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WWC3 inhibits epithelial–mesenchymal transition of lung cancer by activating Hippo-YAP signaling

Authors Han Q, Kremerskothen J, Lin X, Zhang X, Rong X, Zhang D, Wang E

Received 12 January 2018

Accepted for publication 2 March 2018

Published 8 May 2018 Volume 2018:11 Pages 2581—2591

DOI https://doi.org/10.2147/OTT.S162387

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Andrew Yee

Peer reviewer comments 3

Editor who approved publication: Dr Tohru Yamada


Qiang Han,1 Joachim Kremerskothen,2 Xuyong Lin,1 Xiupeng Zhang,1 Xuezhu Rong,1 Di Zhang,1 Enhua Wang1

1Department of Pathology, College of Basic Medical Sciences, First Affiliated Hospital of China Medical University, Shenyang, People’s Republic of China; 2Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology, University Hospital Muenster, Muenster, Germany

Background: Though we recently reported that the WWC3 inhibits the invasiveness and metastasis of lung cancer by activating the Hippo pathway, the impact and underlying mechanisms of this process still remain unclear.
Methods: To identify the role of WWC3 in epithelial-mesenchymal transition of lung cancer, we performed immunohistochemistry to detect the expression levels of WWC3 and EMT-related biomarker, and analyzed their correlations in a cohort of 127 patients with NSCLC. Wound healing assay and cell invasion assay were applied to explore cell invasive ability change after WWC3 knockdown. qRT-PCR and immunoblotting were performed to assess mRNA and protein levels of EMT-related biomarkers and the main molecules changes of Hippo signaling caused by WWC3. Immunoprecipition was to examine WWC3 and LATS1 interaction.
Results: WWC3 knockdown drives a pronounced shift from the epithelial to the mesenchymal phenotype in lung cancer cells. In addition, WWC3 ectopic expression in lung cancer cells attenuates mesenchymal markers and increases the epithelial markers expressions; however, WWC3-ΔWW plasmid abrogated these effects. WWC3 silencing by shRNA exerts the opposite effect. Furthermore, WWC3 levels were inversely correlated with the levels of EMT inducers (Snail and Slug) in lung cancer cells and specimens. Immunoblotting revealed that WWC3 wild-type upregulates large tumor suppressor (LATS1) and yes-associated protein (YAP) phosphorylation through its WW domain, hence activating Hippo pathway. Knockdown of YAP and LATS1, as well as the as the Verteporfin (VP) usage, could reverse this effect caused by WWC3 silencing.
Conclusion: These findings suggest that WWC3 works as a tumor suppressor to inhibit EMT process and confer its candidacy as a potential therapeutic target in lung cancer.

Keywords: WWC3, epithelial–mesenchymal transition, Hippo pathway, YAP, nonsmall-cell lung cancer

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