title: Niemann-Pick type C2 protein regulates liver cancer progression via modulating ERK1/2 pathway: Clinicopathological correlations and therapeutical implications.
abstract: Primary hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and the third leading cause of cancer-related death. It is important to identify new targets for early diagnosis and treatment of HCC. Niemann-Pick type C2 (NPC2) plays an important role in the regulation of intracellular cholesterol homeostasis via direct binding with free cholesterol. However, little is known about the significance of NPC2 in HCC tumorigenesis. In this study, we showed that NPC2 is abundantly expressed in normal liver, but is downregulated in human HCC tissues. The patients with NPC2 downregulation expressed much higher α-fetoprotein, multiple tumor type, vascular invasion, later pathological stage and shorter survival rate. Knockdown NPC2 in liver cancer cell lines promote cell proliferation, migration and xenograft tumorigenesis. In contrast, NPC2 overexpression inhibits HuH7 promoted tumor growth. Furthermore, administration of hepatotropic adeno-associated virus 8 (AAV8) delivered NPC2 decreased the inflammatory infiltration, the expression of two early HCC markers-glypican 3 and survivin and suppressed the spontaneous HCC development in mice. To identify the NPC2-dependent mechanism, we emphasized on the status of MAPK/ERK signaling. MEK1/2 inhibitor treatment demonstrated that the expression of NPC2 affected the activation of ERK1/2 but not MEK1/2. In addition, cholesterol trafficking inhibitor treatment did not alter the cell proliferation and the activation of MEK/ERK. In conclusion, our study demonstrates that NPC2 may play an important role in negatively regulate cell proliferation and ERK1/2 activation that were independent of cholesterol accumulation. AAV-NPC2 may thus represent a new treatment strategy for liver cancer.
authors.affiliation: School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yi-Jen
authors.initials: YJ
authors.lastname: Liao
authors.affiliation: Department and Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.|Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan.|Center for Infections Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Cheng-Chieh
authors.initials: CC
authors.lastname: Fang
authors.affiliation: Center for Infections Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan.|Graduate Institute of National Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chia-Hung
authors.initials: CH
authors.lastname: Yen
authors.affiliation: Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Shih-Ming
authors.initials: SM
authors.lastname: Hsu
authors.affiliation: Department of International Medicine, Taipei City Hospital Ranai Branch, Taipei, Taiwan.
authors.forename: Chung-Kwe
authors.initials: CK
authors.lastname: Wang
authors.affiliation: Division of Molecular and Genomic Medicine, National Health Research Institute, Miaoli, Taiwan.
authors.forename: Shiu-Feng
authors.initials: SF
authors.lastname: Huang
authors.affiliation: School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yu-Chih
authors.initials: YC
authors.lastname: Liang
authors.affiliation: Center for Infections Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Ying-Yu
authors.initials: YY
authors.lastname: Lin
authors.affiliation: Institute of Health Policy and Management, College of Public Health, National Taiwan University, Taipei, Taiwan.
authors.forename: Yu-Tseng
authors.initials: YT
authors.lastname: Chu
authors.affiliation: Center for Infections Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan.|Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.|Center for Lipid and Glycomedicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Microbiology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yi-Ming
authors.initials: YM
authors.lastname: Arthur Chen
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D018450:Disease Progression; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D006023:Glycoproteins / Q000235:genetics*; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D015996:Survival Rate; D033921:Vesicular Transport Proteins; D000509:alpha-Fetoproteins / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D006023:Glycoproteins; C104585:NPC2 protein, human; D033921:Vesicular Transport Proteins; D000509:alpha-Fetoproteins
keywords: Adeno-associated virus 8; ERK1/2; Niemann-Pick type C2; hepatocellular carcinoma; proliferation