Plasma glutamate carboxypeptidase is a negative regulator in liver cancer metastasis

// Jae-Hye Lee 1, 3, * , Hyun-Soo Cho 1, 3, * , Jeong-Ju Lee 1 , Soo Young Jun 1, 3 , Jun-Ho Ahn 1 , Ju-Sik Min 1 , Ji-Yong Yoon 1 , Min-Hyuk Choi 1, 3 , Su-Jin Jeon 1, 3 , Jung Hwa Lim 2 , Cho-Rok Jung 2 , Dae-Soo Kim 1, 3 , Hyun-Taek Kim 4 , Valentina M. Factor 5 , Yun-Han Lee 6 , Snorri S. Thorgeirsson 7 , Cheol-Hee Kim 4 , Nam-Soon Kim 1, 3 1 Genome Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333, Republic of Korea 2 Gene Therapy Research Unit, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333, Republic of Korea 3 Department of Functional Genomics, Korea University of Science and Technology, Daejeon 305-333, Republic of Korea 4 Department of Biology, Chungnam National University, Daejeon 305-764, Republic of Korea 5 Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892-5068, USA 6 Department of Molecular Medicine, Keimyung University School of Medicine, Daegu 704-701, Republic of Korea 7 Laboratory of Human Carcinogenesis, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892-4255, USA * Both authors are shared co-first authorship Correspondence to: Nam-Soon Kim, email: nskim37@kribb.re.kr Keywords: liver cancer, metastasis, PGCP, Wnt/β-catenin Received: July 25, 2016 Accepted: October 14, 2016 Published: October 28, 2016 ABSTRACT Tumor metastasis is the leading cause of cancer death. In the metastatic process, EMT is a unique phenotypic change that plays an important role in cell invasion and changes in cell morphology. Despite the clinical significance, the mechanism underlying tumor metastasis is still poorly understood. Here we report a novel mechanism by which secreted plasma glutamate carboxypeptidase(PGCP) negatively involves Wnt/β-catenin signaling by DKK4 regulation in liver cancer metastasis. Pathway analysis of the RNA sequencing data showed that PGCP knockdown in liver cancer cell lines enriched the functions of cell migration, motility and mesenchymal cell differentiation. Depletion of PGCP promoted cell migration and invasion via activation of Wnt/β-catenin signaling pathway components such as phospho-LRP6 and β-catenin. Also, addition of DKK4 antagonized the Wnt/β-catenin signaling cascade in a thyroxine (T4)-dependent manner. In an in vivo study, metastatic nodules were observed in the lungs of the mice after injection of shPGCP stable cell lines. Our findings suggest that PGCP negatively associates with Wnt/β-catenin signaling during metastasis. Targeting this regulation may represent a novel and effective therapeutic option for liver cancer by preventing metastatic activity of primary tumor cells.