AEG-1 activates Wnt/PCP signaling to promote metastasis in tongue squamous cell carcinoma.

// Yunping Pan 1, 2, * , Xu Guo 3, * , Zheng Yang 2 ,* , Shan Chen 1 , Yiyan Lei 4 , Millicent Lin 5 , Liantang Wang 2 , Chongjin Feng 1 , Zunfu Ke 2 1 Department of Stomatology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Province Guangdong, P.R.China 2 Department of Pathology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Province Guangdong, P.R.China 3 Department of Gynecology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Province Guangdong, P.R. China 4 Department of Chest Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Province Guangdong, P.R.China 5 Department of Molecular and Medical Pharmacology, Crump Institute for Molecular Imaging (CIMI), California NanoSystems Institute (CNSI), University of California, Los Angeles, California, USA * These authors have contributed equally to this work Correspondence to: Zunfu Ke, e-mail: kezunfu@126.com Chongjin Feng, e-mail: fengchongjin2012@126.com Keywords: AEG-1, epithelial-mesenchymal transition, tongue squamous cell carcinoma, Wnt/PCP, metastasis Received: August 07, 2015      Accepted: November 25, 2015      Published: December 12, 2015 ABSTRACT Despite advances in therapy, survival among patients with locally advanced squamous cell carcinoma of tongue (TSCC) and cervical lymph node metastasis remains dismal. Here, we estimated the functional effect of AEG-1 on TSCC metastasis and explored the molecular mechanism by which AEG-1 stimulates epithelial-mesenchymal transition (EMT). We initially found that AEG-1 mRNA levels were much higher in metastatic TSCC than in non-metastatic TSCC and that AEG-1 expression strongly correlates with EMT status. Receiver operating characteristic analysis showed that the combined AEG-1 and EMT statuses are predictive of the survival rate among TSCC patients. In addition, AEG-1 knockdown inhibited EMT in cultured TSCC cell lines and in a xenograft-mouse model. Recombinant AEG-1 activated Wnt/PCP-Rho signaling, and its stimulatory effects on TSCC cell invasiveness and EMT were reversed by an anti-Wnt5a neutralizing antibody or by inhibition of Rac1 or ROCK. These results highlight the critical stimulatory effect of AEG-1 on cancer cell invasiveness and EMT and indicate that AEG-1 may be a useful prognostic biomarker for TSCC patients.