title: Up-regulation of L1CAM is linked to loss of hormone receptors and E-cadherin in aggressive subtypes of endometrial carcinomas.
abstract: Endometrial carcinomas (ECs) are classified into type 1 (less aggressive) and type 2 (aggressive) tumours that differ in genetic alterations. So far, reliable immunohistochemical markers that can identify patients with high risk for recurrence are rare. We have defined the expression of L1 cell adhesion molecule (L1CAM), a biomarker previously identified for EC, and compared its expression to oestrogen receptor (ER)/progesterone receptor (PR) and E-cadherin. We found that L1CAM was absent in normal endometrium and the vast majority of endometrioid ECs (type 1) but was strongly expressed in serous and clear-cell ECs, considered as type 2. 78/272 cases were identified as L1CAM-positive endometrioid ECs that were correlated with a poor prognosis. Strikingly, we observed an inverse relationship between L1CAM and ER/PR/E-cadherin expression in all ECs. In mixed ECs, composed of endometrioid (L1CAM(-) ER/PR(+) E-cadherin(+)) and clear-cell/serous (L1CAM(+) ER/PR(-) E-cadherin(-)), both phenotypes were co-expressed. In some of these cases L1CAM was up-regulated at the leading edge of the tumour, where ER/PR and E-cadherin expression were selectively lost. In EC cell lines treated with the epithelial-mesenchymal transition (EMT) inducer TGFbeta1, L1CAM and vimentin were strongly up-regulated, while E-cadherin expression was reduced. The treatment also resulted in an increased expression of the EMT transcription factor Slug and an enhanced cell invasion. Depletion of Slug by siRNA knockdown prevented both L1CAM up-regulation and enhanced cell invasion. According to our analysis, we suggest that L1CAM is a novel marker for EMT in ECs and that L1CAM-typing could identify endometrioid ECs that have type 2-like features and are at high risk for recurrence.
authors.affiliation: Department of Pathology, Kaplan Medical Centre, Rehovot, Israel.
authors.forename: Monica
authors.initials: M
authors.lastname: Huszar
authors.forename: Marco
authors.initials: M
authors.lastname: Pfeifer
authors.forename: Uwe
authors.initials: U
authors.lastname: Schirmer
authors.forename: Helena
authors.initials: H
authors.lastname: Kiefel
authors.forename: Gottfried E
authors.initials: GE
authors.lastname: Konecny
authors.forename: Alon
authors.initials: A
authors.lastname: Ben-Arie
authors.forename: Lutz
authors.initials: L
authors.lastname: Edler
authors.forename: Maria
authors.initials: M
authors.lastname: Münch
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Müller-Holzner
authors.forename: Susanne
authors.initials: S
authors.lastname: Jerabek-Klestil
authors.forename: Samira
authors.initials: S
authors.lastname: Abdel-Azim
authors.forename: Christian
authors.initials: C
authors.lastname: Marth
authors.forename: Alain G
authors.initials: AG
authors.lastname: Zeimet
authors.forename: Peter
authors.initials: P
authors.lastname: Altevogt
authors.forename: Mina
authors.initials: M
authors.lastname: Fogel
mesh_terms: D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D015820:Cadherins / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000378:metabolism* / Q000473:pathology; D004717:Endometrium / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007124:Immunoenzyme Techniques; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D009363:Neoplasm Proteins / Q000378:metabolism*; D039842:Neural Cell Adhesion Molecule L1 / Q000096:biosynthesis* / Q000235:genetics; D011379:Prognosis; D012334:RNA, Neoplasm / Q000235:genetics; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D014408:Biomarkers, Tumor; D015820:Cadherins; D009363:Neoplasm Proteins; D039842:Neural Cell Adhesion Molecule L1; D012334:RNA, Neoplasm; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1