Transient depletion of p53 followed by transduction of c-Myc and K-Ras converts ovarian stem-like cells into tumor-initiating cells

Takeshi Motohara, Sachiko Masuko, Takatsugu Ishimoto, Toshifumi Yae, Nobuyuki Onishi, Teruyuki Muraguchi, Atsushi Hirao, Yumi Matsuzaki, Hironori Tashiro, Hidetaka Katabuchi, Hideyuki Saya, Osamu Nagano

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Abstract

Although the existence of tumor-initiating cells (T-ICs) in several types of human cancer has been documented, the contribution of somatic stem cells to the development of T-ICs has remained unclear. Here, we show that normal mouse ovary contains epithelial cell adhesion molecule (EpCAM)-expressing stem-like cells that possess the ability to differentiate into cytokeratin 8 (CK8)-expressing epithelial progeny cells. Furthermore, RNA interference-mediated transient depletion of the tumor suppressor p53 followed by retrovirus-mediated transfer of c-Myc and K-Ras oncogenes in EpCAM-expressing ovarian stem-like cells resulted in the generation of ovarian T-ICs. The established ovarian T-ICs gave rise to hierarchically organized lethal tumors in vivo and were able to undergo peritoneal metastasis. Finally, subsequent RNA interference-mediated knockdown of p53 in tumor cells triggered the expansion of EpCAM-expressing stem-like tumor cells and induced further tumor growth. These data reveal a role for p53 in the development and expansion of ovarian stem-like tumor cells and subsequent malignant progression.

Original languageEnglish
Pages (from-to)1597-1606
Number of pages10
JournalCarcinogenesis
Volume32
Issue number11
DOIs
Publication statusPublished - 2011 Nov

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Neoplastic Stem Cells
Stem Cells
Neoplasms
RNA Interference
Keratin-8
Adult Stem Cells
ras Genes
Retroviridae
Ovary
Epithelial Cells
Neoplasm Metastasis
Growth
Epithelial Cell Adhesion Molecule

ASJC Scopus subject areas

  • Cancer Research

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Transient depletion of p53 followed by transduction of c-Myc and K-Ras converts ovarian stem-like cells into tumor-initiating cells. / Motohara, Takeshi; Masuko, Sachiko; Ishimoto, Takatsugu; Yae, Toshifumi; Onishi, Nobuyuki; Muraguchi, Teruyuki; Hirao, Atsushi; Matsuzaki, Yumi; Tashiro, Hironori; Katabuchi, Hidetaka; Saya, Hideyuki; Nagano, Osamu.

In: Carcinogenesis, Vol. 32, No. 11, 11.2011, p. 1597-1606.

Research output: Contribution to journalArticle

Motohara, T, Masuko, S, Ishimoto, T, Yae, T, Onishi, N, Muraguchi, T, Hirao, A, Matsuzaki, Y, Tashiro, H, Katabuchi, H, Saya, H & Nagano, O 2011, 'Transient depletion of p53 followed by transduction of c-Myc and K-Ras converts ovarian stem-like cells into tumor-initiating cells', Carcinogenesis, vol. 32, no. 11, pp. 1597-1606. https://doi.org/10.1093/carcin/bgr183
Motohara, Takeshi ; Masuko, Sachiko ; Ishimoto, Takatsugu ; Yae, Toshifumi ; Onishi, Nobuyuki ; Muraguchi, Teruyuki ; Hirao, Atsushi ; Matsuzaki, Yumi ; Tashiro, Hironori ; Katabuchi, Hidetaka ; Saya, Hideyuki ; Nagano, Osamu. / Transient depletion of p53 followed by transduction of c-Myc and K-Ras converts ovarian stem-like cells into tumor-initiating cells. In: Carcinogenesis. 2011 ; Vol. 32, No. 11. pp. 1597-1606.
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