title: PHLDA1 expression marks the putative epithelial stem cells and contributes to intestinal tumorigenesis.
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.
authors.affiliation: Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: Anuratha
authors.initials: A
authors.lastname: Sakthianandeswaren
authors.forename: Michael
authors.initials: M
authors.lastname: Christie
authors.forename: Carla
authors.initials: C
authors.lastname: D'Andreti
authors.forename: Cary
authors.initials: C
authors.lastname: Tsui
authors.forename: Robert N
authors.initials: RN
authors.lastname: Jorissen
authors.forename: Shan
authors.initials: S
authors.lastname: Li
authors.forename: Nicholas I
authors.initials: NI
authors.lastname: Fleming
authors.forename: Peter
authors.initials: P
authors.lastname: Gibbs
authors.forename: Lara
authors.initials: L
authors.lastname: Lipton
authors.forename: Jordane
authors.initials: J
authors.lastname: Malaterre
authors.forename: Robert G
authors.initials: RG
authors.lastname: Ramsay
authors.forename: Toby J
authors.initials: TJ
authors.lastname: Phesse
authors.forename: Matthias
authors.initials: M
authors.lastname: Ernst
authors.forename: Rosemary E
authors.initials: RE
authors.lastname: Jeffery
authors.forename: Richard
authors.initials: R
authors.lastname: Poulsom
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Leedham
authors.forename: Stefania
authors.initials: S
authors.lastname: Segditsas
authors.forename: Ian P M
authors.initials: IP
authors.lastname: Tomlinson
authors.forename: Oliver K
authors.initials: OK
authors.lastname: Bernhard
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Simpson
authors.forename: Francesca
authors.initials: F
authors.lastname: Walker
authors.forename: Maree C
authors.initials: MC
authors.lastname: Faux
authors.forename: Nicole
authors.initials: N
authors.lastname: Church
authors.forename: Bruno
authors.initials: B
authors.lastname: Catimel
authors.forename: Dustin J
authors.initials: DJ
authors.lastname: Flanagan
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Vincan
authors.forename: Oliver M
authors.initials: OM
authors.lastname: Sieber
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D003110:Colonic Neoplasms / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology*; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D039421:Integrin alpha2 / Q000378:metabolism; D039503:Integrin alpha6 / Q000096:biosynthesis; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D039421:Integrin alpha2; D039503:Integrin alpha6; C491923:PHLDA1 protein, human; D014157:Transcription Factors