{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,5]],"date-time":"2026-07-05T10:37:03Z","timestamp":1783247823602,"version":"3.54.6"},"reference-count":42,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,6,18]],"date-time":"2022-06-18T00:00:00Z","timestamp":1655510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Lisa Dean Moseley Foundation","award":["#2019-1"],"award-info":[{"award-number":["#2019-1"]}]},{"name":"The Lisa Dean Moseley Foundation","award":["#2018-2"],"award-info":[{"award-number":["#2018-2"]}]},{"name":"Cancer B*Ware Foundation","award":["#2019-1"],"award-info":[{"award-number":["#2019-1"]}]},{"name":"Cancer B*Ware Foundation","award":["#2018-2"],"award-info":[{"award-number":["#2018-2"]}]},{"name":"Cawley Center for Translational Cancer Research Fund","award":["#2019-1"],"award-info":[{"award-number":["#2019-1"]}]},{"name":"Cawley Center for Translational Cancer Research Fund","award":["#2018-2"],"award-info":[{"award-number":["#2018-2"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>HOX proteins are transcription factors that regulate stem cell (SC) function, but their role in the SC origin of cancer is under-studied. Aberrant expression of HOX genes occurs in many cancer types. Our goal is to ascertain how retinoic acid (RA) signaling and the regulation of HOXA9 expression might play a role in the SC origin of human colorectal cancer (CRC). Previously, we reported that aldehyde dehydrogenase (ALDH) and other RA pathway components are co-expressed in colonic cancer SCs (CSCs) and that overpopulation of ALDH-positive CSCs occurs during colon tumorigenesis. Our hypothesis is RA signaling regulates HOXA9 expression, and dysregulated RA signaling results in HOXA9 overexpression, which contributes to CSC overpopulation in CRC. Immunostaining showed that HOXA9 was selectively expressed in ALDH-positive SCs, and HOXA9 expression was increased in CRCs compared to normal epithelium. Modulating RA signaling in CRC cells (HT29 and SW480) with ATRA and DEAB decreased cell proliferation and reduced HOXA9 expression. Bioinformatics analyses identified a network of proteins that functionally interact with HOXA9, and the genes that encode these proteins, as well as HOXA9, contain RA receptor binding sites. These findings indicate that the expression of HOXA9 and its functional network is regulated by RA signaling in normal colonic SCs, and, when dysregulated, HOXA9 may contribute to CSC overpopulation that drives CRC development and growth. Our study provides a regulatory mechanism that might be useful in developing treatments against CSC overpopulation in CRC.<\/jats:p>","DOI":"10.3390\/ijms23126799","type":"journal-article","created":{"date-parts":[[2022,6,18]],"date-time":"2022-06-18T09:51:11Z","timestamp":1655545871000},"page":"6799","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["HOXA9 Overexpression Contributes to Stem Cell Overpopulation That Drives Development and Growth of Colorectal Cancer"],"prefix":"10.3390","volume":"23","author":[{"given":"Brian","family":"Osmond","sequence":"first","affiliation":[{"name":"Cawley Center for Translational Cancer Research, Helen F. Graham Cancer Center & Research Institute, Newark, DE 19713, USA"},{"name":"Department of Biological Sciences, University of Delaware, Newark, DE 19713, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline O. B.","family":"Facey","sequence":"additional","affiliation":[{"name":"Cawley Center for Translational Cancer Research, Helen F. Graham Cancer Center & Research Institute, Newark, DE 19713, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Cawley Center for Translational Cancer Research, Helen F. Graham Cancer Center & Research Institute, Newark, DE 19713, USA"},{"name":"Department of Biological Sciences, University of Delaware, Newark, DE 19713, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce M.","family":"Boman","sequence":"additional","affiliation":[{"name":"Cawley Center for Translational Cancer Research, Helen F. Graham Cancer Center & Research Institute, Newark, DE 19713, USA"},{"name":"Department of Biological Sciences, University of Delaware, Newark, DE 19713, USA"},{"name":"Department of Pharmacology & Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.24966\/SRDT-2060\/100045","article-title":"HOX Genes and Cancer Stem Cells: Update on HOX Expression, DNA Methylation, Biomarker Status, and Genetic Changes in Colorectal Cancer","volume":"6","author":"Osmond","year":"2020","journal-title":"J. Stem Cells Res. Dev. Ther."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Smith, J., Zyoud, A., and Allegrucci, C. (2019). A Case of Identity: HOX Genes in Normal and Cancer Stem Cells. 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