title: Serine protease inhibitor kazal-type 6 inhibits tumorigenesis of human hepatocellular carcinoma cells via its extracellular action.
abstract: Hepatocellular carcinoma (HCC) causes significant medical burdens worldwide. Diagnosis, especially in the early stages, is still challenging. Therapeutic options are limited and often ineffective. Although several risk factors have been known important for development of HCC, the molecular basis of the process is rather complex and has not been fully understood. We have found that a subpopulation of HCC cells which are resistant to oncolytic parvovirus H1 superinfection highly express serine protease inhibitor Kazal-type 6 (SPINK6). This protein is specifically reduced in all HCC cell lines and tissues we analyzed. When upregulated, SPINK6 could suppress the malignant phenotypes of the HCC cells in several in vitro models. The putative tumor suppression role of SPINK6 is, however, independent of its protease inhibitory activity. To suppress the malignancy of HCC cells, SPINK6 has to be secreted to trigger signals which regulate an intracellular signaling molecule, ERK1/2, as well as a series of downstream factors involved in cell cycle progression, apoptosis and migration. Our study supports that SPINK6 is an important tumor suppressor in liver, and further investigations may help develop more effective diagnostic and therapeutic approaches.
authors.affiliation: State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China.
authors.forename: Kuikui
authors.initials: K
authors.lastname: Ge
authors.affiliation: State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China.
authors.forename: Jinjiang
authors.initials: J
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Laboratory of Virology and Infectious Disease Center for the Study of Hepatitis C, Rockefeller University, New York, NY 10065, USA.
authors.forename: Meigang
authors.initials: M
authors.lastname: Gu
authors.affiliation: State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China.
authors.forename: Xinchuan
authors.initials: X
authors.lastname: Dai
authors.affiliation: State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China.
authors.forename: Yuqiang
authors.initials: Y
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China.|Shanghai High-Tech United Bio-Technological R&D Co., Ltd, Shanghai 201206, China.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Wu
authors.affiliation: Shanghai High-Tech United Bio-Technological R&D Co., Ltd, Shanghai 201206, China.
authors.forename: Guodong
authors.initials: G
authors.lastname: Li
authors.affiliation: Shanghai High-Tech United Bio-Technological R&D Co., Ltd, Shanghai 201206, China.
authors.forename: Hairong
authors.initials: H
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Zhong
authors.affiliation: State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China.
authors.forename: Qingshan
authors.initials: Q
authors.lastname: Huang
mesh_terms: D000818:Animals; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D009368:Neoplasm Transplantation; D000074162:Serine Peptidase Inhibitors, Kazal Type / Q000378:metabolism*
chemical_list: C553928:SPINK6 protein, human; D000074162:Serine Peptidase Inhibitors, Kazal Type
keywords: HCC; SPINK6; invasion; proliferation; tumor suppressor