Abstract
Over 21,000 women are diagnosed with ovarian cancer (OC) in the United States each year and over half that number succumb to this disease annually, often due to recurrent disease. A deeper understanding of the molecular events associated with recurrent disease is needed to identify potential targets. Using genome-scale DNA methylation and gene expression data for 16 matched primary-recurrent advanced stage serous epithelial OCs, we discovered that Claudin-1 (CLDN1), a tight junction protein, shows a stronger correlation between expression and methylation in recurrent versus primary OC at multiple CpG sites (R= –0.47 to −0.64 versus R= -0.32 to −0.57, respectively). An independent dataset showed that this correlation is stronger in tumors from short-term (<3y) survivors than in tumors from long-term (>7y) survivors (R= −0.41 to −0.46 versus R= 0.06 to −0.19, respectively). The presence of this inverse correlation in short-term survivors and recurrent tumors suggests an important role for this relationship and potential predictive value for disease prognosis. CLDN1 expression increased following pharmacologic inhibition of DNA methyltransferase activity (p< 0.001), thus validating the role of methylation in CLDN1 gene inhibition. CLDN1 knockdown enhanced chemosensitivity and suppressed cell proliferation, migration, and wound healing (p< 0.05). Stable CLDN1 knockdown in vivo resulted in reduced xenograft tumor growth but did not reach significance. Our results indicate that the relationship between CLDN1 methylation and expression plays an important role in OC aggressiveness and recurrence.
Highlights
Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer deaths in women
Tight junctions have been previously implicated in epithelial cell derived cancers, but their role has not been clearly defined in OCs, despite the fact that epithelial fallopian tube cells may lead to high-grade serious OCs [16,17,18]
OC has a high mortality rate largely due to the fact that 75% of patients are diagnosed with advanced stage disease that has metastasized throughout the peritoneal cavity [44], and an understanding of the mechanisms of metastasis is critical
Summary
Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer deaths in women. The American Cancer Society estimates that 21,410 women in the United States will be diagnosed with ovarian cancer (OC) and 13,770 women will die of the disease in the year 2021. The high mortality rate in OC is largely due to late-stage diagnoses as a result of non-specific early symptoms [1]. Despite a strong initial response to treatment, most patients will develop recurrent tumors that are often drug resistant [2], resulting in high mortality due to a lack of effective treatments [3]. The mechanisms that drive OC relapse and therapies to effectively delay and prevent this relapse are still unknown
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