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Hypermethylation of the TGF-β target, ABCA1 is associated with poor prognosis in ovarian cancer patients.

Chou JL, Huang RL, Shay J, Chen LY, Lin SJ, Yan PS, Chao WT, Lai YH, Lai YL, Chao TK, Lee CI, Tai CK, Wu SF, Nephew KP, Huang TH, Lai HC, Chan MW - Clin Epigenetics (2015)

Bottom Line: The reduced expression of ABCA1 in A2780 and CP70 cells was associated with promoter hypermethylation, as demonstrated by bisulfite pyro-sequencing.Kaplan-Meier analysis also found that patients with higher levels of methylation of ABCA1 have shorter overall survival (P = 0.019).Hypermethylation of ABCA1 is associated with poor prognosis in these patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Science, National Chung Cheng University, 168 University Road, Min-Hsiung, Chia-Yi 621, Taiwan ; Institute of Molecular Biology, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan ; Division of Gastroenterology, Chang Gung Memorial Hospital, Chia-Yi, Taiwan.

ABSTRACT

Background: The dysregulation of transforming growth factor-β (TGF-β) signaling plays a crucial role in ovarian carcinogenesis and in maintaining cancer stem cell properties. Classified as a member of the ATP-binding cassette (ABC) family, ABCA1 was previously identified by methylated DNA immunoprecipitation microarray (mDIP-Chip) to be methylated in ovarian cancer cell lines, A2780 and CP70. By microarray, it was also found to be upregulated in immortalized ovarian surface epithelial (IOSE) cells following TGF-β treatment. Thus, we hypothesized that ABCA1 may be involved in ovarian cancer and its initiation.

Results: We first compared the expression level of ABCA1 in IOSE cells and a panel of ovarian cancer cell lines and found that ABCA1 was expressed in HeyC2, SKOV3, MCP3, and MCP2 ovarian cancer cell lines but downregulated in A2780 and CP70 ovarian cancer cell lines. The reduced expression of ABCA1 in A2780 and CP70 cells was associated with promoter hypermethylation, as demonstrated by bisulfite pyro-sequencing. We also found that knockdown of ABCA1 increased the cholesterol level and promoted cell growth in vitro and in vivo. Further analysis of ABCA1 methylation in 76 ovarian cancer patient samples demonstrated that patients with higher ABCA1 methylation are associated with high stage (P = 0.0131) and grade (P = 0.0137). Kaplan-Meier analysis also found that patients with higher levels of methylation of ABCA1 have shorter overall survival (P = 0.019). Furthermore, tissue microarray using 55 ovarian cancer patient samples revealed that patients with a lower level of ABCA1 expression are associated with shorter progress-free survival (P = 0.038).

Conclusions: ABCA1 may be a tumor suppressor and is hypermethylated in a subset of ovarian cancer patients. Hypermethylation of ABCA1 is associated with poor prognosis in these patients.

No MeSH data available.


Related in: MedlinePlus

Association between expression ofABCA1and survival in ovarian cancer patients. Expression of ABCA1 in 55 ovarian cancer patient samples was determined by IHC in tissue microarray. (A) Representative image of ovarian cancer showing high (left panel) and low (right panel) ABCA1 expression on the cell membrane or cytoplasm (×400). (B) Kaplan-Meier analysis found that patients with low ABCA1 expression have shorter progression-free survival than patients with high ABCA1 expression (P = 0.038). (C) Similar results can be observed in TCGA ovarian cancer RNA-Seq dataset that patients with low expression of ABCA1 are associated with shorter overall survival (P = 0.0008). Log-rank P values are shown.
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Fig5: Association between expression ofABCA1and survival in ovarian cancer patients. Expression of ABCA1 in 55 ovarian cancer patient samples was determined by IHC in tissue microarray. (A) Representative image of ovarian cancer showing high (left panel) and low (right panel) ABCA1 expression on the cell membrane or cytoplasm (×400). (B) Kaplan-Meier analysis found that patients with low ABCA1 expression have shorter progression-free survival than patients with high ABCA1 expression (P = 0.038). (C) Similar results can be observed in TCGA ovarian cancer RNA-Seq dataset that patients with low expression of ABCA1 are associated with shorter overall survival (P = 0.0008). Log-rank P values are shown.

Mentions: To further investigate the association between expression of ABCA1 and survival of ovarian cancer patients, we performed tissue microarray on a different cohort containing 55 ovarian patient samples (Table 4, Figure 5A). Although expression of ABCA1 is not associated with any clinicopathological parameters of the samples (Table 5), patients with low expression of ABCA1 are associated with shorter progression-free survival (Figure 5B). Similarly, analysis of TCGA ovarian cancer RNA-Seq dataset [14] also found that patients with lower expression of ABCA1 are associated with shorter overall survival (Figure 5C).Table 4


Hypermethylation of the TGF-β target, ABCA1 is associated with poor prognosis in ovarian cancer patients.

Chou JL, Huang RL, Shay J, Chen LY, Lin SJ, Yan PS, Chao WT, Lai YH, Lai YL, Chao TK, Lee CI, Tai CK, Wu SF, Nephew KP, Huang TH, Lai HC, Chan MW - Clin Epigenetics (2015)

Association between expression ofABCA1and survival in ovarian cancer patients. Expression of ABCA1 in 55 ovarian cancer patient samples was determined by IHC in tissue microarray. (A) Representative image of ovarian cancer showing high (left panel) and low (right panel) ABCA1 expression on the cell membrane or cytoplasm (×400). (B) Kaplan-Meier analysis found that patients with low ABCA1 expression have shorter progression-free survival than patients with high ABCA1 expression (P = 0.038). (C) Similar results can be observed in TCGA ovarian cancer RNA-Seq dataset that patients with low expression of ABCA1 are associated with shorter overall survival (P = 0.0008). Log-rank P values are shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4307187&req=5

Fig5: Association between expression ofABCA1and survival in ovarian cancer patients. Expression of ABCA1 in 55 ovarian cancer patient samples was determined by IHC in tissue microarray. (A) Representative image of ovarian cancer showing high (left panel) and low (right panel) ABCA1 expression on the cell membrane or cytoplasm (×400). (B) Kaplan-Meier analysis found that patients with low ABCA1 expression have shorter progression-free survival than patients with high ABCA1 expression (P = 0.038). (C) Similar results can be observed in TCGA ovarian cancer RNA-Seq dataset that patients with low expression of ABCA1 are associated with shorter overall survival (P = 0.0008). Log-rank P values are shown.
Mentions: To further investigate the association between expression of ABCA1 and survival of ovarian cancer patients, we performed tissue microarray on a different cohort containing 55 ovarian patient samples (Table 4, Figure 5A). Although expression of ABCA1 is not associated with any clinicopathological parameters of the samples (Table 5), patients with low expression of ABCA1 are associated with shorter progression-free survival (Figure 5B). Similarly, analysis of TCGA ovarian cancer RNA-Seq dataset [14] also found that patients with lower expression of ABCA1 are associated with shorter overall survival (Figure 5C).Table 4

Bottom Line: The reduced expression of ABCA1 in A2780 and CP70 cells was associated with promoter hypermethylation, as demonstrated by bisulfite pyro-sequencing.Kaplan-Meier analysis also found that patients with higher levels of methylation of ABCA1 have shorter overall survival (P = 0.019).Hypermethylation of ABCA1 is associated with poor prognosis in these patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Science, National Chung Cheng University, 168 University Road, Min-Hsiung, Chia-Yi 621, Taiwan ; Institute of Molecular Biology, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan ; Division of Gastroenterology, Chang Gung Memorial Hospital, Chia-Yi, Taiwan.

ABSTRACT

Background: The dysregulation of transforming growth factor-β (TGF-β) signaling plays a crucial role in ovarian carcinogenesis and in maintaining cancer stem cell properties. Classified as a member of the ATP-binding cassette (ABC) family, ABCA1 was previously identified by methylated DNA immunoprecipitation microarray (mDIP-Chip) to be methylated in ovarian cancer cell lines, A2780 and CP70. By microarray, it was also found to be upregulated in immortalized ovarian surface epithelial (IOSE) cells following TGF-β treatment. Thus, we hypothesized that ABCA1 may be involved in ovarian cancer and its initiation.

Results: We first compared the expression level of ABCA1 in IOSE cells and a panel of ovarian cancer cell lines and found that ABCA1 was expressed in HeyC2, SKOV3, MCP3, and MCP2 ovarian cancer cell lines but downregulated in A2780 and CP70 ovarian cancer cell lines. The reduced expression of ABCA1 in A2780 and CP70 cells was associated with promoter hypermethylation, as demonstrated by bisulfite pyro-sequencing. We also found that knockdown of ABCA1 increased the cholesterol level and promoted cell growth in vitro and in vivo. Further analysis of ABCA1 methylation in 76 ovarian cancer patient samples demonstrated that patients with higher ABCA1 methylation are associated with high stage (P = 0.0131) and grade (P = 0.0137). Kaplan-Meier analysis also found that patients with higher levels of methylation of ABCA1 have shorter overall survival (P = 0.019). Furthermore, tissue microarray using 55 ovarian cancer patient samples revealed that patients with a lower level of ABCA1 expression are associated with shorter progress-free survival (P = 0.038).

Conclusions: ABCA1 may be a tumor suppressor and is hypermethylated in a subset of ovarian cancer patients. Hypermethylation of ABCA1 is associated with poor prognosis in these patients.

No MeSH data available.


Related in: MedlinePlus