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P038. SOCS3 promoter hypermethylation status in ulcerative colitis related colorectal cancer

Y. Li, C. de Haar, C.J. van der Woude, E.J. Kuipers

Erasmus Medical Center, Rotterdam, The Netherlands

Background: Ulcerative colitis (UC) is associated with an increased risk of developing colorectal cancer (CRC). We have previously shown that increased expression of IL-6 and p-STAT3 in epithelial cells from UC-CRC patients coincided with decreased levels or the absence of the negative regulator suppressor of cytokine signaling 3 (SOCS3).

Aim: Since hypermethylation of the SOCS3 promoter regions has been implicated in tumorigenesis in various cancers, we assessed whether methylation of the SOCS3 promoter was involved in the lack of SOCS3 expression in UC-CRC.

Materials and Methods: Methylation of the SOCS3 promoter region was examined on DNA isolated from the macro-dissected epithelial layer of colon biopsies from patients with inactive UC, active UC, and UC-CRC patients and from various colon cancer-derived epithelial cell lines. DNA was bisulfate-treated and analyzed using methylation-specific PCR and pyrosequencing. Methylation in cell lines was confirmed by studying the IL-6/p-STAT3 induced expression of SOCS3 after demethylation using 5-aza-2'-deoxycytidine (DAC).

Results: Various regions of the SOCS3 promoter, with binding elements for different transcription factors, were methylated in DNA from UC-CRC biospies. No signs of SOCS3 promoter methylation was dected in inactive-UC patients, whereas limited methylation was detected in some of the active UC patients. In all the CRC cell lines, the SOCS3 methylation status correlated with the disability to upregulate SOCS3 upon IL-6 stimulation. Treatment with DAC restored IL-6 induced SOCS3 expression in the cells.

Conclusion: Hypermethylation of the SOCS3 promoter region was detected in UC-CRC and in some of the CRC cell lines, explaining the lack of SOCS3 expression. Methylation of the SOCS3 enables uncontrolled IL-6/p-STAT3 signaling leading to enhanced proliferation and survival associated with carcinogenesis. As such, the restoration of SOCS3 may provide therapeutic target for UC-CRC.