Overexpression of CENP-H as a novel prognostic biomarker for human hepatocellular carcinoma progression and patient survival

Lu,Guifang; Shan,Tao; He,Shuixiang; Ren,Mudan; Zhu,Meng; Hu,Yannan; Lu,Xinlan; Zhang,Dan

doi:10.3892/or.2013.2675

Overexpression of CENP-H as a novel prognostic biomarker for human hepatocellular carcinoma progression and patient survival

Authors:
- Guifang Lu
- Tao Shan
- Shuixiang He
- Mudan Ren
- Meng Zhu
- Yannan Hu
- Xinlan Lu
- Dan Zhang
View Affiliations

Affiliations: Department of Gastroenterology, First Affiliated Hospital of the Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, Department of General Surgery, Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
Published online on: August 20, 2013 https://doi.org/10.3892/or.2013.2675
Pages: 2238-2244

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Centromere protein H (CENP-H) has been shown to be significantly upregulated in many types of cancers and is associated with disrupted cell cycle regulation, cell proliferation and genetic instability. The aim of the present study was to explore the expression and localization of CENP-H in hepatocellular carcinoma (HCC) and determine whether its overexpression is a prognostic biomarker for HCC. Reverse transcription-polymerase chain reaction (pcr), real-time qPCR and western blotting were used to compare CENP-H expression at the mRNA and protein levels in HCC samples and corresponding adjacent non-cancerous samples. CENP-H protein levels were determined in 60 paired paraffin-embedded HCC tissues using immunohistochemistry (IHC), and the correlation with clinicopathological features and patient prognosis was analyzed. In addition, an immunofluorescence assay was performed to test the expression and localization of CENP-H protein in HCC cells. Results showed that levels of CENP-H mRNA and protein were higher in HCC samples than in the corresponding adjacent non-cancerous samples. In 60 paired paraffin-embedded tissues, CENP-H was upregulated in the HCC samples (38/60, 63.3%) relative to the adjacent non-cancerous samples (21/60, 35%, P=0.003), and a higher level of upregulation was associated with tumor size (P=0.032); higher histological grade (P=0.001); more advanced TNM stage (P=0.002) and Chinese clinical stage (P=0.008); and poorer prognosis. In addition, consistent with the results of IHC, the immunofluorescence assay showed that CENP-H was localized in the nucleus of Hep3B cells. CENP-H was overexpressed in HCC, and its level of upregulation was an independent prognostic indicator, suggesting that CENP-H may be an effective therapeutic strategy for the treatment of HCC.

View Figures

View References

1	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 63:11–30. 2013. View Article : Google Scholar
2	Jemal A, Bray F, Center MM, et al: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar
3	Altekruse SF, McGlynn KA and Reichman ME: Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol. 27:1485–1491. 2009. View Article : Google Scholar : PubMed/NCBI
4	Khorsandi SE and Heaton N: Contemporary strategies in the management of hepatocellular carcinoma. HPB Surg. 2012:1540562012. View Article : Google Scholar : PubMed/NCBI
5	Llovet JM, Fuster J and Bruix J: Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology. 30:1434–1440. 1999. View Article : Google Scholar : PubMed/NCBI
6	Franco D, Capussotti L, Smadja C, et al: Resection of hepatocellular carcinomas. Results in 72 European patients with cirrhosis. Gastroenterology. 98:733–738. 1990.PubMed/NCBI
7	Schwartz M, Roayaie S and Konstadoulakis M: Strategies for the management of hepatocellular carcinoma. Nat Clin Pract Oncol. 4:424–432. 2007. View Article : Google Scholar : PubMed/NCBI
8	Rajagopalan H and Lengauer C: Aneuploidy and cancer. Nature. 432:338–341. 2004. View Article : Google Scholar
9	Ricke RM and van Deursen JM: Aneuploidy in health, disease, and aging. J Cell Biol. 201:11–21. 2013. View Article : Google Scholar : PubMed/NCBI
10	Cimini D and Degrassi F: Aneuploidy: a matter of bad connections. Trends Cell Biol. 15:442–451. 2005. View Article : Google Scholar : PubMed/NCBI
11	Bakhoum SF and Compton DA: Chromosomal instability and cancer: a complex relationship with therapeutic potential. J Clin Invest. 122:1138–1143. 2012. View Article : Google Scholar : PubMed/NCBI
12	Liang QJ, Lu XF, Cheng XL, et al: The active expression of CenpB, a constitutive protein in the centromeres of chromosomes, in breast cancer tissues. Yi Chuan Xue Bao. 31:236–240. 2004.(In Chinese).
13	Sugata N, Munekata E and Todokoro K: Characterization of a novel kinetochore protein, CENP-H. J Biol Chem. 274:27343–27346. 1999. View Article : Google Scholar : PubMed/NCBI
14	Yuen KW, Montpetit B and Hieter P: The kinetochore and cancer: what’s the connection? Curr Opin Cell Biol. 17:576–582. 2005.
15	Bakhoum SF and Compton DA: Kinetochores and disease: keeping microtubule dynamics in check! Curr Opin Cell Biol. 24:64–70. 2012.PubMed/NCBI
16	Kramer A, Neben K and Ho A: Centrosome replication, genomic instability and cancer. Leukemia. 16:767–775. 2002. View Article : Google Scholar : PubMed/NCBI
17	Fukagawa T, Mikami Y, Nishihashi A, et al: CENP-H, a constitutive centromere component, is required for centromere targeting of CENP-C in vertebrate cells. EMBO J. 20:4603–4617. 2001. View Article : Google Scholar : PubMed/NCBI
18	Sugata N, Li S, Earnshaw WC, et al: Human CENP-H multimers colocalize with CENP-A and CENP-C at active centromere - kinetochore complexes. Hum Mol Genet. 9:2919–2926. 2000. View Article : Google Scholar : PubMed/NCBI
19	Liao WT, Wang X, Xu LH, et al: Centromere protein H is a novel prognostic marker for human nonsmall cell lung cancer progression and overall patient survival. Cancer. 115:1507–1517. 2009. View Article : Google Scholar : PubMed/NCBI
20	Liao WT, Song LB, Zhang HZ, et al: Centromere protein H is a novel prognostic marker for nasopharyngeal carcinoma progression and overall patient survival. Clin Cancer Res. 13:508–514. 2007. View Article : Google Scholar : PubMed/NCBI
21	Guo XZ, Zhang G, Wang JY, et al: Prognostic relevance of Centromere protein H expression in esophageal carcinoma. BMC Cancer. 8:2332008. View Article : Google Scholar : PubMed/NCBI
22	Liao WT, Yu CP, Wu DH, et al: Upregulation of CENP-H in tongue cancer correlates with poor prognosis and progression. J Exp Clin Cancer Res. 28:742009. View Article : Google Scholar : PubMed/NCBI
23	Shigeishi H, Higashikawa K, Ono S, et al: Increased expression of CENP-H gene in human oral squamous cell carcinomas harboring high-proliferative activity. Oncol Rep. 16:1071–1075. 2006.PubMed/NCBI
24	Orthaus S, Ohndorf S and Diekmann S: RNAi knockdown of human kinetochore protein CENP-H. Biochem Biophys Res Commun. 348:36–46. 2006. View Article : Google Scholar : PubMed/NCBI
25	Tomonaga T, Matsushita K and Ishibashi M: Centromere protein H is up-regulated in primary human colorectal cancer and its overexpression induces aneuploidy. Cancer Res. 65:4683–4689. 2005. View Article : Google Scholar : PubMed/NCBI
26	Hamilton SR and Aaltonen LA: World Health Organization Classification of Tumors: Pathology and Genetics of Tumours of the Digestive System. LARC Press; Lyon: 2000
27	Sobin LH and Fleming ID: TNM Classification of Malignant Tumors, fifth edition (1997). Union Internationale Contrele Cancer and the American Joint Committee on Cancer. Cancer. 80:1803–1804. 1997. View Article : Google Scholar : PubMed/NCBI
28	Cleveland DW, Mao Y and Sullivan KF: Centromeres and kinetochores: from epigenetics to mitotic checkpoint signaling. Cell. 112:407–421. 2003. View Article : Google Scholar : PubMed/NCBI
29	Schmidt JC, Arthanari H and Boeszoermenyi A: The kinetochore-bound Ska1 complex tracks depolymerizing microtubules and binds to curved protofilaments. Dev Cell. 23:968–980. 2012. View Article : Google Scholar : PubMed/NCBI
30	Kops GJ, Weaver BA and Cleveland DW: On the road to cancer: aneuploidy and the mitotic checkpoint. Nat Rev Cancer. 5:773–785. 2005. View Article : Google Scholar : PubMed/NCBI
31	Tomonaga T, Matsushita K, Yamaguchi S, et al: Overexpression and mistargeting of centromere protein-A in human primary colorectal cancer. Cancer Res. 63:3511–3516. 2003.PubMed/NCBI
32	Li Y, Zhu Z, Zhang S, et al: ShRNA-targeted centromere protein A inhibits hepatocellular carcinoma growth. PLoS One. 6:e177942011. View Article : Google Scholar : PubMed/NCBI
33	McGovern SL, Qi Y, Pusztai L, et al: Centromere protein-A, an essential centromere protein, is a prognostic marker for relapse in estrogen receptor-positive breast cancer. Breast Cancer Res. 14:R722012. View Article : Google Scholar : PubMed/NCBI
34	Wu Q, Qian YM, Zhao XL, et al: Expression and prognostic significance of centromere protein A in human lung adenocarcinoma. Lung Cancer. 77:407–414. 2012. View Article : Google Scholar : PubMed/NCBI
35	Wood KW, Lad L, Luo L, et al: Antitumor activity of an allosteric inhibitor of centromere-associated protein-E. Proc Natl Acad Sci USA. 107:5839–5844. 2010. View Article : Google Scholar : PubMed/NCBI
36	O’Brien SL, Fagan A, Fox EJ, et al: CENP-F expression is associated with poor prognosis and chromosomal instability in patients with primary breast cancer. Int J Cancer. 120:1434–1443. 2007.PubMed/NCBI
37	Shigeishi H, Mizuta K, Higashikawa K, et al: Correlation of CENP-F gene expression with tumor-proliferating activity in human salivary gland tumors. Oral Oncol. 41:716–722. 2005. View Article : Google Scholar : PubMed/NCBI
38	Barbanis S, Ioannou M, Kouvaras E, et al: INCENP (inner centromere protein) is overexpressed in high grade non-Hodgkin B-cell lymphomas. Pathol Oncol Res. 15:11–17. 2009. View Article : Google Scholar : PubMed/NCBI
39	Nakajima T, Moriguchi M, Mitsumoto Y, et al: Centrosome aberration accompanied with p53 mutation can induce genetic instability in hepatocellular carcinoma. Mod Pathol. 17:722–727. 2004. View Article : Google Scholar : PubMed/NCBI