title: A functional and protein-protein interaction analysis of neuroepithelial cell transforming gene 1 in hepatocellular carcinoma.
abstract: In our previous study, we reported that the expression of neuroepithelial transforming gene 1 (NET1) was increased in hepatocellular carcinoma (HCC) tissues and suggested that NET1 may serve as a novel prognostic predictor and a useful target for HCC therapy. The aim of this study was to determine the role of NET1 in HCC by monitoring the proliferation, migration, invasion, and metastasis of HCC cells in which NET1 has been stably knocked down. Additionally, to provide targets for therapeutic intervention, we aimed to identify the protein which interacts with NET1. NET1 knockdown significantly reduced the migration, invasion, and metastasis of MHCC-97H cells by 44, 65, and 77%, respectively, while cell proliferation was not significantly altered following NET1 knockdown. During our efforts to find potential NET1 modulators through protein-protein interactions, we identified merlin as a NET1-binding protein in a yeast two-hybrid screen. The interaction between NET1 and merlin was confirmed by co-immunoprecipitation. We found that the levels of NET1 protein decreased along with the increase of merlin levels. Furthermore, we demonstrated that merlin facilitates NET1 ubiquitination via the ubiquitin-proteasome pathway. Taken together, this study suggests that NET1 plays an important role in HCC cell migration, invasion, and metastasis, which are key aspects of HCC progression. Furthermore, merlin may serve as a tumor suppressor for HCC by facilitating ubiquitination of NET1.
authors.affiliation: Department of General Surgery, Xiangya Hospital, Central South University, No. 87 Xiangya Road, Changsha, 410008, Hunan, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Ye
authors.forename: Shi
authors.initials: S
authors.lastname: Chang
authors.forename: Jindong
authors.initials: J
authors.lastname: Li
authors.forename: Xinying
authors.initials: X
authors.lastname: Li
authors.forename: Yuedu
authors.initials: Y
authors.lastname: Zhou
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Wang
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000556:secondary; D002465:Cell Movement; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047468:Immunoprecipitation; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D025581:Neurofibromin 2 / Q000378:metabolism*; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D060066:Protein Interaction Maps; D034741:RNA, Small Interfering / Q000235:genetics; D014407:Tumor Cells, Cultured; D020798:Two-Hybrid System Techniques; D054875:Ubiquitination; D014945:Wound Healing; D023041:Xenograft Model Antitumor Assays
chemical_list: C099763:NET1 protein, human; D025581:Neurofibromin 2; D015513:Oncogene Proteins; D034741:RNA, Small Interfering
references.citation: Oncogene. 1996 Mar 21;12(6):1259-66
references.pmid: 8649828
references.citation: Clin Exp Metastasis. 2006;23(5-6):301-13
references.pmid: 17086355
references.citation: Genes Dev. 2002 May 1;16(9):1060-5
references.pmid: 12000789
references.citation: Cancer Biol Ther. 2008 Oct;7(10):1555-60
references.pmid: 18708758
references.citation: Curr Biol. 2003 May 13;13(10):R409-18
references.pmid: 12747855
references.citation: CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90
references.pmid: 21296855
references.citation: Lancet Oncol. 2004 Apr;5(4):254-8
references.pmid: 15050959
references.citation: J Gastroenterol Hepatol. 2011 Sep;26(9):1354-60
references.pmid: 21679247
references.citation: Genes Dev. 1998 Apr 15;12(8):1121-33
references.pmid: 9553042
references.citation: Curr Opin Cell Biol. 1997 Feb;9(1):70-5
references.pmid: 9013673
references.citation: Nat Rev Mol Cell Biol. 2005 Feb;6(2):167-80
references.pmid: 15688002
references.citation: Genes Dev. 2000 Jul 1;14(13):1617-30
references.pmid: 10887156
references.citation: Int J Cancer. 1996 Apr 10;66(2):239-43
references.pmid: 8603818
references.citation: Gastroenterology. 2011 May;140(5):1501-12.e2
references.pmid: 21320499
references.citation: J Cancer Res Clin Oncol. 2004 Jul;130(7):375-82
references.pmid: 15133661
references.citation: PLoS One. 2013 Dec 20;8(12):e83332
references.pmid: 24376686
references.citation: BMC Cancer. 2011 Feb 01;11:50
references.pmid: 21284875
references.citation: Genes Dev. 1997 May 15;11(10):1253-65
references.pmid: 9171370
references.citation: J Biol Chem. 2004 Jul 16;279(29):30265-73
references.pmid: 15123692
references.citation: Nat Rev Mol Cell Biol. 2002 Aug;3(8):586-99
references.pmid: 12154370
references.citation: J Cell Sci. 2002 Nov 1;115(Pt 21):3991-4000
references.pmid: 12356905
references.citation: Breast Cancer Res Treat. 2004 Mar;84(1):21-32
references.pmid: 14999151
references.citation: Leuk Res. 2002 Aug;26(8):713-20
references.pmid: 12191565
references.citation: Cancer Res. 2006 Jun 15;66(12):6319-26
references.pmid: 16778209
references.citation: Curr Opin Genet Dev. 1996 Feb;6(1):87-92
references.pmid: 8791482
references.citation: Int J Oncol. 2013 Mar;42(3):817-22
references.pmid: 23337976
references.citation: Nat Cell Biol. 2003 Mar;5(3):211-5
references.pmid: 12598901
references.citation: Br J Cancer. 2006 Apr 24;94(8):1204-12
references.pmid: 16552434
references.citation: Mol Cell Biochem. 1997 Jul;172(1-2):67-79
references.pmid: 9278233
references.citation: J Biol Chem. 2003 Apr 11;278(15):13207-15
references.pmid: 12547822
references.citation: J Hepatol. 2013 Dec;59(6):1264-70
references.pmid: 23928407
references.citation: J Invest Surg. 2010 Jun;23(3):163-9
references.pmid: 20590388