eIF4E‑related miR‑320a and miR‑340‑5p inhibit endometrial carcinoma cell metastatic capability by preventing TGF‑β1‑induced epithelial‑mesenchymal transition

Abstract

Endometrial cancer (EC) is a common form of cancer in women. Metastasis is the main cause of EC treatment failure. Eukaryotic translation initiation factor 4E (eIF4E) is an oncogene that is overexpressed in a variety of malignancies and their distant metastases. The present study analyzed microarray data from the Oncomine database and revealed that high eIF4E expression was associated with poor prognosis and high pathological grade of EC. The expression of eIF4E was higher in EC tissues compared with in adjacent normal tissues. In addition, microRNA (miR)-320a and miR-340-5p expression levels were downregulated in EC tissues compared with those in adjacent normal tissues, which suggested that these microRNAs may serve as EC tumor suppressor genes. miR-320a and miR-340-5p could bind to the 3'-UTR of eIF4E mRNA, thus downregulating the expression of eIF4E and phosphorylated (p)-eIF4E in EC cells. Overexpression of miR-320a or miR-340-5p effectively suppressed HEC-1A cell migration and invasion. The downregulation of eIF4E and p-eIF4E following miR-320a or miR-340-5p transfection reduced the invasiveness and metastatic capability of EC cells in a manner associated with decreased expression of matrix metallopeptidase (MMP)-3 and MMP-9. In addition, one of the effects of transforming growth factor β1 (TGF-β1), which is to induce the phosphorylation of eIF4E, was suppressed by miR-320a and miR-340-5p overexpression. These two microRNAs also attenuated the features of TGF-β1-induced epithelial-mesenchymal transition (EMT). In conclusion, the results of the present study demonstrated that eIF4E was upregulated in EC, whereas miR-320a and miR-340-5p were downregulated in EC compared with adjacent normal tissues. In vitro, miR-320a and miR-340-5p inhibited the migratory capability of EC cells by downregulating MMP-3 and MMP-9 and prevented TGF-β1-induced EMT through p-eIF4E.

The Interplay of Tumor Stroma and Translational Factors in Endometrial Cancer

“…Related to this, Zhang et al discovered that micro RNAs (miRNAs) miR-320a and miR-340-5p are downregulated in EC in comparison to adjacent normal tissue [25]. As these two miRNAs bind to the 5 UTR of eIF4E mRNA, they potentially downregulate eIF4E expression [25]. Correspondingly, experimental overexpression of miR-320a and miR-340-5p suppresses migration and invasion of HEC-1A cells.…”

“…Correspondingly, experimental overexpression of miR-320a and miR-340-5p suppresses migration and invasion of HEC-1A cells. Subsequently, the downregulation of EIF4E and phosphorylated eIF4E results in reduced expression of MMP-9 and MMP-3, thus impairing cellular migration [25]. Transforming growth factor beta 1 (TGF-beta1) is likewise suppressed by overexpression of miR-340-5p and miR-320a, usually being responsible for phosphorylation of eIF4E [25].…”

“…Subsequently, the downregulation of EIF4E and phosphorylated eIF4E results in reduced expression of MMP-9 and MMP-3, thus impairing cellular migration [25]. Transforming growth factor beta 1 (TGF-beta1) is likewise suppressed by overexpression of miR-340-5p and miR-320a, usually being responsible for phosphorylation of eIF4E [25]. Due to the downregulation of TGF-beta1, features of epithelial-to-mesenchymal transition (EMT), normally induced by TGF-beta1, are attenuated in EC tissues in vitro [25,26].…”

“…Transforming growth factor beta 1 (TGF-beta1) is likewise suppressed by overexpression of miR-340-5p and miR-320a, usually being responsible for phosphorylation of eIF4E [25]. Due to the downregulation of TGF-beta1, features of epithelial-to-mesenchymal transition (EMT), normally induced by TGF-beta1, are attenuated in EC tissues in vitro [25,26]. Another eIF, namely eIF2beta, is overexpressed in EC according to the Human Protein Atlas, with high eIF2beta levels being associated with significantly poorer patient survival [27].…”

“…PERK-eIF2alpha is involved in noncancerous processes and in carcinogenesis [37]. eIF2beta eIF2beta was found overexpressed in EC [25,26] and is related to a poorer patient survival [27].…”