MicroRNA-101 targets EZH2, MCL-1 and FOS to suppress proliferation, invasion and stem cell-like phenotype of aggressive endometrial cancer cells

Abstract

MicroRNA-101 has been implicated as a tumor suppressor miRNA in human tumors. However, its potential functional impact and the underlying mechanisms in endometrial cancer progression have not been determined. Here, we report that in aggressive endometrial cancer cells, re-expression of microRNA-101 leads to inhibition of cell proliferation and induction of apoptosis and senescence. Ectopic overexpression of microRNA-101 attenuates the epithelial-mesenchymal transition-associated cancer cell migration and invasion, abrogates the sphere-forming capacity and enhances chemosensitivity to paclitaxel. Algorithm and microarray-based strategies identifies potential microRNA-101 targets. Among these, we validated EZH2, MCL-1 and FOS as direct targets of miR-101 and silencing of these genes mimics the tumor suppressive effects observed on promoting microRNA-101 function. Importantly, further results suggest an inverse correlation between low miR-101 and high EZH2, MCL-1 and FOS expression in EC specimens. We conclude that, as a crucial tumor suppressor, microRNA-101 suppresses cell proliferation, invasiveness and self-renewal in aggressive endometrial cancer cells via modulating multiple critical oncogenes. The microRNA-101-EZH2/MCL-1/FOS axis is a potential therapeutic target for endometrial cancer.

miR-135a modulates tendon stem/progenitor cell senescence via suppressing ROCK1

“…In aggressive endometrial cancer cells, re-expression of miR-101 leads to inhibition of cell proliferation and induction of apoptosis and senescence [22]. In human diploid fibroblasts (HDFs), miR-141 induces premature senescence via posttranscriptionally downregulating BMI1.…”

Tumor progression, metastasis, and modulators of epithelial–mesenchymal transition in endometrioid endometrial carcinoma: an update

“…miR-101 was found to suppress the EMT and CSC properties of aggressive EC cells at least in part by attenuating EZH2 expression, followed by elevation of BAX, p21, epithelial markers and TIMP3, downregulation of mesenchymal markers and suppression of Wnt/ B-catenin pathway (Konno et al 2014). A recent study suggested oncogenic role for hsa-miR-181a in endometrial tumorigenesis and its critical role in tumor metastasis of advanced EC (He et al 2015).…”

Clinical translation for endometrial cancer stem cells hypothesis

“…Micro-RNA also seems to have a role on EMT, namely micro-RNA-194 that suppresses the gene BMI-1 in endometrial cell lines, involved in EMT and possibly also on metastasis process [60]. The overexpression of micro-RNA 101 was linked to stem cell-like properties, including EMT, cell migration, inhibited tumorosphere capacity and chemosensitivity to paclitaxel in human serous endometrial cancer cell line [73]. A transcriptional factor important for self-renewal capacity and undifferentiated state of embryonic stem cells is SALL4 that was already described in endometrial cancer [74].…”