Abstract 2054: A microRNA hypothesis for the precursor lesions of ovarian cancer

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Ovarian cancer is the leading cause of death among gynecologic diseases in Western countries. Ovarian surface epithelial (OSE) cells were previously considered as the cells of origin of ovarian cancer. The ovarian surface epithelium is derived from the coelomic layer, which is consisted of peritoneal mesothelial cells. Malignant ovarian cancer cells, however, are found to be associated with epithelial phenotypes resembling cells from fallopian tube, uterus, and cervix. Recent studies have suggested that significant percentages of familial and sporadic high-grade serous ovarian carcinomas could be explained by an origin in the distal fallopian tube. We and others have identified overexpression of miR-200 family members in ovarian caner cells. In order to investigate whether the miR-200 pathway is involved in the early stages of ovarian pathogenesis, we have studied the expression levels of the pathway components in a panel of samples isolated from primary cultures and laser microdissection. The ovarian samples included OSEs, epithelial tumor cells from benign tumors, borderline tumors, nonserous invasive tumors, serous invasive tumors, ovarian cancer cell lines, and tumor-associated stromal fibroblasts. Fallopian tube samples included normal fallopian tubal epithelial (FTE) cells, tumor cells and stromal fibroblasts from frozen tubal intraepithelial carcinomas (TICs) of fallopian tube. Gene expression was determined using quantitative real-time polymerase chain reactions (qRT-PCRs). The reactions for the 4 target genes of miR-200s (ZEB1, ZEB2, TGFb1 and TGFb2), and 21 effector genes that were regulated by the target genes, were performed using a high-throughput BioMark array platform (Fluidigm). qRT-PCR of epithelial tumor cells from ovarian tumors and fallopian TICs showed concurrent up-regulation of miR-200s, down-regulation of the target genes, and up-regulation of several effector genes. To confirm the role of miR-200 family in regulating gene expression, synthetic miRNA precursors were transfected into normal OSE and FTE cells and qRT-PCRs were performed to determine the expression of target and effector genes. The results showed similar reduced expression of target genes and elevated levels of CDH1 and EpCAM effector genes in both normal OSE and FTE cells. However, the most interesting finding was the specific induction of tumor marker, CA125, in the normal FTE cells. Immunocytochemistry confirmed the induced CA125 proteins in FTE cells. In conclusion, the activation of the miR-200 pathway may be an early lesion that renders the OSE and FTE cells more susceptible to oncogenic mutations and histologic differentiation. As high-grade serous ovarian tumors usually express higher levels of CA125, the greater capacity of FTE cells to express CA125 by miR-200 induction is consistent with the notion that high-grade serous ovarian tumors have an origin in the distal fallopian tube. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2054.