Role of Centromere Protein H and Ki67 in Relapse-free Survival of Patients after Primary Surgery for Hypopharyngeal Cancer

  • Wang, Jun-Xi (Department of Otolaryngology-Head and Neck Surgery, Qi-Lu Hospital, Shandong University) ;
  • Zhang, Ying-Yao (Department of Otolaryngology-Head and Neck Surgery, Qi-Lu Hospital, Shandong University) ;
  • Yu, Xue-Min (Department of Otolaryngology-Head and Neck Surgery, Qi-Lu Hospital, Shandong University) ;
  • Jin, Tong (Department of Otolaryngology-Head and Neck Surgery, Qi-Lu Hospital, Shandong University) ;
  • Pan, Xin-Liang (Department of Otolaryngology-Head and Neck Surgery, Qi-Lu Hospital, Shandong University)
  • Published : 2012.03.31


Purpose: Centromere protein H (CENP-H) and Ki67 are overexpressed in some malignancies, but whether they are predictors of survival after primary resection for hypopharyngeal squamous cell carcinoma (HSCC) remains unknown. Methods: We assessed immunohistochemical expression of CENP-H and Ki67 in 112 HSCC specimens collected between March 2003 and March 2005 for analysis by clinical characteristics. The Kaplan-Meier method was used to analyze relapse-free survival and logistic multivariate regression to determine risk factors of relapse-free survival. Cholecystokinin octapeptide assays and flow cytometry were used to examine cell proliferation and apoptosis after siRNA inhibition of CENP-H in HSCC cells. Results: Overall, 50 (44.6%) HSCC specimens showed upregulated CENP-H expression and 69 (61.6%) upregulated Ki67. An increased CENP-H protein level was associated with advanced cancer stage and alcohol history (P=0.012 and P=0.048, respectively) but an increased Ki67 protein level only with advanced cancer stage (P=0.021). Increased CENP-H or Ki67 were associated with short relapse-free survival (P<0.001 or P=0.009, respectively) and were independent predictors of relapse-free survival (P=0.001 and P=0.018, respectively). siRNA knockdown of CENP-H mRNA inhibited cell proliferation and promoted cancer cell apoptosis in vitro. Conclusions: Upregulated CENP-H and Ki67 levels are significantly associated with short relapse-free survival in HSCC. These factors may be predictors of a relapsing phenotype in HSSC cases.


  1. Bharadwaj R, Yu H (2004). The spindle checkpoint, aneuploidy, and cancer. Oncogene, 23, 2016-27.
  2. Brenner H, Francisc Si, de Angelis R, et al (2009). Long-term survival expectations of cancer patients in Europe in 2000-2002. Eur J Cancer, 45, 1028-41.
  3. Cleveland DW, Mao Y, Sullivan KF (2003). Centromeres and kinetochores: from epigenetics to mitotic checkpoint signaling. Cell, 112, 407-21.
  4. Cooper JS, Porter K, Mallin K, et al (2009). National Cancer Database report on cancer of the head and neck: 10-year update. Head Neck, 31, 748-58.
  5. Duesberg P, Li R (2003). Multistep carcinogenesis: a chain reaction of aneuploidizations. Cell Cycle, 2, 202-10.
  6. Duesberg P, Rasnick D (2000). Aneuploidy, the somatic mutation that makes cancer a species of its own. Cell Motil Cytoskeleton, 47, 81-107.<81::AID-CM1>3.0.CO;2-#
  7. Faratzis G, Tsiambas E, Rapidis AD, et al (2009). VEGF and ki 67 expression in squamous cell carcinoma of the tongue: An immunohistochemical and computerized image analysis study. Oral Oncol, 45, 584-8.
  8. Fukagawa T, Mikmi Y, Nishihashi A (2000). CENP-H, a constitutive centromere component, is required for centromere targeting of CENP-C in verberate cells. EMBO J, 20, 4603-17.
  9. Gerdes J, SchwabU, Lemke H, Stein H (1983). Production of a mouse monoclonal antibody reactive with a human nuclear antigen associated with cell proliferation. Int J Cancer, 31, 13-20.
  10. Gourin CG, Terris DJ (2004). Carcinoma of the hypopharynx. Surg Oncol Clin N Am, 13, 81-98.
  11. Guardia de la C, Casiano CA, Trinidad-Pinedo J, Baez A (2001). CENP-F gene amplification and overexpression in head and neck squamous cell carcinomas. Head Neck, 23, 104-12.<104::AID-HED1005>3.0.CO;2-0
  12. Guo XZ, Zhang G, Wang JY, et al (2008). Prognostic relevance of Centromere protein H expression in esophageal carcinoma. BMC Cancer, 8, 233.
  13. Hanahan D, Weinberg RA (2000). The hallmarks of cancer. Cell, 100, 57-70.
  14. Hoffman HT, Karnell LH, Funk GF, Robinson RA, Menck HR (1998).The National Cancer Data Base report on cancer of the head and neck. Arch Otolaryngol Head Neck Surg, 124, 951-62.
  15. Hoffman HT, Karnell LH , ShahJP, et al (1997). Hypopharyngeal cancer patient care evaluation. Laryngoscope, 107, 1005-17.
  16. Liao WT, Song LB, Zhang HZ, et al (2007). Centromere protein H is a novel prognostic marker for nasopharyngeal carcinoma progression and overall patient survival. Clin Cancer Res, 13, 508-14.
  17. Liao WT, Wang X, Xu LH, et al (2009). Centromere protein H is a novel prognostic marker for human nonsmall cell lung cancer progression and overall patient survival. Cancer, 115, 1507-17.
  18. Martinez AC, van Wely KH (2011). Centromere fission, not telomere erosion, triggers chromosomal instability in human carcinomas. Carcinogenesis, 32, 796-803.
  19. Mikami Y, Hori T, Kimura H, Fukagawa T (2005). The functional region of CENP-H interacts with the Nuf2 complex that locaises to centromere during mitosis. Mol Cell Bio, 25, 1958-70.
  20. O'Brien SL, Fagan A, Fox EJ (2007). CENP-F expression is associated with poor prognosis and chromosomal instability in patients with primary breast cancer. Int J Cancer, 120, 1434-43.
  21. Okada M, Cheeseman IM, Hori T, et al (2006). The CENP-H-I complex is required for the efficient incorporation of newly synthesized CENP-A into centromeres. Nat Cell Biol, 8, 446-57.
  22. Orthaus S, Ohndorf S, Diekmann S (2006). RNAi knockdown of human kinetochore protein CENP-H. Biochem Biophys Res Commun, 348, 36-46.
  23. Scholzen T, Gerdes J (2000). The Ki-67 protein: from the known and the unknown. J Cell Physiol, 182, 311-22.<311::AID-JCP1>3.0.CO;2-9
  24. Shigeishi H, Higashikawa K, Ono S, et al (2006). Increased expression of CENP-H gene in human oral squamous cell carcinomas harboring high-proliferative activity. Oncol Rep, 16, 1071-5.
  25. Sugata N, Li S, Earnshaw WC, et al (2000). Human CENP-H multimers colocalize with CENP-A and CENP-C at active centromere--kinetochore complexes. Hum Mol Genet, 9, 2919-26.
  26. Sugata N, Munekata E, Todokoro K (1999). Characterization of a novel kinetochore protein, CENP-H. J Biol Chem, 274, 27343-6.
  27. Tomonaga T, Matsushita K, Ishibashi M, et al (2005). Centromere protein H is up-regulated in primary human colorectal cancer and its overexpression induces aneuploidy. Cancer Res, 65, 4683-9.
  28. Tomonaga T, Matsushita K, Yamaguchi S (2003). Overexpression and mistargeting of centromere protein-A in human primary colorectal cancer. Cancer Res, 63, 3511-6.
  29. van Diest PJ, BrugalG, Baak JP (1998). Proliferation markers in tumours:interpretation and clinical value. J Clin Pathol, 51, 716-24.
  30. Wangsa D, Ryott M, Avall-Lundqvist E, et al (2008). Ki-67 expression predicts locoregional recurrence in stage I oral tongue carcinoma. Br J Cancer, 99, 1121-8.
  31. Zhao X, Zhao L, Tian T (2010). Interruption of cenph causes mitotic failure and embryonic death, and its haploinsufficiency suppresses cancer in zebrafish. J Biol Chem, 285, 27924-34.

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