title: Increased Cdc7 expression is a marker of oral squamous cell carcinoma and overexpression of Cdc7 contributes to the resistance to DNA-damaging agents.
abstract: Cdc7-Dbf4 kinase (Dbf4-dependent kinase, DDK) is an essential factor of DNA replication and DNA damage response (DDR), which is associated with tumorigenesis. However, Cdc7 expression has never been associated to the outcome of oral squamous cell carcinoma (OSCC) patients, and the mechanism underlying cancer cell survival mediated by Cdc7 remains unclear. The Cdc7 protein expression of 105 OSCC tumor and 30 benign tissues was examined by immunohistochemistry assay. Overall survival rates of 80 OSCC patients were measured using Kaplan-Meier estimates and the log-rank tests. Cdc7 overexpression by adenovirus system was used to scrutinize the underlying mechanism contributed to cancer cell survival upon DDR. In silico analysis showed that increased Cdc7 is a common feature of cancer. Cdc7 overexpression was found in 96 of 105 (91.4%) studied cases of OSCC patients. Patients with higher Cdc7 expression, either categorized into two groups: Cdc7 high expression (2+ to 3+) versus Cdc7 low expression (0 to 1+) [hazard ratios (HR)=2.6; 95% confidence interval (CI)=1.28-5.43; P=0.0087] or four groups (0 to 3+) [HR=1.71; 95% CI=1.20-2.44; P=0.0032], exhibited a poorer outcome. Multivariate analysis showed that Cdc7 is an independent marker for survival prediction. Overexpressed Cdc7 inhibits genotoxin-induced apoptosis to increase the survival of cancer cells. In summary, Cdc7 expression, which is universally upregulated in cancer, is an independent prognostic marker of OSCC. Cdc7 inhibits genotoxin-induced apoptosis and increases survival in cancer cells upon DDR, suggesting that high expression of Cdc7 enhances the resistance to chemotherapy.
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli, Taiwan.
authors.forename: An Ning
authors.initials: AN
authors.lastname: Cheng
authors.forename: Shih Sheng
authors.initials: SS
authors.lastname: Jiang
authors.forename: Chi-Chen
authors.initials: CC
authors.lastname: Fan
authors.forename: Yu-Kang
authors.initials: YK
authors.lastname: Lo
authors.forename: Chan-Yen
authors.initials: CY
authors.lastname: Kuo
authors.forename: Chung-Hsing
authors.initials: CH
authors.lastname: Chen
authors.forename: Ying-Lan
authors.initials: YL
authors.lastname: Liu
authors.forename: Chun-Chung
authors.initials: CC
authors.lastname: Lee
authors.forename: Wei-Shone
authors.initials: WS
authors.lastname: Chen
authors.forename: Tze-Sing
authors.initials: TS
authors.lastname: Huang
authors.forename: Tao-Yeuan
authors.initials: TY
authors.lastname: Wang
authors.forename: Alan Yueh-Luen
authors.initials: AY
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002166:Camptothecin / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D016009:Chi-Square Distribution; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D009062:Mouth Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D015999:Multivariate Analysis; D011379:Prognosis; D016016:Proportional Hazards Models; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D011836:Radiation Tolerance; D015996:Survival Rate; D013997:Time Factors; D014162:Transfection; D014466:Ultraviolet Rays; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C068619:CDC7 protein, human; D017346:Protein Serine-Threonine Kinases; D006918:Hydroxyurea; D002166:Camptothecin
keywords: CI; CPT; Cdc7; Chemotherapy resistance; DDK; DDR; DNA damage response; Dbf4-dependent kinase; HR; HU; IHC; OSCC; Oral cancer; Prognostic marker; TUNEL; camptothecin; confidence interval; hazard ratios; hydroxyurea; immunohistochemistry; oral squamous cell carcinoma; terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling