| Autor: |
Chou JL; Department of Life Science, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan, ROC., Su HY, Chen LY, Liao YP, Hartman-Frey C, Lai YH, Yang HW, Deatherage DE, Kuo CT, Huang YW, Yan PS, Hsiao SH, Tai CK, Lin HJ, Davuluri RV, Chao TK, Nephew KP, Huang TH, Lai HC, Chan MW |
| Jazyk: |
angličtina |
| Zdroj: |
Laboratory investigation; a journal of technical methods and pathology [Lab Invest] 2010 Mar; Vol. 90 (3), pp. 414-25. Date of Electronic Publication: 2010 Jan 11. |
| DOI: |
10.1038/labinvest.2009.138 |
| Abstrakt: |
Resistance to TGF-beta is frequently observed in ovarian cancer, and disrupted TGF-beta/SMAD4 signaling results in the aberrant expression of downstream target genes in the disease. Our previous study showed that ADAM19, a SMAD4 target gene, is downregulated through epigenetic mechanisms in ovarian cancer with aberrant TGF-beta/SMAD4 signaling. In this study, we investigated the mechanism of downregulation of FBXO32, another SMAD4 target gene, and the clinical significance of the loss of FBXO32 expression in ovarian cancer. Expression of FBXO32 was observed in the normal ovarian surface epithelium, but not in ovarian cancer cell lines. FBXO32 methylation was observed in ovarian cancer cell lines displaying constitutive TGF-beta/SMAD4 signaling, and epigenetic drug treatment restored FBXO32 expression in ovarian cancer cell lines regardless of FBXO32 methylation status, suggesting that epigenetic regulation of this gene in ovarian cancer may be a common event. In advanced-stage ovarian tumors, a significant (29.3%; P<0.05) methylation frequency of FBXO32 was observed and the association between FBXO32 methylation and shorter progression-free survival was significant, as determined by both Kaplan-Meier analysis (P<0.05) and multivariate Cox regression analysis (hazard ratio: 1.003, P<0.05). Reexpression of FBXO32 markedly reduced proliferation of a platinum-resistant ovarian cancer cell line both in vitro and in vivo, due to increased apoptosis of the cells, and resensitized ovarian cancer cells to cisplatin. In conclusion, the novel tumor suppressor FBXO32 is epigenetically silenced in ovarian cancer cell lines with disrupted TGF-beta/SMAD4 signaling, and FBXO32 methylation status predicts survival in patients with ovarian cancer. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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