Journal
INTERNATIONAL JOURNAL OF CANCER
Volume 137, Issue 4, Pages 765-775Publisher
WILEY
DOI: 10.1002/ijc.29451
Keywords
cell cycle; DNA copy number; DNA polymerase alpha; NOXIN
Categories
Funding
- China National Key Projects for Infectious Disease [2012ZX10002012-008, 2013ZX10002010-006]
- National Natural Science Foundation of China [81272271, 81472621]
- Chinese National Key Program on Basic Research [2010CB529200]
- Shanghai Commission for Science and Technology
- National High Technology Research and Development Program of China (863 Program) [2012AA02A205, 2012AA020103]
- Program of Shanghai Subject Chief Scientist [12XD1421400]
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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 alpha, 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 a.
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