The tumour suppressor SOX11 is associated with improved survival among high grade epithelial ovarian cancers and is regulated by reversible promoter methylation

Abstract

BackgroundThe neural transcription factor SOX11 has been described as a prognostic marker in epithelial ovarian cancers (EOC), however its role in individual histological subtypes and tumour grade requires further clarification. Furthermore, methylation-dependent silencing of SOX11 has been reported for B cell lymphomas and indicates that epigenetic drugs may be used to re-express this tumour suppressor, but information on SOX11 promoter methylation in EOC is still lacking.MethodsSOX11 expression and clinicopathological data was compared using χ2 test in a cohort of 154 cases of primary invasive EOC. Kaplan-Meier analysis and the log rank test were applied to evaluate ovarian cancer-specific survival (OCSS) and overall survival (OS) in strata, according to SOX11 expression. Also, the methylation status of the SOX11 promoter was determined by sodium bisulfite sequencing and methylation specific PCR (MSP). Furthermore, the effect of ectopic overexpression of SOX11 on proliferation was studied through [3H]-thymidine incorporation.ResultsSOX11 expression was associated with an improved survival of patients with high grade EOC, although not independent of stage. Further analyses of EOC cell lines showed that SOX11 mRNA and protein were expressed in two of five cell lines, correlating with promoter methylation status. Demethylation was successfully performed using 5'-Aza-2'deoxycytidine (5-Aza-dC) resulting in SOX11 mRNA and protein expression in a previously negative EOC cell line. Furthermore, overexpression of SOX11 in EOC cell lines confirmed the growth regulatory role of SOX11.ConclusionsSOX11 is a functionally associated protein in EOC with prognostic value for high-grade tumours. Re-expression of SOX11 in EOC indicates a potential use of epigenetic drugs to affect cellular growth in SOX11-negative tumours.

763 Expanded Clinical and Experimental Use of SOX11 – Using a Monoclonal Antibody

“…Finally, we have recently published data, demonstrating a growth regulatory role for SOX11 in in-vitro models of MCL [18] and EOC [8], which was further confirmed using xenotransplants in mice [19]. Together these data suggest a key growth regulatory role of SOX11 in these neoplasms and emphasize the need for functional antibodies for experimental use in various technologies, including imaging and flow cytometry applications.…”

“…Furthermore, in EOC, SOX11 has prognostic significance and identifies a subgroup of patients with improved recurrence-free survival [7] and may also identify an histological subtype of EOC [8]. Finally, we have recently published data, demonstrating a growth regulatory role for SOX11 in in-vitro models of MCL [18] and EOC [8], which was further confirmed using xenotransplants in mice [19].…”

“…The transcription factor SOX11 has recently been identified as a diagnostic, prognostic and/or functional antigen in a variety of cancers including mantle cell lymphoma (MCL) [1][2][3][4][5][6], epithelial ovarian cancer (EOC) [7,8] and gliomas [9]. This transcription factor is a member of the SOX protein family, which is characterized by a conserved high mobility DNA binding domain (HMG) [9].…”

Emerging role of SOX11 in mantle cell lymphoma

“…The neural transcription factor SOX11 has during recent years been shown to be aberrantly expressed in several types of cancers, such as medulloblastoma, 32 glioma, 33 MCL, 34 and epithelial ovarian cancer, 35,36 while corresponding non-malignant tissues lack expression.…”

“…However, many tumors methylate SOX11 de novo during their pathogenesis as reported in B-cell lymphomas (excluding MCL) 64 and subgroups of epithelial ovarian cancer. 36 Additionally, SOX11 methylation has been correlated to lymph node metastasis in nasopharyngeal carcinoma 67 and included in a five gene signature for detection of bladder cancer. 68 With the growing interest in using epigenetic therapies in hematological malignancies, investigations on genetic and epigenetic regulation of SOX11 are needed to understand its aberrant expression in disease.…”