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 1

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ASJC Scopus subject areas

  • Cancer Research

Cite this

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, 32(11), 1597-1606. https://doi.org/10.1093/carcin/bgr183