NOXIN as a cofactor of DNA polymerase‐primase complex could promote hepatocellular carcinoma
NOXIN as a cofactor of DNA polymerase‐primase complex could promote hepatocellular carcinoma
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DOI：
10.1002/ijc.29451
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发表时间：
2015-08
影响因子：
6.4
通讯作者：
Zhuang-Zhuang Zhang-Zhuang;Jian Huang;Yuping Wang;B. Cai;Ze-Guang Han
中科院分区：
文献类型：
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作者：
Zhuang-Zhuang Zhang-Zhuang;Jian Huang;Yuping Wang;B. Cai;Ze-Guang Han
癌基因的激活或抑癌基因的失活对肿瘤的发生和发展至关重要。DNA拷贝数扩增是许多肿瘤（包括肝细胞癌（HCC））中激活癌基因的许多机制之一。虽然已经知道一些癌基因如c-myc扩增参与HCC发病机制，但更多具有DNA拷贝扩增的癌基因有助于HCC的发生和进展仍有待表征。在这里，我们通过基于单核苷酸多态性微阵列的全基因组DNA拷贝数分析，对43例人HCC样本进行DNA拷贝数扩增，将NOXIN鉴定为一种新的潜在癌基因。我们确定了染色体11q14.1上含有NOXIN的局部DNA获得和扩增区域以及NOXIN过表达与HCC进展显著相关。然后我们评估了NOXIN在HCC细胞中的作用。NOXIN过表达促进细胞增殖、集落形成、细胞迁移和体内致瘤性，而NOXIN敲低减弱这些作用。有趣的是，NOXIN过表达通过增强DNA合成加速G1-S相变。此外，我们发现NOXIN与DNA聚合酶α相互作用，表明NOXIN可能通过促进DNA聚合酶-引发酶复合物的形成来促进从头DNA合成。这些集体数据表明，作为基因组DNA获得或扩增的结果，NOXIN过表达通过加速DNA合成和细胞周期进展促进HCC肿瘤发生，其中NOXIN通过与DNA聚合酶α结合而作为DNA聚合酶-引发酶复合物的辅因子发挥作用。
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.