Overexpression of Cdx1 and Cdx2 homeogenes enhances expression of the HLA-I in HT-29 cells.
We have previously reported that down-regulation of Cdx1 and Cdx2 mRNA expression is associated with colon carcinogenesis, and that coordinated reexpression of these genes in the HT29 colon cancer-derived cell line leads to a reduced malignant phenotype. Here we show that restoring Cdx1 and Cdx2 expression in HT29 cells enhanced the antigen presentation system, as reflected by a strong induction of the concentration of HLA-I molecules at the cell surface, resulting from increased expression of the HLA-I mRNA. Expression of the LMP2 proteasomal protein was also strongly induced by Cdx1 and Cdx2 at the transcriptional level, whereas TAP1 expression which is under the control of the same bidirectional promoter as LMP2 remained unchanged. Furthermore, expression of the adhesion molecule ICAM-1, which works in concert with HLA-I, and of the cell death promoter Fas was also increased upon Cdx1 and Cdx2 expression. Taken together, these results suggest that loss of Cdx1 and Cdx2 expression during colorectal carcinogenesis could favor the escape of tumor cells from the immune system. In conclusion, restoration of Cdx1 and Cdx2 expression should be considered in immunotherapeutic strategies for colorectal cancer.
Soubeyran
P
P
Laboratoire de Recherche de Physiologie et Pathologie Digestives, INSERM U.315, 46 Boulevard de la Gaye, Marseille, 13009, France.
Mallo
G V
GV
Moucadel
V
V
Dagorn
J C
JC
Iovanna
J L
JL
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D030161:Avian Proteins; D018968:CD58 Antigens / Q000235:genetics / Q000378:metabolism; D000071616:CDX2 Transcription Factor; D003110:Colonic Neoplasms / Q000235:genetics*; D003546:Cysteine Endopeptidases; D053222:Fas Ligand Protein; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005801:Genes, Homeobox / Q000235:genetics*; D005805:Genes, MHC Class I; D019073:HT29 Cells; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007111:Immunity, Cellular; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D030161:Avian Proteins; D018968:CD58 Antigens; C491273:CDX1 protein, human; D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D015395:Histocompatibility Antigens Class I; D018398:Homeodomain Proteins; D008562:Membrane Glycoproteins; D011506:Proteins; C073119:TAP1 protein, human; D015534:Trans-Activators; D018799:Intercellular Adhesion Molecule-1; C071313:LMP-2 protein; D007371:Interferon-gamma; D003546:Cysteine Endopeptidases