HOXA5 Counteracts Stem Cell Traits by Inhibiting Wnt Signaling in Colorectal Cancer
Open accessAbstract
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.
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De-differentiation is exemplified by colon carcinogenesis due to loss of HOXA5 and SMAD4, melanomagenesis due to loss of MITF, and pancreatic neuroendocrine tumors due to loss of a differentiation-inducing miRNA in beta cells.
“De-differentiation is exemplified by colon carcinogenesis (due to the loss of the differentiation-inducing transcription factor HOXA5 and SMAD4), 141,142 melanomagenesis (due to the loss of the transcription factor MITF), 143 or pancreatic neuroendocrine tumors (due to the loss of a differentiation-inducing miRNA in b cells).144”
From Meta-hallmarks of aging and cancer (2023) · cites this paper as [142]
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- Authors
- Ordóñez-Morán, P., Dafflon, C., Imajo, M., Nishida, E., & Huelsken, J.
- Affiliations
- École Polytechnique Fédérale de Lausanne (CH)
- Kyoto University (JP)
- Corresponding author
- Huelsken, Joerg
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2015-12
- Volume
- 28
- Issue
- 6
- Pages
- 815-829
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2189633061
- Cited by
- 209
- References
- 73
- Citations by year
- 2026: 6 · 2025: 14 · 2024: 12 · 2023: 20 · 2022: 18 · 2021: 31 · 2020: 27 · 2019: 25 · 2018: 21 · 2017: 23 · 2016: 11 · 2015: 1
- FWCI
- 8.10
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Repository@Nottingham (University of Nottingham) (submittedVersion)
- Funders
- Japan Society for the Promotion of Science (25870363)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- HOXA5, Wnt signaling, colorectal cancer, cancer stem cells, intestinal stem cells, stemness, cell differentiation, retinoids, tumor regression, metastasis, tumor progression
- MeSH terms
- Aged, Aged, 80 and over, Animals, Antineoplastic Agents, Cell Differentiation, Cell Transformation, Neoplastic, Female, Humans, Intestinal Mucosa, Male, Mice, Inbred C57BL, Mice, Transgenic, Middle Aged, Neoplasm Metastasis, Phenotype, Phosphoproteins, Retinoids, Time Factors, Transcription Factors, Transfection, Tumor Cells, Cultured, Neoplastic Stem Cells, Colorectal Neoplasms, Gene Expression Regulation, Neoplastic, Homeodomain Proteins, Caco-2 Cells, HT29 Cells, Feedback, Physiological, RNA Interference, HCT116 Cells, Tissue Culture Techniques, Cell Proliferation, Wnt Signaling Pathway
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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