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Hypermethylation of let-7a-3 in Epithelial Ovarian Cancer Is Associated with Low Insulin-like Growth Factor-II Expression and Favorable Prognosis

¹ Department of Epidemiology and Public Health, Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut and ² Department of Obstetrics and Gynecology, Gynecologic Oncology and Breast Cancer Unit, University of Turin, Turin, Italy

Requests for reprints: Herbert Yu, Department of Epidemiology and Public Health, Yale Cancer Center, Yale University School of Medicine, 60 College Street, New Haven, CT 06520-8034. Phone: 203-785-5688; Fax: 203-785-2850; E-mail: herbert.yu{at}yale.edu.

MicroRNAs (miRNA) are endogenous noncoding small RNAs that regulate the activity of mRNAs. Many miRNA genes, including let-7a-3, are located in CpG islands, suggesting possible epigenetic regulation of their expression. Promoter CpG island methylation of tumor suppressor genes is involved in cancer development and progression. Using real-time methylation-specific PCR and real-time reverse transcription-PCR, we analyzed DNA methylation in the let-7a-3 gene and miRNA expression of let-7a in 214 patients with epithelial ovarian cancer to assess the effect of let-7a-3 methylation on the expressions of let-7a as well as a possible target of let-7 regulation, insulin-like growth factor-II (IGF-II). The association of let-7a-3 methylation with patient survival outcomes was also evaluated. let-7a-3 methylation was detected in epithelial ovarian cancer, and the expression of let-7a was slightly affected by the methylation, but the effect was not substantial. The methylation of let-7a-3, however, was inversely correlated with IGF-II expression and positively with insulin-like growth factor binding protein-3 (IGFBP-3) expression. Patients with methylated let-7a-3 seemed to have reduced risk for death compared with those without, and the association was independent of patient age at surgery, tumor grade, disease stage, and IGF-II or IGFBP-3 expression. No association was found for let-7a-3 methylation and disease progression. These results suggest that the let-7a-3 gene is methylated and the methylation may affect IGF-II expression and the survival of ovarian cancer patients. Further investigation of the role of miRNAs and their regulation in cancer is warranted. [Cancer Res 2007;67(21):10117–22]

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