The PAX2-null immunophenotype defines multiple lineages with common expression signatures in benign and neoplastic oviductal epithelium.
The PAX2-null immunophenotype defines multiple lineages with common expression signatures in benign and neoplastic oviductal epithelium.
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DOI：
10.1002/path.4417
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发表时间：
2014-12
影响因子：
7.3
通讯作者：
Xian, Wa
中科院分区：
文献类型：
--
作者：
Ning, Gang;Bijron, Jonathan G.;Yamamoto, Yusuke;Wang, Xia;Howitt, Brooke E.;Herfs, Michael;Yang, Eric;Hong, Yue;Cornille, Maxence;Wu, Lingyan;Hanamornroongruang, Suchanan;McKeon, Frank D.;Crum, Christopher P.;Xian, Wa
输卵管含有高级浆液性癌 (HGSC) 前体（浆液性输卵管上皮内瘤变或 STIN），其呈 γ-H2AXp 和 TP53 突变阳性。尽管它们表达野生型 p53，但分泌细胞增生 (SCOUT) 与老年和浆液性癌症有关；此外，STIN 和 SCOUT 均缺失 PAX2 表达 (PAX2n)。我们评估了增殖的成体和胚胎输卵管细胞、正常粘膜、SCOUT、Walthard 细胞巢 (WCN)、STIN 和 HGSC 中的 PAX2 表达，以及根据经验或从 SCOUT 表达阵列中选择的基因的表达。从胚胎妇科和成人输卵管体外产生的克隆是 Krt7p/PAX2n/EZH2p，并进行纤毛 (PAX2n/EZH2n/FOXJ1p) 和基底 (Krt7n/EZH2n/Krt5p) 分化。类似地，正常粘膜中的非纤毛细胞是PAX2p，但在经历纤毛或基底（Walthard细胞巢或WCN）细胞分化的多层上皮中变成PAX2n。 PAX2n SCOUT 分为两组； I 型是具有“输卵管”表型的分泌型或分泌型/纤毛型，并且是 ALDH1n 和 β-cateninmem（仅膜型）。 II 型显示柱状至假复层（子宫内膜样）表型，具有 EZH2p、ALDH1p、β-cateninnc（核和细胞质）、stathminp、LEF1p、RCN1p 和 RUNX2p 表达特征。 STIN 和 HGSC 具有 PAX2n、ALDH1n、β-cateninmem 的 I 型免疫表型，但高表达 EZH2p、LEF1p、RCN1p 和 stathminp。这项研究首次将 PAX2n 与正在进行基底分化和纤毛分化的增殖胎儿和成人输卵管细胞联系起来，并表明这种表达状态在 SCOUT、STIN 和 HGSC 中得以维持。所有三个实体都可以证明与潜在肿瘤抑制基因沉默（EZH2）、转录调节（LEF1）、分化调节（RUNX2）、钙结合（RCN1）和肿瘤发生（stathmin）相关的基因存在一致的扰动。良性和肿瘤实体之间的这种共享表达特征将正常祖细胞扩张与输卵管中的异常和肿瘤生长联系起来，并暴露了可能成为早期预防目标的共同途径。
The oviducts contain high grade serous cancer (HGSC) precursors (serous tubal intraepithelial neoplasia or STINs), which are γ-H2AXp- 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 (PAX2n). 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 gynecologic tract and adult fallopian tube were Krt7p/PAX2n/EZH2p and underwent ciliated (PAX2n/EZH2n/FOXJ1p) and basal (Krt7n/EZH2n/Krt5p) differentiation. Similarly non-ciliated cells in normal mucosa were PAX2p but became PAX2n in multilayered epithelium undergoing ciliated or basal (Walthard cell nests or WCN) cell differentiation. PAX2n SCOUTs fell into two groups; Type I were secretory or secretory/ciliated with a “tubal” phenotype and were ALDH1n and β-cateninmem (membraneous only). Type II displayed a columnar to pseudostratified (endometrioid) phenotype, with an EZH2p, ALDH1p, β-cateninnc (nuclear and cytoplasmic), stathminp, LEF1p, RCN1p and RUNX2p expression signature. STINs and HGSCs shared the Type I immunophenotype of PAX2n, ALDH1n, β-cateninmem, but highly expressed EZH2p, LEF1p, RCN1p, and stathminp. This study, for the first time, links PAX2n 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 tumor 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.
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影响因子：
64.5
作者：
Kumar PA;Hu Y;Yamamoto Y;Hoe NB;Wei TS;Mu D;Sun Y;Joo LS;Dagher R;Zielonka EM;Wang de Y;Lim B;Chow VT;Crum CP;Xian W;McKeon F
通讯作者：
McKeon F
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
11.5
作者：
Marquez, RT;Baggerly, KA;Lu, KH
通讯作者：
Lu, KH
影响因子：
5.6
作者：
Laury, Anna R.;Ning, Gang;Crum, Christopher P.
通讯作者：
Crum, Christopher P.
影响因子：
4.7
作者：
Conner, James R.;Meserve, Emily;Feltmate, Colleen
通讯作者：
Feltmate, Colleen