Plasma glutamate carboxypeptidase is a negative regulator in liver cancer metastasis
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Jae-Hye Lee1,3,*, Hyun-Soo Cho1,3,*, Jeong-Ju Lee1, Soo Young Jun1,3, Jun-Ho Ahn1, Ju-Sik Min1, Ji-Yong Yoon1, Min-Hyuk Choi1,3, Su-Jin Jeon1,3, Jung Hwa Lim2, Cho-Rok Jung2, Dae-Soo Kim1,3, Hyun-Taek Kim4, Valentina M. Factor5, Yun-Han Lee6, Snorri S. Thorgeirsson7, Cheol-Hee Kim4, Nam-Soon Kim1,3
1Genome Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333, Republic of Korea
2Gene Therapy Research Unit, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333, Republic of Korea
3Department of Functional Genomics, Korea University of Science and Technology, Daejeon 305-333, Republic of Korea
4Department of Biology, Chungnam National University, Daejeon 305-764, Republic of Korea
5Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892-5068, USA
6Department of Molecular Medicine, Keimyung University School of Medicine, Daegu 704-701, Republic of Korea
7Laboratory of Human Carcinogenesis, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892-4255, USA
*Both authors are shared co-first authorship
Nam-Soon Kim, email: email@example.com
Keywords: liver cancer, metastasis, PGCP, Wnt/β-catenin
Received: July 25, 2016 Accepted: October 14, 2016 Published: October 28, 2016
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.
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