Promoter hypermethylation of FBXO32, a novel TGF-β/SMAD4 target gene and tumor suppressor, is associated with poor prognosis in human ovarian cancer

被引：102

作者：

Chou, Jian-Liang ^{[1
,2
]}

Su, Her-Young ^{[3
]}

Chen, Lin-Yu ^{[1
,2
]}

Liao, Yu-Ping ^{[4
]}

Hartman-Frey, Corinna ^{[5
]}

Lai, Yi-Hui ^{[1
,2
]}

Yang, Hui-Wen ^{[1
,2
]}

Deatherage, Daniel E. ^{[6
]}

Kuo, Chieh-Ti ^{[6
]}

Huang, Yi-Wen ^{[6
]}

Yan, Pearlly S. ^{[6
]}

Hsiao, Shu-Huei ^{[1
,7
]}

Tai, Chien-Kuo ^{[1
,2
]}

Lin, Huey-Jen L. ^{[6
,8
]}

Davuluri, Ramana V. ^{[9
]}

Chao, Tai-Kuang ^{[10
]}

Nephew, Kenneth P. ^{[5
]}

Huang, Tim H-M ^{[6
]}

Lai, Hung-Cheng ^{[3
,11
]}

Chan, Michael W-Y ^{[1
,7
]}

机构：

[1] Natl Chung Cheng Univ, Dept Life Sci, Chiayi 621, Taiwan

[2] Natl Chung Cheng Univ, Inst Mol Biol, Chiayi 621, Taiwan

[3] Natl Def Med Ctr, Grad Inst Med Sci, Taipei, Taiwan

[4] Natl Def Med Ctr, Grad Inst Life Sci, Taipei, Taiwan

[5] Indiana Univ, Sch Med, Dept Med Sci, Bloomington, IN USA

[6] Ohio State Univ, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet, Human Canc Genet Program, Columbus, OH 43210 USA

[7] Natl Chung Cheng Univ, Human Epigenom Ctr, Chiayi 621, Taiwan

[8] Ohio State Univ, Sch Allied Med Profess, Div Med Technol, Columbus, OH 43210 USA

[9] Wistar Inst Anat & Biol, Ctr Syst & Computat Biol, Mol & Cellular Oncogenesis Program, Philadelphia, PA 19104 USA

[10] Natl Def Med Ctr, Tri Serv Gen Hosp, Dept Pathol, Taipei, Taiwan

[11] Natl Def Med Ctr, Dept Obstet & Gynecol, Taipei, Taiwan

来源：

LABORATORY INVESTIGATION | 2010年 / 90卷 / 03期

关键词：

ovarian cancer; epigenetics; TGF-beta; FBXO32; PROGRESSION-FREE SURVIVAL; HISTONE METHYLTRANSFERASE; CELL-LINES; UBIQUITIN LIGASES; DNA METHYLATION; MUSCLE ATROPHY; EXPRESSION; CARCINOMA; COMPLEX; EPIGENETICS;

D O I：

10.1038/labinvest.2009.138

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

100103 [病原生物学]; 100218 [急诊医学];

摘要：

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.

引用

页码：414 / 425

页数：12

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