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

doi:10.1093/carcin/bgr183

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

Carcinogenesis. 2011 Nov;32(11):1597-606. doi: 10.1093/carcin/bgr183. Epub 2011 Aug 8.

Authors

Takeshi Motohara¹, Sachiko Masuko, Takatsugu Ishimoto, Toshifumi Yae, Nobuyuki Onishi, Teruyuki Muraguchi, Atsushi Hirao, Yumi Matsuzaki, Hironori Tashiro, Hidetaka Katabuchi, Hideyuki Saya, Osamu Nagano

Affiliation

¹ Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.

PMID: 21828057
DOI: 10.1093/carcin/bgr183

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, Neoplasm / genetics
Antigens, Neoplasm / metabolism
Apoptosis
Blotting, Western
Cell Adhesion
Cell Adhesion Molecules / genetics
Cell Adhesion Molecules / metabolism
Cell Differentiation
Cell Movement
Cell Proliferation
Cell Transformation, Neoplastic / metabolism
Cell Transformation, Neoplastic / pathology*
Epithelial Cell Adhesion Molecule
Female
Flow Cytometry
Immunoenzyme Techniques
Mice
Mice, Inbred C57BL
Neoplastic Stem Cells / metabolism
Neoplastic Stem Cells / pathology*
Ovarian Neoplasms / genetics
Ovarian Neoplasms / metabolism
Ovarian Neoplasms / pathology*
Ovary / metabolism
Ovary / pathology*
Peritoneal Neoplasms / genetics
Peritoneal Neoplasms / metabolism
Peritoneal Neoplasms / secondary*
Proto-Oncogene Proteins c-myc / genetics
Proto-Oncogene Proteins c-myc / metabolism
Proto-Oncogene Proteins p21(ras) / genetics
Proto-Oncogene Proteins p21(ras) / metabolism
RNA, Messenger / genetics
RNA, Small Interfering / genetics
Reverse Transcriptase Polymerase Chain Reaction
Tumor Suppressor Protein p53 / antagonists & inhibitors
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism*

Substances

Antigens, Neoplasm
Cell Adhesion Molecules
Epithelial Cell Adhesion Molecule
Myc protein, mouse
Proto-Oncogene Proteins c-myc
RNA, Messenger
RNA, Small Interfering
Tumor Suppressor Protein p53
Hras protein, mouse
Proto-Oncogene Proteins p21(ras)