Loss of p57KIP2expression confers resistance to contact inhibition in human androgenetic trophoblast stem cells
Loss of p57KIP2expression confers resistance to contact inhibition in human androgenetic trophoblast stem cells
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p57KIP2表达缺失赋予人雄激素滋养层干细胞对接触抑制的抵抗力
DOI：
10.1073/pnas.1916019116
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发表时间：
2019
期刊：
影响因子：
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通讯作者：
Arima Takahiro
中科院分区：
文献类型：
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作者：
Takahashi Sota;Okae Hiroaki;Kobayashi Norio;Kitamura Akane;Kumada Kanako;Yaegashi Nobuo;Arima Takahiro
完全性葡萄胎（CHM）起源于雄激素，其特征是滋养层细胞增生增强和胎儿组织缺失。在15%至20%的病例中，CHM之后是恶性妊娠滋养细胞肿瘤，包括绒毛膜癌。异常的基因组印记可能是导致中草药滋养层细胞肥大的原因，但其详细机制仍不清楚，部分原因是缺乏合适的动物或体外模型。我们最近开发了一种人滋养层干细胞（TS）培养系统。在这项研究中，我们将这一系统应用于CHMs，以更好地了解其分子病理学。CHM衍生的TS细胞，称为TS分子细胞，在形态上类似于双亲TS（TSbip）细胞，并表达TS特异性标志物，如GATA 3、KRT 7和TFAP 2C。有趣的是，TSmolecules细胞只有在达到汇合后才具有比TSbipcells更大的生长优势。我们发现，p57 KIP 2，一个母源表达的基因编码的细胞周期蛋白依赖性激酶抑制剂，强烈诱导增加细胞密度在TSbip细胞，但不是在TSmolecules。敲除和过表达研究表明，p57 KIP 2表达的缺失可能是CHMs对接触抑制敏感性降低的主要原因。我们的研究结果揭示了CHMs发病机制的分子机制，并可能对CHMs以外的肿瘤发生产生广泛的影响，因为在各种人类肿瘤中经常观察到p57 KIP 2的沉默。
A complete hydatidiform mole (CHM) is androgenetic in origin and characterized by enhanced trophoblastic proliferation and the absence of fetal tissue. In 15 to 20% of cases, CHMs are followed by malignant gestational trophoblastic neoplasms including choriocarcinoma. Aberrant genomic imprinting may be responsible for trophoblast hypertrophy in CHMs, but the detailed mechanisms are still elusive, partly due to the lack of suitable animal or in vitro models. We recently developed a culture system of human trophoblast stem (TS) cells. In this study, we apply this system to CHMs for a better understanding of their molecular pathology. CHM-derived TS cells, designated as TSmolecells, are morphologically similar to biparental TS (TSbip) cells and express TS-specific markers such as GATA3, KRT7, and TFAP2C. Interestingly, TSmolecells have a growth advantage over TSbipcells only after they reach confluence. We found that p57KIP2, a maternally expressed gene encoding a cyclin-dependent kinase inhibitor, is strongly induced by increased cell density in TSbipcells, but not in TSmolecells. Knockout and overexpression studies suggest that loss of p57KIP2expression would be the major cause of the reduced sensitivity to contact inhibition in CHMs. Our findings shed light on the molecular mechanism underlying the pathogenesis of CHMs and could have broad implications in tumorigenesis beyond CHMs because silencing ofp57KIP2is frequently observed in a variety of human tumors.