title: Mitogen activated protein kinase kinase kinase 3 (MAP3K3/MEKK3) overexpression is an early event in esophageal tumorigenesis and is a predictor of poor disease prognosis.
abstract: BACKGROUND
  Mitogen-activated protein kinase kinase kinase3 (MAP3K3/MEKK3) was identified to be differentially expressed in esophageal squamous cell carcinoma (ESCC) using cDNA microarrays by our laboratory. Here in we determined the clinical significance of MEKK3 in ESCC.
  
  
  METHODS
  Immunohistochemical analysis of MEKK3 expression was carried out in archived tissue sections from 93 ESCCs, 47 histologically normal and 61 dysplastic esophageal tissues and correlated with clinicopathological parameters and disease prognosis over up to 7.5 years for ESCC patients.
  
  
  RESULTS
  MEKK3 expression was significantly increased in esophageal dysplasia and ESCC in comparison with normal mucosa (ptrend < 0.001). Kaplan Meier survival analysis showed significantly reduced median disease free survival median DFS = 10 months in patients with MEKK3 positive ESCCs compared to patients with no immunopositivity (median DFS = 19 months, p = 0.04). ESCC patients with MEKK3 positive and lymph node positive tumors had median DFS = 9 months, as compared to median DFS = 21 months in patients who did not show the alterations (p = 0.01). In multivariate Cox regression analysis, combination of MEKK3 overexpression and node positivity [p = 0.015, hazard ratio (HR) = 2.082, 95% CI = 1.154 - 3.756] emerged as important predictor of reduced disease free survival and poor prognosticator for ESCC patients.
  
  
  CONCLUSIONS
  Alterations in MEKK3 expression occur in early stages of development of ESCC and are sustained during disease progression; MEKK3 in combination with lymph node positivity has the potential to serve as adverse prognosticator in ESCC.
authors.forename: Raghibul
authors.initials: R
authors.lastname: Hasan
authors.forename: Rinu
authors.initials: R
authors.lastname: Sharma
authors.forename: Anoop
authors.initials: A
authors.lastname: Saraya
authors.forename: Tushar K
authors.initials: TK
authors.lastname: Chattopadhyay
authors.forename: Siddartha
authors.initials: S
authors.lastname: DattaGupta
authors.forename: Paul G
authors.initials: PG
authors.lastname: Walfish
authors.affiliation: Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India. s_s_chauhan@hotmail.com.
authors.forename: Shyam S
authors.initials: SS
authors.lastname: Chauhan
authors.forename: Ranju
authors.initials: R
authors.lastname: Ralhan
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D018572:Disease-Free Survival; D004938:Esophageal Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D048748:MAP Kinase Kinase Kinase 3 / Q000032:analysis*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016017:Odds Ratio; D016016:Proportional Hazards Models; D012307:Risk Factors; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D048748:MAP Kinase Kinase Kinase 3; C482625:MAP3K3 protein, human