HOXA5 Counteracts Stem Cell Traits by Inhibiting Wnt Signaling in Colorectal Cancer

Paloma Ordóñez-Morán; Caroline Dafflon; Masamichi Imajo; Eisuke Nishida; Joerg Huelsken

doi:10.1016/j.ccell.2015.11.001

HOXA5 Counteracts Stem Cell Traits by Inhibiting Wnt Signaling in Colorectal Cancer

Cancer Cell. 2015 Dec 14;28(6):815-829. doi: 10.1016/j.ccell.2015.11.001.

Authors

Paloma Ordóñez-Morán¹, Caroline Dafflon¹, Masamichi Imajo², Eisuke Nishida³, Joerg Huelsken⁴

Affiliations

¹ École Polytechnique Fédérale de Lausanne (EPFL), ISREC (Swiss Institute for Experimental Cancer Research), Lausanne 1015, Switzerland.
² Laboratory of Bioimaging and Cell Signaling, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan; Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan; JST, CREST, Chiyoda-ku, Tokyo 102-0075, Japan.
³ Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan; JST, CREST, Chiyoda-ku, Tokyo 102-0075, Japan.
⁴ École Polytechnique Fédérale de Lausanne (EPFL), ISREC (Swiss Institute for Experimental Cancer Research), Lausanne 1015, Switzerland. Electronic address: joerg.huelsken@epfl.ch.

PMID: 26678341
DOI: 10.1016/j.ccell.2015.11.001

Abstract

Hierarchical organization of tissues relies on stem cells, which either self-renew or produce committed progenitors predestined for lineage differentiation. Here we identify HOXA5 as an important repressor of intestinal stem cell fate in vivo and identify a reciprocal feedback between HOXA5 and Wnt signaling. HOXA5 is suppressed by the Wnt pathway to maintain stemness and becomes active only outside the intestinal crypt where it inhibits Wnt signaling to enforce differentiation. In colon cancer, HOXA5 is downregulated, and its re-expression induces loss of the cancer stem cell phenotype, preventing tumor progression and metastasis. Tumor regression by HOXA5 induction can be triggered by retinoids, which represent tangible means to treat colon cancer by eliminating cancer stem cells.

Keywords: MYC; cancer stem cells; retinoids; β-catenin.

Publication types

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

MeSH terms

Aged
Aged, 80 and over
Animals
Antineoplastic Agents / pharmacology
Caco-2 Cells
Cell Differentiation
Cell Proliferation
Cell Transformation, Neoplastic / genetics
Cell Transformation, Neoplastic / metabolism
Cell Transformation, Neoplastic / pathology
Colorectal Neoplasms / drug therapy
Colorectal Neoplasms / genetics
Colorectal Neoplasms / metabolism*
Colorectal Neoplasms / pathology
Feedback, Physiological
Female
Gene Expression Regulation, Neoplastic
HCT116 Cells
HT29 Cells
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism*
Humans
Intestinal Mucosa / metabolism*
Intestinal Mucosa / pathology
Male
Mice, Inbred C57BL
Mice, Transgenic
Middle Aged
Neoplasm Metastasis
Neoplastic Stem Cells / drug effects
Neoplastic Stem Cells / metabolism*
Neoplastic Stem Cells / pathology
Phenotype
Phosphoproteins / genetics
Phosphoproteins / metabolism*
RNA Interference
Retinoids / pharmacology
Time Factors
Tissue Culture Techniques
Transcription Factors
Transfection
Tumor Cells, Cultured
Wnt Signaling Pathway* / drug effects

Substances

Antineoplastic Agents
HOXA5 protein, human
Homeodomain Proteins
Hoxa5 protein, mouse
Phosphoproteins
Retinoids
Transcription Factors

Associated data

GEO/GSE74862