Abstract
The majority of studies on microRNA-200 family members (miR-200s) in human cancers are based on the premise that miR-200s maintain epithelial cell integrity by suppressing epithelial-mesenchymal transition (EMT) through direct inhibition of mesenchymal transcription factors zinc finger E-box-binding homeobox 1/2 (ZEB1/ZEB2) and transforming growth factor-β (TGF-β), a potent inducer of EMT. Hence, downregulation of miR-200 in cancer cells promotes EMT and cancer metastasis. Yet, miR-200s are highly expressed in ovarian cancer, and ovarian cancer metastasizes primarily by dissemination within the pelvic cavity. In this review, we will refocus the epithelial property of ovarian cancer cells and the role of miR-200s in safeguarding this property, as well as the diverse roles of miR-200s in inclusion cyst formation, cancer cell growth, collective movement, angiogenesis, exosome-mediated cell communication, and chemoresponse. Taken together, miR-200s play a significant role in the initiation, progression and metastasis of ovarian cancer and may serve as diagnostic biomarkers and a target in therapeutic development.
Highlights
MicroRNAs are short single-stranded non-coding RNAs (~22 nucleotides in length) which are able to negatively regulate gene expression by binding to complementary sites in the target messenger RNA at the RNA-induced silencing complex (RISC) and inducing mRNA degradation or translation inhibition [1]. miRNAs have been recognized as molecular regulators and potential therapeutic targets in cancers. miR-200 family is one of the several miRNAs that have been studied for the diagnosis and prognosis of ovarian cancers [2] and well known as the master suppressor of epithelial-mesenchymal transition (EMT) for the expression of E-cadherin, the classical calcium-dependent cell–cell adhesion protein to maintain epithelial cell phenotype [3]
We have shown by quantitative reverse transcription-polymerase chain reaction (RT-PCR) that miR-200 pathway genes are up-regulated in microdissected cells derived from ovarian tumor tissues and serous tubal intraepithelial carcinoma (STIC), a precursor lesion for high-grade serous ovarian carcinoma (HGSOC) [32,33,45,46,47], relative to normal ovarian surface epithelial (OSE) and fallopian tube epithelial (FTE) cells
Our work has shown that nuclear phosphoprotein Pinin and some epigenetic transcriptional co-repressor proteins play key roles in epithelial cell identity, growth and multidimensional adhesion of ovarian cancer cells [55]
Summary
MicroRNAs (miRNAs) are short single-stranded non-coding RNAs (~22 nucleotides in length) which are able to negatively regulate gene expression by binding to complementary sites in the target messenger RNA (mRNA) at the RNA-induced silencing complex (RISC) and inducing mRNA degradation or translation inhibition [1]. miRNAs have been recognized as molecular regulators and potential therapeutic targets in cancers. miR-200 family is one of the several miRNAs that have been studied for the diagnosis and prognosis of ovarian cancers [2] and well known as the master suppressor of epithelial-mesenchymal transition (EMT) for the expression of E-cadherin, the classical calcium-dependent cell–cell adhesion protein to maintain epithelial cell phenotype [3]. Characterization of circulating tumor cells in the vasculature demonstrated activation of the Erb-B2 receptor tyrosine kinase 3/neuregulin (ErbB3/NRG1) axis and EMT promoted this hematogenous metastasis, and perturbation of ErbB3 signaling inhibited omental metastasis The results of this interesting study suggest that there can be the presence of an alternative hematogenous omental metastasis besides the classical theory of direct spread of migrating cancer cells. Further studies have shown that GRHL2 and ZEB1 formed a double negative feedback loop for the reciprocal regulation of miR-200s expression and epithelial phenotype [78] Given that all these studies provide seemingly contradictory findings, it is crucial to evaluate all genetic interactions in a cell context-dependent manner in different ovarian cancer cell populations in order to infer the likely metastatic pathways. As there are cysts present in pre-malignant ovaries of laying hens, it would be of great interest to study the expression level of miR-200s in the inclusion cysts of both human and laying hen specimens and compare the level from the epithelium of the normal ovary, which may provide a clinical validation of our in vitro 3D results
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