Abstract
BackgroundEpithelial-mesenchymal transition (EMT) is the key process driving cancer metastasis. Oncogene/self renewal factor BMI-1 has been shown to induce EMT in cancer cells. Recent studies have implied that noncoding microRNAs (miRNAs) act as crucial modulators for EMT. The aims of this study was to determine the roles of BMI-1 in inducing EMT of endometrial cancer (EC) cells and the possible role of miRNA in controlling BMI-1 expression.Methods and resultsWe evaluated the expression of BMI-1 gene in a panel of EC cell lines, and detected a strong association with invasive capability. Stable silencing of BMI-1 in invasive mesenchymal-type EC cells up-regulated the epithelial marker E-cadherin, down-regulated mesenchymal marker Vimentin, and significantly reduced cell invasion in vitro. Furthermore, we discovered that the expression of BMI-1 was suppressed by miR-194 via direct binding to the BMI-1 3'-untranslated region 3'-UTR). Ectopic expression of miR-194 in EC cells induced a mesenchymal to epithelial transition (MET) by restoring E-cadherin, reducing Vimentin expression, and inhibiting cell invasion in vitro. Moreover, BMI-1 knockdown inhibited in vitro EC cell proliferation and clone growth, correlated with either increased p16 expression or decreased expression of stem cell and chemoresistance markers (SOX-2, KLF4 and MRP-1).ConclusionThese findings demonstrate the novel mechanism for BMI-1 in contributing to EC cell invasion and that repression of BMI-1 by miR-194 could have a therapeutic potential to suppress EC metastasis.
Highlights
Endometrial cancer (EC) is the most frequent gynecologic malignancy in the developed countries [1]
These findings demonstrate the novel mechanism for BMI-1 in contributing to endometrial cancer (EC) cell invasion and that repression of BMI-1 by miR-194 could have a therapeutic potential to suppress EC metastasis
The number of HEC-50B-highly invasive (HI) cells that passed through the membrane was 5.0 times larger than the number of HHUA cells (Figure 1B), suggesting that BMI-1 expression level seemed to be closely associated with the enhanced invasive activities of EC cell lines
Summary
Endometrial cancer (EC) is the most frequent gynecologic malignancy in the developed countries [1]. The incidence of EC is lower in East Asian than in Western countries, it tends to increase markedly in recent years [2]. Myometrial invasion and distant metastasis decreases the survival rates of patients after surgical treatment. Type II EC is often related to poor prognostic factors, such as high grade or deep myometrial penetration. Epithelial-mesenchymal transition (EMT) is the key process driving cancer metastasis. Oncogene/self renewal factor BMI-1 has been shown to induce EMT in cancer cells. Recent studies have implied that noncoding microRNAs (miRNAs) act as crucial modulators for EMT. The aims of this study was to determine the roles of BMI-1 in inducing EMT of endometrial cancer (EC) cells and the possible role of miRNA in controlling BMI-1 expression
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