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Abstract 2236: Emergence of epigenetic regulation of tight junction genes in recurrent serous epithelial ovarian cancer

Publication ,  Conference
Huang, Z; Visco, Z; Sfakianos, G; Whitaker, R; Berchuck, A; Murphy, SK
Published in: Cancer Research
August 1, 2015

Purpose: Despite a complete clinical response following treatment with surgery and first-line chemotherapy, about 70-90% of advanced ovarian cancer (OC) patients experience cancer recurrence. Our objective was to identify potential new therapeutic targets to prevent recurrence by identifying changes in gene regulation that occur in recurrent versus matched primary tumors.Procedures: We used 16 primary-recurrent tumor pairs from patients with stage III/IV serous epithelial OC from the Duke Gynecologic Oncology Tissue Bank. Illumina Infinium HumanMethylation450 BeadChip was used to quantify DNA methylation and Affymetrix Human Genome U133A arrays were used to quantify gene expression. Methylation data were analyzed using Illumina's GenomeStudio software and Pearson's r values for correlation between gene expression (log2 RMA normalized) and methylation beta values were generated using Prism 6. Genes with significant correlation between expression and methylation (p<0.05) were entered into GATHER to identify pathways. Gene expression was further analyzed by tumor stage using an independent dataset. Expression of CLDNs in 28 OC cell lines following treatment by DNA methyltransferase inhibitor decitabine (DEC) was analyzed using Affymetrix U133A arrays and RT-PCR. RT-PCR and Western Blotting were performed for gene expression in siCLDN1 cells.Results: Methylation-expression relationships for 67 tight junction genes, including multiple CLDN family genes, emerged as significantly enriched in recurrent but not primary OCs (Bayes factor 7; p<0.0001). These Claudins were also upregulated following DEC treatment, supporting that DNA methylation regulates their expression. CLDNs expression correlated with tumor stage and most showed higher expression in tumors as compared to normal fallopian tube fimbriae and ovarian epithelia (p<0.05), while CLDN1 showed lower in tumor than in normal. Treatment with PIKfyve Inhibitor YM201636, which blocks continuous recycling of CLDN1/2 to cell membrane, prevented spheroid formation under stem cell culture conditions. Specifically, knockdown CLDN1 downregulates CD44 and CD133, and represses spheroid formation in OC cells. CLDN1 knockdown significantly reduces cell proliferation, migration and wound healing. In addition, CD44 and CLDN1 expression are inversely correlated in primary OC but positively correlated in recurrent OC (p<0.05), indicating a shift in regulatory mechanisms that may involve stem cells. Thus, CLDNs may be important for OC stem cell survival and function, which is postulated as an underlying cause of tumor recurrence.Conclusion: Our findings indicate that methylation-regulated expression of CLDNs are significantly associated with recurrent OC and suggest that changes in DNA methylation modulate emergence of these relationships. CLDNs regulation may play an important role in tumor recurrence and may offer new therapeutic opportunities.Citation Format: Zhiqing Huang, Zachery Visco, Gregory Sfakianos, Regina Whitaker,Andrew Berchuck, Susan K. Murphy. Emergence of epigenetic regulation of tight junction genes in recurrent serous epithelial ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2236. doi:10.1158/1538-7445.AM2015-2236

Duke Scholars

Published In

Cancer Research

DOI

EISSN

1538-7445

ISSN

0008-5472

Publication Date

August 1, 2015

Volume

75

Issue

15_Supplement

Start / End Page

2236 / 2236

Publisher

American Association for Cancer Research (AACR)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 3211 Oncology and carcinogenesis
  • 3101 Biochemistry and cell biology
  • 1112 Oncology and Carcinogenesis
 

Citation

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Huang, Z., Visco, Z., Sfakianos, G., Whitaker, R., Berchuck, A., & Murphy, S. K. (2015). Abstract 2236: Emergence of epigenetic regulation of tight junction genes in recurrent serous epithelial ovarian cancer. In Cancer Research (Vol. 75, pp. 2236–2236). American Association for Cancer Research (AACR). https://doi.org/10.1158/1538-7445.am2015-2236
Huang, Zhiqing, Zachery Visco, Gregory Sfakianos, Regina Whitaker, Andrew Berchuck, and Susan K. Murphy. “Abstract 2236: Emergence of epigenetic regulation of tight junction genes in recurrent serous epithelial ovarian cancer.” In Cancer Research, 75:2236–2236. American Association for Cancer Research (AACR), 2015. https://doi.org/10.1158/1538-7445.am2015-2236.
Huang Z, Visco Z, Sfakianos G, Whitaker R, Berchuck A, Murphy SK. Abstract 2236: Emergence of epigenetic regulation of tight junction genes in recurrent serous epithelial ovarian cancer. In: Cancer Research. American Association for Cancer Research (AACR); 2015. p. 2236–2236.
Huang, Zhiqing, et al. “Abstract 2236: Emergence of epigenetic regulation of tight junction genes in recurrent serous epithelial ovarian cancer.” Cancer Research, vol. 75, no. 15_Supplement, American Association for Cancer Research (AACR), 2015, pp. 2236–2236. Crossref, doi:10.1158/1538-7445.am2015-2236.
Huang Z, Visco Z, Sfakianos G, Whitaker R, Berchuck A, Murphy SK. Abstract 2236: Emergence of epigenetic regulation of tight junction genes in recurrent serous epithelial ovarian cancer. Cancer Research. American Association for Cancer Research (AACR); 2015. p. 2236–2236.

Published In

Cancer Research

DOI

EISSN

1538-7445

ISSN

0008-5472

Publication Date

August 1, 2015

Volume

75

Issue

15_Supplement

Start / End Page

2236 / 2236

Publisher

American Association for Cancer Research (AACR)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 3211 Oncology and carcinogenesis
  • 3101 Biochemistry and cell biology
  • 1112 Oncology and Carcinogenesis