Prognostic significance and therapeutic implications of centromere protein F expression in human nasopharyngeal carcinoma

Mol Cancer. 2010 Sep 9;9:237. doi: 10.1186/1476-4598-9-237.

Abstract

Background: Our recent cDNA microarray data showed that centromere protein F (CENP-F) is significantly upregulated in primary cultured nasopharyngeal carcinoma (NPC) tumor cells compared with normal nasopharyngeal epithelial cells. The goal of this study was to further investigate the levels of CENP-F expression in NPC cell lines and tissues to clarify the clinical significance of CENP-F expression in NPC as well as the potential therapeutic implications of CENP-F expression.

Methods: Real-time RT-PCR and western blotting were used to examine CENP-F expression levels in normal primary nasopharyngeal epithelial cells (NPEC), immortalized nasopharyngeal epithelial cells and NPC cell lines. Levels of CENP-F mRNA were determined by real-time RT-PCR in 23 freshly frozen nasopharyngeal biopsy tissues, and CENP-F protein levels were detected by immunohistochemistry in paraffin sections of 202 archival NPC tissues. Statistical analyses were applied to test for prognostic associations. The cytotoxicities of CENP-F potential target chemicals, zoledronic acid (ZOL) and FTI-277 alone, or in combination with cisplatin, in NPC cells were determined by the MTT assay.

Results: The levels of CENP-F mRNA and protein were higher in NPC cell lines than in normal and immortalized NPECs. CENP-F mRNA level was upregulated in nasopharyngeal carcinoma biopsy tissues compared with noncancerous tissues. By immunohistochemical analysis, CENP-F was highly expressed in 98 (48.5%) of 202 NPC tissues. Statistical analysis showed that high expression of CENP-F was positively correlated with T classification (P < 0.001), clinical stage (P < 0.001), skull-base invasion (P < 0.001) and distant metastasis (P = 0.012) inversely correlated with the overall survival time in NPC patients. Multivariate analysis showed that CENP-F expression was an independent prognostic indicator for the survival of the patient. Moreover, we found that ZOL or FTI-277 could significantly enhance the chemotherapeutic sensitivity of NPC cell lines (HONE1 and 6-10B) with high CENP-F expression to cisplatin, although ZOL or FTI-277 alone only exhibited a minor inhibitory effect to NPC cells.

Conclusion: Our data suggest that CENP-F protein is a valuable marker of NPC progression, and CENP-F expression is associated with poor overall survival of patients. In addition, our data indicate a potential benefit of combining ZOL or FTI-277 with cisplatin in NPC suggesting that CENP-F expression may have therapeutic implications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Blotting, Western
  • Bone Density Conservation Agents / pharmacology
  • Bone Density Conservation Agents / therapeutic use
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cells, Cultured
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism*
  • Cisplatin / pharmacology
  • Cisplatin / therapeutic use
  • Diphosphonates / pharmacology
  • Diphosphonates / therapeutic use
  • Drug Synergism
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Female
  • Fluorescent Antibody Technique
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Imidazoles / pharmacology
  • Imidazoles / therapeutic use
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Male
  • Methionine / analogs & derivatives
  • Methionine / pharmacology
  • Methionine / therapeutic use
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism*
  • Middle Aged
  • Multivariate Analysis
  • Nasopharyngeal Neoplasms / genetics
  • Nasopharyngeal Neoplasms / metabolism*
  • Nasopharyngeal Neoplasms / mortality
  • Nasopharyngeal Neoplasms / pathology*
  • Oligonucleotide Array Sequence Analysis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Young Adult
  • Zoledronic Acid

Substances

  • Antineoplastic Agents
  • Bone Density Conservation Agents
  • Chromosomal Proteins, Non-Histone
  • Diphosphonates
  • Enzyme Inhibitors
  • FTI 277
  • Imidazoles
  • Microfilament Proteins
  • centromere protein F
  • Zoledronic Acid
  • Methionine
  • Cisplatin