PHLDA1 expression marks the putative epithelial stem cells and contributes to intestinal tumorigenesis

Anuratha Sakthianandeswaren, Michael Christie, Carla D'Andreti, Cary Tsui, Robert Jorissen, Shan Li, Nicholas I. Fleming, Peter Gibbs, Lara Lipton, Jordane Malaterre, Robert G. Ramsay, Toby J. Phesse, Matthias Ernst, Rosemary E. Jeffery, Richard Poulsom, Simon J. Leedham, Stefania Segditsas, Ian P.M. Tomlinson, Oliver K. Bernhard, Richard J. SimpsonFrancesca Walker, Maree C. Faux, Nicole Church, Bruno Catimel, Dustin J. Flanagan, Elizabeth Vincan, Oliver M. Sieber

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

Studies employing mouse models have identified crypt base and position +4 cells as strong candidates for intestinal epithelial stem cells. Equivalent cell populations are thought to exist in the human intestine; however robust and specific protein markers are lacking. Here, we show that in the human small and large intestine, PHLDA1 is expressed in discrete crypt base and some position +4 cells. In small adenomas, PHLDA1 was expressed in a subset of undifferentiated and predominantly Ki-67-negative neoplastic cells, suggesting that a basic hierarchy of differentiation is retained in early tumorigenesis. In large adenomas, carcinomas, and metastases PHLDA1 expression became widespread, with increased expression and nuclear localization at invasive margins. siRNA-mediated suppression of PHLDA1 in colon cancer cells inhibited migration and anchorage-independent growth in vitro and tumor growth in vivo. The integrins ITGA2 and ITGA6 were downregulated in response to PHLDA1 suppression, and accordingly cell adhesion to laminin and collagen was significantly reduced. We conclude that PHLDA1 is a putative epithelial stem cell marker in the human small and large intestine and contributes to migration and proliferation in colon cancer cells.

Original languageEnglish
Pages (from-to)3709-3719
Number of pages11
JournalCancer Research
Volume71
Issue number10
DOIs
Publication statusPublished - 15 May 2011
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Sakthianandeswaren, A., Christie, M., D'Andreti, C., Tsui, C., Jorissen, R., Li, S., ... Sieber, O. M. (2011). PHLDA1 expression marks the putative epithelial stem cells and contributes to intestinal tumorigenesis. Cancer Research, 71(10), 3709-3719. https://doi.org/10.1158/0008-5472.CAN-10-2342