Abstract
BackgroundOvarian cancer is the leading cause of death among gynecologic diseases in Western countries. We have previously identified a miR-200-E-cadherin axis that plays an important role in ovarian inclusion cyst formation and tumor invasion. The purpose of this study was to determine if the miR-200 pathway is involved in the early stages of ovarian cancer pathogenesis by studying the expression levels of the pathway components in a panel of clinical ovarian tissues, and fallopian tube tissues harboring serous tubal intraepithelial carcinomas (STICs), a suggested precursor lesion for high-grade serous tumors.MethodsRNA prepared from ovarian and fallopian tube epithelial and stromal fibroblasts was subjected to quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR) to determine the expression of miR-200 families, target and effector genes and analyzed for clinical association. The effects of exogenous miR-200 on marker expression in normal cells were determined by qRT-PCR and fluorescence imaging after transfection of miR-200 precursors.ResultsOvarian epithelial tumor cells showed concurrent up-regulation of miR-200, down-regulation of the four target genes (ZEB1, ZEB2, TGFβ1 and TGFβ2), and up-regulation of effector genes that were negatively regulated by the target genes. STIC tumor cells showed a similar trend of expression patterns, although the effects did not reach significance because of small sample sizes. Transfection of synthetic miR-200 precursors into normal ovarian surface epithelial (OSE) and fallopian tube epithelial (FTE) cells confirmed reduced expression of the target genes and elevated levels of the effector genes CDH1, CRB3 and EpCAM in both normal OSE and FTE cells. However, only FTE cells had a specific induction of CA125 after miR-200 precursor transfection.ConclusionsThe activation of the miR-200 pathway may be an early event that renders the OSE and FTE cells more susceptible to oncogenic mutations and histologic differentiation. As high-grade serous ovarian carcinomas (HGSOC) usually express high levels of CA125, the induction of CA125 expression in FTE cells by miR-200 precursor transfection is consistent with the notion that HGSOC has an origin in the distal fallopian tube.
Highlights
Ovarian cancer is the leading cause of death among gynecologic diseases in Western countries
We explored the potential involvement of miR-200 pathway in the hypothesized fallopian tube precursor lesions of high-grade serous tumors and have collected four primary cultures of normal fallopian tube epithelial (FTE) cells derived from distal fallopian tube scrapes, epithelial tumor cells and stromal cells microdissected from three cases of frozen serous tubal intraepithelial carcinomas (STICs) tissues. quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR) were performed to determine the expression levels of the five members of the miR-200 family and miR-205, another miRNA involved in more differentiated phenotype (MET) [27]; the target genes ZEB1, ZEB2, TGFβ1, and TGFβ2; and a panel of potential effector genes downstream of the ZEB1 transcriptional repressor selected from the article by Aigner et al [30]
Activation of miR-200 pathway in ovarian and fallopian tube cancer cells confirms the previous findings of suppression of transforming growth factor β (TGFβ) pathway [36] and epithelial characteristics of ovarian cancer cells when compared with ovarian surface epithelial (OSE) and likely FTE [8, 37,38,39]
Summary
Ovarian cancer is the leading cause of death among gynecologic diseases in Western countries. A study on serous ovarian carcinomas without Brca mutations have shown that approximately one-half of these tumors co-existed with a STIC, and p53 mutation analysis in the STIC and metastatic tumors disclosed the same mutations, suggesting that they were genetically linked [12]. These emerging data offer evidence that a significant percentage of familial and sporadic HGSOC could be explained by an origin in the distal fallopian tube
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