Abstract
The galectins are a family of lectins, beta-galactoside sugar chain binding proteins, that have been identified as mediator of cell adhesion, cell growth regulators, and as triggers or inhibitors of apoptosis. Their expression pattern is deregulated during inflammation and in breast, colon, prostate, and thyroid cancers and their overexpression correlates to metastatic potential. Galectin-1 is a pleiotropic dimeric protein participating in cancer progression. The gene encoding galectin-1 is located in an 11-kb region on chromosome 22q13.1. Induction of apoptosis in activated T lymphocytes is a well-known function of this galectin. The association of accumulation of galectin-1 in the stroma of malignant tissue and aggressiveness of the tumor suggested a role for this lectin in the acquisition of the invasive phenotype and may act as an immunological shield by inducing activated T-cell apoptosis. To be susceptible to galectin-1 induced apoptosis, the T cell must express specific glycoprotein receptors, such as CD7, that bear the specific oligosaccharides recognized by galectin-1. The sensitivity to galectin-1 is associated with repression of the endogenous galectin-1 gene whereas non-sensitive cells express high levels of galectin-1. The current analysis has been performed in myeloid cells negative or positive for BCR-ABL, a chimeric gene derived by the t(9;22), that is present in chronic myeloid leukemia patients. The BCR-ABL gene, the expression of which was governed by the tetracycline inducible promoter, has been introduced by transfection in a myeloid cell line. Total RNA for microarray analysis, in presence or absence of BCR-ABL gene expression, has been isolated. The comparison involved ~5300 transcripts. A comprehensive galectin fingerprinting in these cells by microarray gene expression analysis to define the pattern in BCR-ABL positive and negative cells has been done. The results showed in the table clearly demonstrated that myeloid cells express more mRNA species for galectin-1 than for galectin-9 while none of the other lectins belonging to this family are expressed in either BCR-ABL positive or negative cells. A significant statistical difference has been found between the levels of expression of galectin-1 compared to galectin-9. A higher significant statistical difference has been found in the levels of galectin-1 overexpression in BCR-ABL positive cells. To better understand the preliminary data, a time course after the addition of tetracycline to the 32Dtetp210Bcr-Abl cells has been carried out. This last experiment demonstrated that galectin expression levels decrease over 18 hours and the expression of galectin-9 is already absent after 6 hours from the addition of tetracycline to the culture medium while the expression of galectin-1 is still present after 12 hours but at a level comparable to normal cells. These results might suggest a role for the modulation of galectin-1 activity as a new strategy for molecular treatment of BCR-ABL positive leukemia.
Galectins gene expression profile in myeloid cells BCR-ABL negative BCR-ABL positive raw t-test p-value flags raw t-test p-value flags Gal9 776 0,238 P 520,2 0,347 P Gal7 15,8 0,874 A 13,2 0,849 A Gal6 39,6 0,928 A 61,9 0,962 A Gal8 71,2 1 A 51,2 0,937 A Gal3 6 0,853 A 4,6 0,83 A Gal1 5.652,80 0,0315 P 12.087,30 0,0142 P
Identification of Chemical Modulators of the Constitutive Activated Receptor (CAR) in a Gene Expression Compendium
