Plasma glutamate carboxypeptidase is a negative regulator in liver cancer metastasis.
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.
Genome Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333, Republic of Korea.|Department of Functional Genomics, Korea University of Science and Technology, Daejeon 305-333, Republic of Korea.
Jae-Hye
JH
Lee
Genome Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333, Republic of Korea.|Department of Functional Genomics, Korea University of Science and Technology, Daejeon 305-333, Republic of Korea.
Hyun-Soo
HS
Cho
Genome Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333, Republic of Korea.
Jeong-Ju
JJ
Lee
Genome Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333, Republic of Korea.|Department of Functional Genomics, Korea University of Science and Technology, Daejeon 305-333, Republic of Korea.
Soo Young
SY
Jun
Genome Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333, Republic of Korea.
Jun-Ho
JH
Ahn
Genome Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333, Republic of Korea.
Ju-Sik
JS
Min
Genome Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333, Republic of Korea.
Ji-Yong
JY
Yoon
Genome Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333, Republic of Korea.|Department of Functional Genomics, Korea University of Science and Technology, Daejeon 305-333, Republic of Korea.
Min-Hyuk
MH
Choi
Genome Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333, Republic of Korea.|Department of Functional Genomics, Korea University of Science and Technology, Daejeon 305-333, Republic of Korea.
Su-Jin
SJ
Jeon
Gene Therapy Research Unit, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333, Republic of Korea.
Jung Hwa
JH
Lim
Gene Therapy Research Unit, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333, Republic of Korea.
Cho-Rok
CR
Jung
Genome Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333, Republic of Korea.|Department of Functional Genomics, Korea University of Science and Technology, Daejeon 305-333, Republic of Korea.
Dae-Soo
DS
Kim
Department of Biology, Chungnam National University, Daejeon 305-764, Republic of Korea.
Hyun-Taek
HT
Kim
Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892-5068, USA.
Valentina M
VM
Factor
Department of Molecular Medicine, Keimyung University School of Medicine, Daegu 704-701, Republic of Korea.
Yun-Han
YH
Lee
Laboratory of Human Carcinogenesis, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892-4255, USA.
Snorri S
SS
Thorgeirsson
Department of Biology, Chungnam National University, Daejeon 305-764, Republic of Korea.
Cheol-Hee
CH
Kim
Genome Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333, Republic of Korea.|Department of Functional Genomics, Korea University of Science and Technology, Daejeon 305-333, Republic of Korea.
Nam-Soon
NS
Kim
D000818:Animals; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors / Q000097:blood* / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008113:Liver Neoplasms / Q000097:blood* / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D034741:RNA, Small Interfering / Q000494:pharmacology; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D034741:RNA, Small Interfering; D002268:Carboxypeptidases; C026134:glutamate carboxypeptidase
PGCP; Wnt/β-catenin; liver cancer; metastasis