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[Effects of 5-Aza-2'-deoxycitydine and trichostatin A on expression and apoptosis of ALDH1a2 gene in human bladder cancer cell lines]
Abstract
To study the effect on promoter de-methylation, expression of ALDH1a2 gene and cell apoptosis by treated with 5-Aza-dC and TSA in five human bladder cancer cell lines.
Human bladder cancer cell lines RT-4, 253J, 5637, BIU-87 and T24 were cultured and treated with 5-Aza-dC and(or) TSA. The expression of the ALDH1a2 gene was detected by RT-PCR and Western blot. The methylation status of gene promoter was determined by MSP, and the cell cycle profile was established by flow cytometry.
ALDH1a2 was silenced in five human bladder cancer cell lines. Re-expression of ALDH1a2 was detected after treated with 5-Aza-dC alone or TSA in combination. ALDH1a2 transcript was marked in each cell lines combined with 5-Aza-dC and TSA treatment which showed a synergistic effect on expression of ALDH1a2 transcript. Early apoptotic was the main mode of apoptosis and death of human bladder cancer cell lines induced by 5-Aza-dC and TSA. The percentage of early apoptotic cells was 1.4% in control group and 2.8% in TSA group, however, 20.2% in 5-Aza-dC group and 33.8% in 5-Aza-dC + TSA group, respectively. The groups of TSA, 5-Aza-dC and 5-Aza-dC + TSA were significantly different from control group (P < 0.05).
Aberrant methylation of ALDH1a2 gene is the main cause for gene transcriptional inactivation. Re-expression of ALDH1a2 gene and cell apoptosis are detected after either treatment with 5-Aza-dC alone or in combination with TSA.
... ALDH1A2 is identified to be a candidate TSG in prostate cancer whose expression is induced by DNA demethylation, which is reduced in prostate tumors compared with normal prostate, and negatively correlated with tumor-free survival (57). A further study indicate that ALDH1A2 is involved in apoptosis in bladder cancer cells (58), and has significant effects on cell proliferation and drug resistance in leukemia (59,60) and lung cancer cell lines (59). A more recent study indicate that high expression of ALDH1A2 is implicated in conveying tolerance to cisplatin in the three malignant pleural mesothelioma cell lines (61). ...
Ovarian cancer is the most lethal cancer of female reproductive system. There is a consistent and urgent need to better understand its mechanism. In this study, we retrieved 186 genes that were dysregulated by at least 4-fold in 594 ovarian serous cystadenocarcinomas in comparison with eight normal ovaries, according to The Cancer Genome Atlas Ovarian Statistics data deposited in Oncomine database. DAVID analysis of these genes enriched two biological processes indicating that the cell cycle and microtubules might play critical roles in ovarian cancer progression. Among these 186 genes, 46 were dysregulated by at least 10-fold and their expression was further confirmed by the Bonome Ovarian Statistics data deposited in Oncomine, which covered 185 cases of ovarian carcinomas and 10 cases of normal ovarian surface epithelium. Six genes, including aldehyde dehydrogenase 1 family, member A2 (ALDH1A2), alcohol dehydrogenase 1B (class I), β polypeptide (ADH1B), NEL-like 2 (chicken) (NELL2), hemoglobin, β (HBB), ATP-binding cassette, sub-family A (ABC1), member 8 (ABCA8) and hemoglobin, α1 (HBA1) were identified to be downregulated by at least 10-fold in 779 ovarian cancers compared with 18 normal controls. Using mRNA expression profiles retrieved from microarrays deposited in the Gene Expression Omnibus Profiles database, RT-qPCR measurement and bioinformatics analysis, we further indicated that high expression of HBB might predict a poorer 5-year survival, high expression of ALDH1A2 and ABCA8 might predict a poor outcome; while ALDH1A2, ADH1B, HBB and ABCA8, in particular the former two genes, might be associated with drug resistance, and ALDH1A2 and NELL2 might contribute to invasiveness and metastasis in ovarian cancer. This study thus contributes to our understanding of the mechanism of ovarian cancer progression and development, and the six identified genes may be potential therapeutic targets and biomarkers for diagnosis and prognosis.
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