Trophoblast subtype-specific EGFR/ERBB4 expression correlates with cell cycle progression and hyperplasia in complete hydatidiform moles
Trophoblast subtype-specific EGFR/ERBB4 expression correlates with cell cycle progression and hyperplasia in complete hydatidiform moles
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DOI：
10.1093/humrep/dev027
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发表时间：
2015-04-01
影响因子：
6.1
通讯作者：
Pollheimer, Juergen
中科院分区：
文献类型：
--
作者：
Fock, Valerie;Plessl, Kerstin;Pollheimer, Juergen
研究问题：滋养层细胞亚型在表达成红细胞白血病病毒癌基因同源物（ERBB）受体家族成员和对特异性生长因子配体的反应性方面是否存在差异？简要答复：我们的数据揭示了表皮生长因子受体（EGFR）/ERBB 4在增殖型滋养层和ERBB 2/ERBB 3在浸润型滋养层亚型中的相互表达模式，以及对表皮生长因子（EGF）和肝素结合（HB）-EGF的有限反应。EGFR由绒毛细胞滋养层细胞（vCTB）表达，但不存在于绒毛外滋养层细胞（EVT）中，其特异性地上调ERBB 2。研究设计、大小、持续时间：使用从选择性妊娠终止中获得的人早期妊娠胎盘（n = 50）和蜕膜（n = 5）的组织样品来研究滋养层亚型特异性ERBB受体表达和对重组人EGF和HB-EGF的反应性。方法：采用微阵列、实时定量PCR、免疫印迹以及胎盘和蜕膜组织切片的免疫荧光染色等方法，对12例完全性葡萄胎（CHM）胎盘组织中EGFR和ERBB 4在增殖活性区的表达进行分析。检测EGF和HB-EGF激活纯化的EGFR（+）和HLA-G（+）滋养层细胞中ERBB受体的潜力。进行5-乙炔基-2 '-脱氧尿苷掺入测定以研究两种配体对胎盘漂浮外植体中的原代滋养层以及vCTB和近端细胞柱滋养层（pCCT）的增殖能力的影响。最后，EGFR（+）vCTB和pCCT层的平均数在CHM胎盘和健康的年龄匹配controls.Main结果和机会的作用进行了比较：复发性vCTB和pCCT共表达EGFR和ERBB 4，但缺乏ERBB 2和ERBB 3。相反，HLA-G（+）滋养层细胞亚型表现出EGFR/ERBB 4和ERBB 2/ERBB 3（+）表型。EGF和HB-EGF激活EGFR（+）原代滋养细胞中的EGFR、ERBB 4、AKT和细胞外信号调节激酶1/2;然而，它们对HLA-G（+）EVT没有显示出作用。两种配体均强烈诱导原代滋养层细胞（P < 0.05）和胎盘绒毛相关vCTB（P < 0.05）和pCCT（P < 0.05）的细胞周期进程。值得注意的是，EGFR（+）vCTB（P < 0.0001）和pCCT（P < 0.0001）层显着扩大时，在CHM胎盘与健康controls.Limitations，原因为prostitution：细胞被从他们的生理环境中删除，因此可能会对各种刺激不同的反应。在这项研究中，我们将EGFR定义为人类胎盘内增殖滋养层亚型的标志物。因此，EGFR信号的操纵可能为滋养层增生相关的葡萄胎妊娠的治疗提供一个有前途的治疗途径。
STUDY QUESTION: Do trophoblast subtypes differ in their expression of erythroblastic leukaemia viral oncogene homologue (ERBB) receptor family members and responsiveness towards specific growth factor ligands?SUMMARY ANSWER: Our data reveal a reciprocal expression pattern of epidermal growth factor receptor (EGFR)/ERBB4 in proliferative and ERBB2/ERBB3 in invasive trophoblast subtypes, as well as a restricted responsiveness to epidermal growth factor (EGF) and heparin-binding (HB)-EGF.WHAT IS KNOWN ALREADY: EGFR is expressed by villous cytotrophoblasts (vCTBs), but absent from extravillous trophoblasts (EVTs), which specifically up-regulate ERBB2.STUDY DESIGN, SIZE, DURATION: Tissue samples of human first trimester placentae (n = 50) and deciduae (n = 5) obtained from elective pregnancy terminations were used to study trophoblast subtype-specific ERBB receptor expression and responsiveness to recombinant human EGF and HB-EGF. Age-matched complete hydatidiform mole (CHM) placentae (n = 12) were assessed for EGFR and ERBB4 expression in proliferation-competent regions.PARTICIPANTS/MATERIALS, SETTING, METHODS: ERBB receptor expression was analysed in primary trophoblast cell isolates by means of microarray, quantitative real-time PCR and western blotting, as well as immunofluorescence stainings of placental and decidual tissue sections. EGF and HB-EGF were tested for their potential to activate ERBB receptors in purified EGFR(+) and HLA-G(+) trophoblasts. 5-Ethynyl-2'-deoxyuridine incorporation assays were performed to study the effect of both ligands on the proliferative capacity of primary trophoblasts as well as of vCTBs and proximal cell column trophoblasts (pCCTs) in placental floating explants. Finally, the average number of EGFR(+) vCTB and pCCT layers was determined in CHM placentae and compared with healthy age-matched controls.MAIN RESULTS AND THE ROLE OF CHANCE: Proliferative vCTBs and pCCTs co-express EGFR and ERBB4, but are devoid of ERBB2 and ERBB3. In contrast, HLA-G(+) trophoblast subtypes exhibit an EGFR/ERBB4 and ERBB2/ERBB3(+) phenotype. EGF and HB-EGF activate EGFR, ERBB4, AKT and extracellular signal-regulated kinase 1/2 in EGFR(+) primary trophoblasts; however, they do not show an effect on HLA-G(+) EVTs. Both ligands strongly induce cell cycle progression in primary trophoblasts (P < 0.05) and placental explant-associated vCTBs (P < 0.05) and pCCTs (P < 0.05). Notably, EGFR(+) vCTB (P < 0.0001) and pCCT (P < 0.0001) layers are significantly expanded in CHM placentae when compared with healthy controls.LIMITATIONS, REASONS FOR CAUTION: Cells were removed from their physiological context and may therefore respond differently to various stimuli.WIDER IMPLICATIONS OF THE FINDINGS: In this study we define EGFR as a marker for proliferative trophoblast subtypes within the human placenta. Manipulation of EGFR signalling might thus offer a promising therapeutic avenue for the treatment of molar pregnancies associated with trophoblast hyperplasia.