Loss of p57KIP2 expression confers resistance to contact inhibition in human androgenetic trophoblast stem cells
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 TSmole cells, are morphologically similar to biparental TS (TSbip) cells and express TS-specific markers such as GATA3, KRT7, and TFAP2C. Interestingly, TSmole cells have a growth advantage over TSbip cells 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 TSbip cells, but not in TSmole cells. Knockout and overexpression studies suggest that loss of p57KIP2 expression 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 of p57KIP2 is frequently observed in a variety of human tumors.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:116 |
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| Enthalten in: |
Proceedings of the National Academy of Sciences of the United States of America - 116(2019), 52 vom: 26. Dez., Seite 26606-26613 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Takahashi, Sota [VerfasserIn] |
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| Links: |
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| Themen: |
Choriocarcinoma |
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| Anmerkungen: |
Date Revised 05.12.2022 published: Print-Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1073/pnas.1916019116 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM303941537 |
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| 520 | |a 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 TSmole cells, are morphologically similar to biparental TS (TSbip) cells and express TS-specific markers such as GATA3, KRT7, and TFAP2C. Interestingly, TSmole cells have a growth advantage over TSbip cells 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 TSbip cells, but not in TSmole cells. Knockout and overexpression studies suggest that loss of p57KIP2 expression 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 of p57KIP2 is frequently observed in a variety of human tumors | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a choriocarcinoma | |
| 650 | 4 | |a complete hydatidiform mole | |
| 650 | 4 | |a genomic imprinting | |
| 650 | 4 | |a p57KIP2 | |
| 650 | 4 | |a trophoblast stem cells | |
| 700 | 1 | |a Okae, Hiroaki |e verfasserin |4 aut | |
| 700 | 1 | |a Kobayashi, Norio |e verfasserin |4 aut | |
| 700 | 1 | |a Kitamura, Akane |e verfasserin |4 aut | |
| 700 | 1 | |a Kumada, Kanako |e verfasserin |4 aut | |
| 700 | 1 | |a Yaegashi, Nobuo |e verfasserin |4 aut | |
| 700 | 1 | |a Arima, Takahiro |e verfasserin |4 aut | |
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