Discovery of NKCC1 as a potential therapeutic target to inhibit hepatocellular carcinoma cell growth and metastasis
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Yaya Zhou1,*, Wei Sun1,*, Ning Chen1,*, Chen Xu1, Xinxin Wang2, Kun Dong2, Binxue Zhang1, Jian Zhang1, Ning Hao1, Aihua Sun1, Handong Wei1, Fuchu He1,3 and Ying Jiang1
1State Key Laboratory of Proteomics, National Center for Protein Sciences Beijing, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 102206, P. R. China
2Department of Pathology, Beijing Youan Hospital of Capital Medical University, Beijing 100069, P. R. China
3Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P. R. China
*These authors have contributed equally to this work
Ying Jiang, email: [email protected]
Fuchu He, email: [email protected]
Keywords: hepatocellular carcinoma, metastasis, plasma membrane protein, NKCC1, therapeutic target
Received: April 07, 2016 Accepted: July 11, 2017 Published: August 12, 2017
Metastasis is the essential cause for the high mortality of hepatocellular carcinoma (HCC). In order to investigate the mechanism of metastasis, and to discover therapeutic targets for HCC, the quantitative proteomic technique was applied to characterize the plasma membrane proteins of two HCC cell lines with low (MHCC97L) or high (MHCC97H) metastatic potentials. One of the plasma membrane proteins, sodium-potassium-chloride cotransporter 1 (NKCC1), was upregulated in MHCC97H cell line. Immunohistochemistry result in HCC patients showed that NKCC1 expression was associated with poor differentiation and microvascular invasion. Knockdown of NKCC1 via RNA interference reduced HCC cell proliferation and invasion abilities in vitro and in vivo, whereas over-expression of NKCC1 significantly increased HCC cell proliferation and invasion abilities in vitro and in vivo. Additionally, blocking NKCC1 activity with bumetanide attenuated the proliferation and invasion abilities of HCC cells in vitro and limited the HCC growth in vivo. Further results suggested that NKCC1 promotes the invasion ability via MMP-2 activity, and that the WNK1/OSR1/NKCC1 signal pathway might play roles in HCC metastasis. For the first time, our study demonstrated that NKCC1 plays a role in HCC metastasis, and could be served as a potential target to inhibit HCC cell growth and metastasis.
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