Targeting of metastasis-related miRNAs in human tumors may offer potential therapeutic strategies for these diseases [34, 35]. Recent findings have identified miR-548c family members as universe miRNA, and illustrated the possibility that these miRNAs exert broad effects on many features of tumor cells through a broad range of targets and pathways [17]. Although one such miRNA, miR-548c, has been shown to inhibit cancer cell growth [19], its cellular functions, underlying mechanisms and clinical significance have not been comprehensively studied in gynecological cancers. Here, we found that miR-548c was under-expressed in both EC and OC samples, compared to their non-tumor counterparts. At the molecular level, miR-548c represses migration and invasion of EC and OC cells partially by targeting Twist. We demonstrate that miR-548c expression was inversely correlated with Twist level in EC and OC tissues, and reduced miR-548c expression was associated with poor prognosis in EC patients. These findings reveal for the first time that in EC and OC cells, miR-548c is a tumor-suppressive miRNA that inhibits multiple malignant features of the metastatic cascade.
Twist has been known as a novel oncogene overexpressed in diverse tumors [36], and activation of Twist inhibits apoptosis and promotes the induction of EMT, cancer stemness, proliferation, angiogenesis and vasculogenic mimicry in human tumor cells, all of which contributes to metastasis [37, 38]. Several upstream regulators and downstream effector of Twist have been reported [37], however our knowledge of the detailed molecular mechanisms involved in Twist overexpression, especially the epigenetic regulation of Twist expression, is still incomplete. Here, we reported a previously unidentified mechanism whereby loss of miR-548c expression is partially responsible for increased Twist levels in EC and OC, two of the most common gynecologic cancers.
Twist has been shown to upregulate the expression of some miRNAs, such as miR-10b [39] and miR-424 [40]. Twist promotes the expression of miR-10b by directly binding to the promoter of miR-10b, which initiates tumor invasion and metastasis in breast cancer [39]. Furthermore, miR-424, another miRNA that can be induced by Twist, drives EMT-like phenotypes in breast cancers [40]. The impact of Twist on miR-548c expression in EC and OC cells warrants further investigation.
MiR-548c was reported to be an independent prognostic factor for breast cancer. Patients with a good prognosis presented higher intratumoral expression of miR-548c [41]. Consistently, our meta-analysis suggested that high expression of miR-548c in EC and OC appears to correlate with better survival in patients with EC and OC, implying that miR-548c may be a new promising prognostic factor in these cancers. Since miR-548c directly regulates Twist in EC and OC cells, this miRNA might also represent an attractive target for the treatment of Twist-overexpressing tumors.