title: NOXIN as a cofactor of DNA polymerase-primase complex could promote hepatocellular carcinoma.
abstract: Oncogene activation or inactivation of tumor suppressor genes are crucial to tumor initiation and progression. DNA copy number amplification is one of many mechanisms that activate oncogenes in many tumors, including hepatocellular carcinoma (HCC). Although it has been known that some oncogenes such as c-myc amplification is involved in HCC pathogenesis, more oncogenes with DNA copy amplification contribute to HCC initiation and progression remain to be characterized. Here, we identified NOXIN as a novel potential oncogene with DNA copy number amplification by Single Nucleotide Polymorphism microarray-based genome-wide DNA copy number analysis of 43 human HCC samples. We identified the focal DNA gain and amplification region containing NOXIN on chromosome 11q14.1 and NOXIN overexpression significantly associated with HCC progression. We then assessed the role of NOXIN in HCC cells. NOXIN overexpression promoted cellular proliferation, colony formation, cellular migration and in vivo tumorigenicity, whereas NOXIN knockdown attenuated these effects. Interestingly, NOXIN overexpression accelerated the G1-S phase transition by enhancing DNA synthesis. Furthermore, we found that NOXIN interacts with DNA polymerase α, suggesting that NOXIN may promote de novo DNA synthesis by promoting DNA polymerase-primase complex formation. These collective data indicated that NOXIN overexpression, as a result of genomic DNA gain or amplification, promotes HCC tumorigenesis by accelerating DNA synthesis and cell cycle progression, where NOXIN functions as a cofactor of DNA polymerase-primase complex by associating with DNA polymerase α.
authors.affiliation: Key Laboratory of Systems Biomedicine (Ministry of Education) and Collaborative Innovation Center of Systems Biomedicine of Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China.
authors.forename: Zhuang-Zhuang
authors.initials: ZZ
authors.lastname: Zhang
authors.affiliation: Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.affiliation: Key Laboratory of Systems Biomedicine (Ministry of Education) and Collaborative Innovation Center of Systems Biomedicine of Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China.
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Wang
authors.affiliation: Department of Hepatobiliary Surgery, Wuxi People's Hospital of Nanjing Medical University, Jiangsu, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Cai
authors.affiliation: Key Laboratory of Systems Biomedicine (Ministry of Education) and Collaborative Innovation Center of Systems Biomedicine of Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China.|Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Ze-Guang
authors.initials: ZG
authors.lastname: Han
mesh_terms: D000368:Aged; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D063646:Carcinogenesis; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D018797:Cell Cycle Proteins; D049109:Cell Proliferation / Q000235:genetics; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics*; D019915:DNA Primase / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D023041:Xenograft Model Antitumor Assays
chemical_list: D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; C522175:noxin protein, mouse; D004247:DNA; D019915:DNA Primase; D004259:DNA-Directed DNA Polymerase
keywords: DNA copy number; DNA polymerase α; NOXIN; cell cycle