Journal
ONCOTARGET
Volume 8, Issue 39, Pages 66328-66342Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.20240
Keywords
hepatocellular carcinoma; metastasis; plasma membrane protein; NKCC1; therapeutic target
Categories
Funding
- Chinese State Key Projects for Basic Research (973 Program) [2014CBA02001, 2013CB910502]
- Chinese State High-tech Program (863 Program) [2012AA020204, 2014AA020906]
- National Natural Science Foundation of China [81170399, 81570526, 81123001, 81201821]
- Program of International ST Cooperation [2014DFB30020, 2014DFB30010]
- National Key Technologies R&D Program for New Drugs [2012ZX09301-002]
- Beijing Nova Program [Z121107002512015]
- Beijing Municipal Science and Technology Commission [Z141100000214014]
- Capital medical university Basic-Clinical Research Cooperation Fund of China [16JL63]
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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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