Identification of a developmental gene expression signature, including HOX genes, for the normal human colonic crypt stem cell niche: overexpression of the signature parallels stem cell overpopulation during colon tumorigenesis.

Authors

Seema Bhatlekar, Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, University of Delaware
Sankar Addya, Kimmel Cancer Center, Department of Cancer Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PennsylvaniaFollow
Moreh Salunek, Kimmel Cancer Center, Thomas Jefferson University
Christopher R Orr, Kimmel Cancer Center, Thomas Jefferson UniversityFollow
Saul Surrey, Department of Medicine, Cardeza Foundation for Hematological Research, Thomas Jefferson University Jefferson Medical CollegeFollow
Steven E. McKenzie, Thomas Jefferson UniversityFollow
Jeremy Z Fields, CA TX Inc., Gladwyne, PA, United StatesFollow
Bruce M Boman, Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, University of Delaware; Kimmel Cancer Center, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

1-15-2014

Comments

This article has been peer reviewed. It was published in: Stems Cells and Development.

Volume 23, Issue 2, 2014, Pages 167-179.

The published version is available at DOI: 10.1089/scd.2013.0039

Copyright © © 2014, Mary Ann Liebert, Inc.

Abstract

Our goal was to identify a unique gene expression signature for human colonic stem cells (SCs). Accordingly, we determined the gene expression pattern for a known SC-enriched region--the crypt bottom. Colonic crypts and isolated crypt subsections (top, middle, and bottom) were purified from fresh, normal, human, surgical specimens. We then used an innovative strategy that used two-color microarrays (∼18,500 genes) to compare gene expression in the crypt bottom with expression in the other crypt subsections (middle or top). Array results were validated by PCR and immunostaining. About 25% of genes analyzed were expressed in crypts: 88 preferentially in the bottom, 68 in the middle, and 131 in the top. Among genes upregulated in the bottom, ∼30% were classified as growth and/or developmental genes including several in the PI3 kinase pathway, a six-transmembrane protein STAMP1, and two homeobox (HOXA4, HOXD10) genes. qPCR and immunostaining validated that HOXA4 and HOXD10 are selectively expressed in the normal crypt bottom and are overexpressed in colon carcinomas (CRCs). Immunostaining showed that HOXA4 and HOXD10 are co-expressed with the SC markers CD166 and ALDH1 in cells at the normal crypt bottom, and the number of these co-expressing cells is increased in CRCs. Thus, our findings show that these two HOX genes are selectively expressed in colonic SCs and that HOX overexpression in CRCs parallels the SC overpopulation that occurs during CRC development. Our study suggests that developmental genes play key roles in the maintenance of normal SCs and crypt renewal, and contribute to the SC overpopulation that drives colon tumorigenesis.

Recommended Citation

Bhatlekar, Seema; Addya, Sankar; Salunek, Moreh; Orr, Christopher R; Surrey, Saul; McKenzie, Steven E.; Fields, Jeremy Z; and Boman, Bruce M, "Identification of a developmental gene expression signature, including HOX genes, for the normal human colonic crypt stem cell niche: overexpression of the signature parallels stem cell overpopulation during colon tumorigenesis." (2014). Kimmel Cancer Center Faculty Papers. Paper 48.
https://jdc.jefferson.edu/kimmelccfp/48

PubMed ID

23980595