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PDZ binding kinase, regulated by FoxM1, enhances malignant phenotype via activation of β-Catenin signaling in hepatocellular carcinoma

2017; Impact Journals LLC; Volume: 8; Issue: 29 Linguagem: Inglês

10.18632/oncotarget.17587

1949-2553

Yu-Feng Yang, Yinghua Pan, Yun Cao, Jia Fu, Yang Xia, Meifang Zhang, Qiu‐Hong Tian,

Hippo pathway signaling and YAP/TAZ

// Yu-Feng Yang 1, * , Ying-Hua Pan 2, * , Yun Cao 3, * , Jia Fu 3 , Xia Yang 3 , Mei-Fang Zhang 3 and Qiu-Hong Tian 4 1 Department of Pathology, Dongguan Third People's Hospital, Dongguan, China 2 Department of Rheumatology and Immunology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China 3 Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China 4 Department of Oncology, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China * These authors contributed equally to this work Correspondence to: Mei-Fang Zhang, email: zhangmf@sysucc.org.cn Qiu-Hong Tian, email: tianqiuhong@hotmail.com Keywords: PBK, FoxM1, β-Catenin, HCC Received: January 13, 2017 Accepted: April 17, 2017 Published: May 03, 2017 ABSTRACT Deregulation of serine/threonine kinase contributes to the development and progression of human diseases. PDZ-binding kinase (PBK) has been implicated in the malignant process of cancers, but its role and clinical significance in hepatocellular carcinoma (HCC) remains unclear. Here we show that PBK expression is increased and associated with larger tumor size, presence of vascular invasion, lymph node metastasis and poor overall and disease-free survivals in two independent cohorts of 879 patients with HCC. In vitro and in vivo data demonstrate PBK exerts oncogenic functions in HCC via activation of β-Catenin signaling pathway. The inhibition of β-Catenin by siRNAs or XAV-939 significantly attenuates PBK-mediated malignant phenotypes. PBK is further identified as a downstream effector of FoxM1. In clinical samples, PBK expression is positively correlated with the expression of FoxM1 and nuclear β-Catenin. Collectively, these findings suggest PBK functions as an oncogene in HCC and the newly identified FoxM1/PBK/β-Catenin axis serves as a promising prognostic factor as well as therapeutic intervention for HCC.