Overexpression of centromere protein K (CENP-K) gene in hepatocellular carcinoma promote cell proliferation by activating AKT/TP53 signal pathway
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Haiyan Wang1,2,*, Weilong Liu2,*, Lei Liu2,*, Chi Wu1,2, Weigang Wu3, Juan Zheng2, Mingxia Zhang2, Xinchun Chen2, Boping Zhou3,#, Zhiliang Gao1,4,# and Jian Huang2,3,5,#
1Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
2Guangdong Key Laboratory of Diagnosis and Treatment for Emerging Infectious Diseases, Shenzhen Key Laboratory of Infection and Immunity, Shenzhen Third People’s Hospital, Shenzhen, Guangdong, China
3Shenzhen People’s Hospital, Second Clinical Medical College of Jinan University, Shenzhen, Guangdong, China
4GuangDong Provincial Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
5Key Laboratory of Systems Biomedicine, Ministry of Education and Collaborative Innovation Center of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China
*These authors contributed equally to this work
#These authors have equally senior contributions
Jian Huang, email: email@example.com
Zhiliang Gao, email: firstname.lastname@example.org
Boping Zhou, email: email@example.com
Keywords: hepatocellular carcinoma, hepatocarcinogenesis, centromere protein K, up-regulation, methylation
Received: October 19, 2016 Accepted: April 28, 2017 Published: May 25, 2017
Hepatocellular carcinoma (HCC) is one of the high-incidence malignant tumors with very poor prognosis. Identification of potential oncogenes is critical to discovering novel therapeutic targets for many cancers, including HCC. In our previous studies, using microarray technology, we conformed that CENP-K was overexpressed in HCCs. However, whether the overexpression of CENP-K contributes to hepatocarcinogenesis remains unclear. In this study, we found that CENP-K was significantly up-regulated in 60% (63 of 105) of HCC specimens at the mRNA level compared to adjacent non-cancerous liver specimens, as determined by RT-qPCR. Immunohistochemical staining confirmed similar results at the protein level. Interestingly, we found that the DNA methylation status of the CENP-K promoter was significantly reduced in HCC specimens with increased CENP-K expression. In addition, CENP-K mRNA expression level was positively correlated with the level of alpha-fetoprotein (AFP) (≥ 400 ng/ml) and tumor size (≥ 3 cm) (p < 0.05). CENP-K overexpression promoted proliferation and migration in SMMC7721 and Focus cells. In contrast, knock down of CENP-K significantly inhibited the growth of MHCC-LM3 and QGY7703 cells. Furthermore, we found that overexpression of CENP-K stimulated the tyrosine phosphorylation of the AKT and MDM2 proteins, but inhibited tyrosine phosphorylation of the TP53 protein. Our data suggest that the up-regulation of CENP-K, a potential oncotarget gene, may be modulated by epigenetic events and can contribute to hepatocarcinogenesis.
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