Serine protease inhibitor kazal-type 6 inhibits tumorigenesis of human hepatocellular carcinoma cells via its extracellular action
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Kuikui Ge1,*, Jinjiang Huang1,*, Wei Wang1, Meigang Gu2, Xinchuan Dai1, Yuqiang Xu1, Hongyu Wu1,3, Guodong Li3, Hairong Lu3, Jiang Zhong1, Qingshan Huang1
1State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China
2Laboratory of Virology and Infectious Disease Center for the Study of Hepatitis C, Rockefeller University, New York, NY 10065, USA
3Shanghai High-Tech United Bio-Technological R&D Co., Ltd, Shanghai 201206, China
*These authors contributed equally to this work
Qingshan Huang, email: firstname.lastname@example.org
Keywords: SPINK6, HCC, tumor suppressor, invasion, proliferation
Received: April 11, 2016 Accepted: December 12, 2016 Published: December 16, 2016
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.
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