The tumor-suppressive microRNA-1/133a cluster targets PDE7A and inhibits cancer cell migration and invasion in endometrial cancer

Abstract

In developed countries, endometrial cancer (EC) is the most common malignancy among women. Unopposed estrogen therapy, obesity, nulliparity, diabetes mellitus and arterial hypertension have been linked to an increased risk of EC. However, the molecular mechanisms of EC oncogenesis and metastasis have not yet been fully elucidated. Our recent studies of microRNA (miRNA) expression signatures revealed that the microRNA-1/133a (miR‑1/133a) cluster is frequently downregulated in various types of human cancers. However, the functional role of the miR‑1/133a cluster in EC cells is still unknown. Thus, the aim of this study was to investigate the functional significance of the miR‑1/133a cluster and its regulated molecular targets, with an emphasis on the contributions of miR‑1/133a to EC oncogenesis and metastasis. We found that the expression levels of miR‑1 and miR‑133a were significantly reduced in EC tissues. Moreover, restoration of mature miR‑1 or miR‑133a miRNAs significantly inhibited cancer cell migration and invasion, suggesting that these clustered miRNAs act as tumor suppressors. Prediction of miRNA targets revealed that phosphodiesterase 7A (PDE7A) was a potential target gene regulated by both miR‑1 and miR‑133a. PDE7A was confirmed to be overexpressed in EC clinical specimens and silencing of PDE7A significantly inhibited cancer cell migration and invasion. Our data demonstrated that downregulation of the miR‑1/133a cluster promoted cancer cell migration and invasion via overexpression of PDE7A in EC cells. Elucidation of the molecular networks regulated by tumor-suppressive miRNAs will provide insights into the molecular mechanisms of EC oncogenesis and metastasis.

Altered microRNA expression patterns during the initiation and promotion stages of neonatal diethylstilbestrol-induced dysplasia/neoplasia in the hamster (Mesocricetus auratus) uterus

“…Lastly, targets of the PS differentially expressed miRNA (miR-133a) did not include any enriched pathways in MirPath3. However, consistent with our finding that miR-133a was DR in PS uteri, another study implicated it as a tumor suppressor in endometrial cancer (Yamamoto et al, 2015). …”

Therapeutically blocking interleukin-11 receptor-α enhances doxorubicin cytotoxicity in high grade type I endometrioid tumours

“…IL11 is a predicted gene target of miR-1 [22] and miR-1 transfection of Hela cells down-regulates IL11, IL11Rα and STAT3 mRNA [29]. Loss of miR-1 expression in primary type I human endometrial cancer [21] correlates with elevated IL11 expression [13, 14]. Similarly, we found loss of miR-1 expression in a panel of human endometrial epithelial cell lines compared to normal proliferative phase endometrial epithelial cells.…”

“…MiR-1 is reported to act as a tumour supressor, since restoration of mature miR-1 impairs endometrial cancer cell migration and invasion [21]. MiR-1 has approximately 1000 predicted targets in different cell types [22, 29], with only phosphodiesterase 7A (PDE7A) experimentally confirmed in endometrial cancer cells [21].…”

“…MiR-1 has approximately 1000 predicted targets in different cell types [22, 29], with only phosphodiesterase 7A (PDE7A) experimentally confirmed in endometrial cancer cells [21]. IL11 is a predicted gene target of miR-1 [22] and miR-1 transfection of Hela cells down-regulates IL11, IL11Rα and STAT3 mRNA [29].…”

“…MicroRNA (miR-1) has previously been demsontrated to act as a tumour suppressor in endometrial tumours [21]. IL11 is a predicted target of miR-1 [22].…”