title: The PAX2-null immunophenotype defines multiple lineages with common expression signatures in benign and neoplastic oviductal epithelium.
abstract: The oviducts contain high-grade serous cancer (HGSC) precursors (serous tubal intraepithelial neoplasia or STINs), which are γ-H2AX(p) - and TP53 mutation-positive. Although they express wild-type p53, secretory cell outgrowths (SCOUTs) are associated with older age and serous cancer; moreover, both STINs and SCOUTs share a loss of PAX2 expression (PAX2(n) ). We evaluated PAX2 expression in proliferating adult and embryonic oviductal cells, normal mucosa, SCOUTs, Walthard cell nests (WCNs), STINs, and HGSCs, and the expression of genes chosen empirically or from SCOUT expression arrays. Clones generated in vitro from embryonic gynaecological tract and adult Fallopian tube were Krt7(p) /PAX2(n) /EZH2(p) and underwent ciliated (PAX2(n) /EZH2(n) /FOXJ1(p) ) and basal (Krt7(n) /EZH2(n) /Krt5(p) ) differentiation. Similarly, non-ciliated cells in normal mucosa were PAX2(p) but became PAX2(n) in multi-layered epithelium undergoing ciliated or basal (WCN) cell differentiation. PAX2(n) SCOUTs fell into two groups: type 1 were secretory or secretory/ciliated with a 'tubal' phenotype and were ALDH1(n) and β-catenin(mem) (membraneous only). Type 2 displayed a columnar to pseudostratified (endometrioid) phenotype, with an EZH2(p) , ALDH1(p) , β-catenin(nc) (nuclear and cytoplasmic), stathmin(p) , LEF1(p) , RCN1(p) , and RUNX2(p) expression signature. STINs and HGSCs shared the type 1 immunophenotype of PAX2(n) , ALDH1(n) , β-catenin(mem) , but highly expressed EZH2(p) , LEF1(p) , RCN1(p) , and stathmin(p) . This study, for the first time, links PAX2(n) with proliferating fetal and adult oviductal cells undergoing basal and ciliated differentiation and shows that this expression state is maintained in SCOUTs, STINs, and HGSCs. All three entities can demonstrate a consistent perturbation of genes involved in potential tumour suppressor gene silencing (EZH2), transcriptional regulation (LEF1), regulation of differentiation (RUNX2), calcium binding (RCN1), and oncogenesis (stathmin). This shared expression signature between benign and neoplastic entities links normal progenitor cell expansion to abnormal and neoplastic outgrowth in the oviduct and exposes a common pathway that could be a target for early prevention.
authors.affiliation: Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Ning
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Bijron
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Xia
authors.initials: X
authors.lastname: Wang
authors.forename: Brooke E
authors.initials: BE
authors.lastname: Howitt
authors.forename: Michael
authors.initials: M
authors.lastname: Herfs
authors.forename: Eric
authors.initials: E
authors.lastname: Yang
authors.forename: Yue
authors.initials: Y
authors.lastname: Hong
authors.forename: Maxence
authors.initials: M
authors.lastname: Cornille
authors.forename: Lingyan
authors.initials: L
authors.lastname: Wu
authors.forename: Suchanan
authors.initials: S
authors.lastname: Hanamornroongruang
authors.forename: Frank D
authors.initials: FD
authors.lastname: McKeon
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Crum
authors.forename: Wa
authors.initials: W
authors.lastname: Xian
mesh_terms: D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage; D004848:Epithelium / Q000473:pathology; D005185:Fallopian Tube Neoplasms / Q000235:genetics* / Q000473:pathology; D005187:Fallopian Tubes / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D016130:Immunophenotyping; D014411:Neoplastic Stem Cells / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D051762:PAX2 Transcription Factor / Q000235:genetics*; D059467:Transcriptome
chemical_list: D051762:PAX2 Transcription Factor; C497318:PAX2 protein, human
keywords: ALDH1; Fallopian tube; PAX2; serous carcinoma; stem cell