cellular proliferation was detected using a CCK8 assay. Cell migration and invasion were analyzed using wound healing and transwell assays. Promoter activity and transcription were investigated using the luciferase reporter assay. Chromatin immunoprecipitation was used to detect the binding of YAP to the promoter of Snail. The interaction between miR-381 and the 3'UTR of YAP mRNA was analyzed using the MS2 expression system and co-immunoprecipitation with biotin. RESULTS:We observed that miR-381 expression is negatively correlated with YAP expression and plays an opposite role to YAP in the regulation of cellular proliferation, invasion, migration, and EMT of NSCLC cells. The miR-381 function as a tumor suppressor was significantly downregulated in lung cancer tissue specimens and cell lines, which decreased the expression of its direct target YAP. In addition, metformin decreased cell growth, migration, invasion, and EMT via up-regulation of miR-381. Moreover, YAP, which functions as a co-transcription factor, enhanced NSCLC progression and metastasis by upregulation of Snail. Snail knockdown downregulated the mesenchymal marker vimentin and upregulated the epithelial marker E-cadherin in lung cancer cells. Furthermore, miR-381, YAP, and Snail constitute the miR-381-YAP-Snail signal axis, which is repressed by metformin, and enhances cancer cell invasiveness by directly regulating EMT. CONCLUSIONS:Metformin-induced repression of miR-381-YAP-Snail axis activity disrupts NSCLC growth and metastasis. Thus, we believe that the miR-381-YAP-Snail signal axis may be a suitable diagnostic marker and a potential therapeutic target for lung cancer.

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Repression of YAP by NCTD disrupts NSCLC progression.

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Repression of YAP by NCTD disrupts NSCLC progression.

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