title: Prognostic and Functional Significance of MAP4K5 in Pancreatic Cancer.
abstract: OBJECTIVE
  MAP4K5 plays an important role in regulating a range of cellular responses and is involved in Wnt signaling in hematopoietic cells. However, its functions in human malignancies have not been studied. The major objectives of this study are to examine the expression, functions and clinical significance of MAP4K5 in pancreatic ductal adenocarcinoma (PDAC).
  
  
  METHODS
  The expression levels of MAP4K5, E-cadherin, vimentin, and carboxylesterase 2 (CES2) were examined by immunohistochemistry in 105 PDAC and matched non-neoplastic pancreas samples from our institution. The RNA sequencing data of 112 PDAC patients were downloaded from the TCGA data portal. Immunoblotting and RNA sequencing analysis were used to examine the expression of MAP4K5 and E-cadherin in pancreatic cancer cell lines. The effect of knockdown MAP4K5 using siRNA on the expression of CDH1 and vimentin were examined by Real-time RT-PCR in Panc-1 and AsPC-1 cells. Statistical analyses were performed using IBM SPSS Statistics.
  
  
  RESULTS
  MAP4K5 protein is expressed at high levels specifically in the pancreatic ductal cells of 100% non-neoplastic pancreas samples, but is decreased or lost in 77.1% (81/105) of PDAC samples. MAP4K5-low correlated with the loss of E-cadherin (P = 0.001) and reduced CES2 expression (P = 0.002) in our patient populations. The expression levels of MAP4K5 mRNA directly correlated with the expression levels of CDH1 mRNA (R = 0.2490, P = 0.008) in the second cohort of 112 PDAC patients from The Cancer Genome Atlas (TCGA) RNA-seq dataset. Similar correlations between the expression of MAP4K5 and E-cadherin were observed both at protein and mRNA levels in multiple pancreatic cancer cell lines. Knockdown MAP4K5 led to decreased CDH1 mRNA expression in Panc-1 and AsPC-1 cells. MAP4K5-low correlated significantly with reduced overall survival and was an independent prognosticator in patients with stage II PDAC.
  
  
  CONCLUSIONS
  MAP4K5 expression is decreased or lost in majority of PDACs. The strong associations between low MAP4K5 expression and loss of E-cadherin, reduced CES2 expression and decreased overall survival may suggest an important role of MAP4K5 in epithelial-to-mesenchymal transition, chemotherapy resistance and tumor progression in pancreatic cancer. Targeting impaired MAP4K5 signaling may represent a new therapeutic strategy for pancreatic cancer.
authors.affiliation: Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Oliver H
authors.initials: OH
authors.lastname: Wang
authors.affiliation: Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Nancy
authors.initials: N
authors.lastname: Azizian
authors.affiliation: Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Ming
authors.initials: M
authors.lastname: Guo
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Michela
authors.initials: M
authors.lastname: Capello
authors.affiliation: Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Defeng
authors.initials: D
authors.lastname: Deng
authors.affiliation: Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Fenglin
authors.initials: F
authors.lastname: Zang
authors.affiliation: Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Jason
authors.initials: J
authors.lastname: Fry
authors.affiliation: Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Katz
authors.affiliation: Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Jason B
authors.initials: JB
authors.lastname: Fleming
authors.affiliation: Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Lee
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Wolff
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Samir
authors.initials: S
authors.lastname: Hanash
authors.affiliation: Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.|Department of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Huamin
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.|Department of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D043182:Carboxylesterase / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D015331:Cohort Studies; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D015151:Immunoblotting; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D015820:Cadherins; C404144:MAP4K5 protein, human; D017346:Protein Serine-Threonine Kinases; C517204:CES2 protein, human; D043182:Carboxylesterase