Expression of retinoid-responsive genes occurs in colorectal carcinoma-derived cells irrespective of the presence of resistance to all-trans retinoic acid.
OBJECTIVE
Retinoids are metabolized in human intestinal epithelial cells to all-trans retinoic acid; however, it is unknown whether these cells express retinoid receptors, and whether sensitivity or resistance to the hormone is associated with a particular pattern of expression of retinoid-responsive genes.


METHODS
Northern blot analysis and reverse transcriptase polymerase chain reaction (RT-PCR) were used to identify mRNAs for retinoid receptors. Both Relative RT-PCR and transfection of retinoid-inducible plasmid were applied to test functionality of the pathway in a model system for colorectal carcinoma progression (primary SW480, all-trans retinoic acid-sensitive cells vs. metastatic SW620, -insensitive cells).


RESULTS
Three colorectal carcinoma-derived cell lines were inhibited by the hormone. Retinoic acid receptor type alpha (hRAR alpha) and retinoid X receptor type alpha (hRXR alpha) mRNAs were detected in normal enterocytes, colonocytes, and in all colorectal carcinoma-derived cells studied. Primary carcinomas and metastatic lesions expressed high amounts of hRAR alpha receptor protein, showing no simple correlation between the amounts of mRNA and receptor protein. No pattern of expression of the retinoid-responsive genes was associated with sensitivity or resistance to the retinoid. Expression of the genes occurred irrespective of resistance to the hormone or inactivity of the pathway.


CONCLUSIONS
Colonocytes possess a molecular system for transduction of the retinoid signal. All-trans retinoic acid modifies gene expression and inhibits proliferation of these cells. Therefore, retinoids are likely to be effective in chemoprevention of colorectal carcinoma.
Waliszewski
P
P
Department of Colorectal Surgery, Cleveland Clinic Foundation, Ohio, USA. waliszp@plpuam1l.amu.edu.pl
Waliszewska
M K
MK
Gupta
M
M
Milsom
J W
JW
Hurst
R E
RE
D000970:Antineoplastic Agents / Q000494:pharmacology*; D015152:Blotting, Northern; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015870:Gene Expression; D006801:Humans; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000235:genetics; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014212:Tretinoin