title: Epithelial-to-mesenchymal transition (EMT) in intraductal papillary mucinous neoplasm (IPMN) is associated with high tumor grade and adverse outcomes.
abstract: BACKGROUND
  Epithelial-to-mesenchymal transition (EMT) is generally associated with increased tumor aggressiveness and poor prognosis. We evaluated EMT characteristics in intraductal papillary mucinous neoplasm (IPMN) tumor specimens and their potential role as biomarkers for malignancy, metastasis, and adverse patient outcomes.
  
  
  METHODS
  IPMN surgical specimens were identified and reviewed by two gastrointestinal pathologists. Immunohistochemical analysis of E-cadherin, vimentin, and ZEB-1 was performed. Samples were linked to clinicopathologic and outcome data for these patients. Western blot test was used to evaluate ZEB-1 expression in IPMN samples; 846 human miRNAs were profiled, and EMT-related differentially expressed miRNAs were validated using quantitative real-time polymerase chain reaction.
  
  
  RESULTS
  Fifty-eight IPMN specimens and five normal pancreatic tissue samples were immunohistochemically stained and scored. E-cadherin expression was significantly lower in malignant versus low-grade IPMN (p < 0.05). Vimentin expression was increased in malignant IPMN tumor samples (p < 0.05). EMT was associated with increased lymph node metastasis and decreased survival of malignant IPMN patients (p < 0.05). ZEB-1, an imperative EMT regulator, was exclusively expressed by malignant IPMN tumors. miRNA hierarchical clustering demonstrated grouping of two main IPMN subgroups: low-grade IPMN versus high-grade IPMN and carcinoma. Twenty-four miRNAs were differentially expressed (14 up-regulated, 10 down-regulated). The EMT-regulatory miRNAs, miR-200c and miR-141, were down-regulated (twofold and 1.8-fold decrease, respectively) in malignant versus low-grade IPMN (p < 0.05).
  
  
  CONCLUSIONS
  EMT may play a role in IPMN tumorigenesis and metastasis. EMT molecular deregulations could be utilized as potential novel biomarkers for the identification of high-risk IPMN patients.
authors: Department of Surgery, Sourasky Medical Center, Tel Aviv, Israel, guyla@tasmc.health.gov.il.
authors: Guy
authors: G
authors: Lahat
authors: Nir
authors: N
authors: Lubezky
authors: Shelly
authors: S
authors: Loewenstein
authors: Eran
authors: E
authors: Nizri
authors: Sarah
authors: S
authors: Gan
authors: Metzada
authors: M
authors: Pasmanik-Chor
authors: Luciile
authors: L
authors: Hayman
authors: Eli
authors: E
authors: Barazowsky
authors: Menahem
authors: M
authors: Ben-Haim
authors: Joseph M
authors: JM
authors: Klausner
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000737:chemistry / Q000235:genetics / Q000556:secondary*; D000231:Adenocarcinoma, Papillary / Q000737:chemistry / Q000235:genetics / Q000556:secondary*; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis; D015820:Cadherins / Q000032:analysis; D021441:Carcinoma, Pancreatic Ductal / Q000737:chemistry / Q000235:genetics / Q000556:secondary*; D002471:Cell Transformation, Neoplastic; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins / Q000032:analysis; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D035683:MicroRNAs / Q000032:analysis / Q000235:genetics*; D008875:Middle Aged; D060787:Neoplasm Grading; D020411:Oligonucleotide Array Sequence Analysis; D010179:Pancreas / Q000737:chemistry; D010190:Pancreatic Neoplasms / Q000737:chemistry / Q000235:genetics / Q000473:pathology*; D011379:Prognosis; D015996:Survival Rate; D014157:Transcription Factors / Q000032:analysis; D015854:Up-Regulation; D014746:Vimentin / Q000032:analysis; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D014408:Biomarkers, Tumor; D015820:Cadherins; D018398:Homeodomain Proteins; D035683:MicroRNAs; D014157:Transcription Factors; D014746:Vimentin; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1