title: 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.
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.
authors: 1 Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, University of Delaware , Newark, Delaware.
authors: Seema
authors: S
authors: Bhatlekar
authors: Sankar
authors: S
authors: Addya
authors: Moreh
authors: M
authors: Salunek
authors: Christopher R
authors: CR
authors: Orr
authors: Saul
authors: S
authors: Surrey
authors: Steven
authors: S
authors: McKenzie
authors: Jeremy Z
authors: JZ
authors: Fields
authors: Bruce M
authors: BM
authors: Boman
mesh_terms: D002471:Cell Transformation, Neoplastic / Q000235:genetics; D003106:Colon / Q000166:cytology / Q000473:pathology*; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010088:Oxidoreductases / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D013234:Stem Cells / Q000166:cytology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; C073547:HOXA4 protein, human; C072064:HOXD10 protein, human; D010088:Oxidoreductases; C467741:STEAP2 protein, human
references: J Biol Chem. 2002 Sep 27;277(39):36689-96
references: 12095985
references: Cancer Res. 2008 Sep 15;68(18):7579-86
references: 18794146
references: Int J Mol Med. 2005 Oct;16(4):581-7
references: 16142390
references: Development. 1997 Nov;124(22):4505-14
references: 9409668
references: Eur J Cancer. 1993;29A(6):887-93
references: 8097920
references: Nature. 2007 Jan 4;445(7123):106-10
references: 17122772
references: Am J Pathol. 2004 Nov;165(5):1489-98
references: 15509520
references: Gastroenterology. 1999 Dec;117(6):1339-51
references: 10579975
references: Annu Rev Pathol. 2009;4:127-50
references: 18767981
references: Stem Cells. 1997;15(2):82-93
references: 9090784
references: Cancer Res. 1982 Oct;42(10):4280-3
references: 7105022
references: Cancer Res. 2010 Jul 15;70(14):5818-28
references: 20587517
references: Cancer Res. 2008 May 1;68(9):3304-13
references: 18451157
references: Development. 2008 Jan;135(1):171-82
references: 18065432
references: Dev Dyn. 2000 Jan;217(1):62-74
references: 10679930
references: Nature. 2007 Jan 4;445(7123):111-5
references: 17122771
references: J Clin Invest. 1963 Dec;42:1922-8
references: 14086779
references: Nat Rev Cancer. 2010 May;10(5):361-71
references: 20357775
references: Clin Pharmacol Ther. 2007 Jun;81(6):893-8
references: 17460605
references: Nucleic Acids Res. 2002 Feb 15;30(4):e15
references: 11842121
references: Ann Oncol. 2004;15 Suppl 4:iv233-9
references: 15477314
references: Biochem Biophys Res Commun. 2000 Jun 7;272(2):513-8
references: 10833444
references: Gut. 1992 Apr;33(4):524-9
references: 1316306
references: J Clin Oncol. 2008 Jun 10;26(17):2828-38
references: 18539961
references: N Engl J Med. 2009 Dec 17;361(25):2449-60
references: 20018966
references: Gastroenterology. 2010 Dec;139(6):2072-2082.e5
references: 20826154
references: Cancer Res. 2001 Dec 1;61(23):8408-11
references: 11731419
references: Oncotarget. 2011 Mar;2(3):197-208
references: 21411865
references: Cancer Res. 2009 Apr 15;69(8):3382-9
references: 19336570
references: In Vitro Cell Dev Biol Anim. 1997 Jan;33(1):18-27
references: 9028830