Dysregulation of microRNA‐204 mediates migration and invasion of endometrial cancer by regulating FOXC1

Abstract

TXMicroRNAs (miRNAs) regulate mRNA stability and protein expression, and certain miRNAs have been demonstrated to act either as oncogenes or tumor suppressors. Differential miRNA expression signatures have been documented in many human cancers but the role of miRNAs in endometrioid endometrial cancer (EEC) remains poorly understood. This study identifies significantly dysregulated miRNAs of EEC cells, and characterizes their impact on the malignant phenotype. We studied the expression of 365 human miRNAs using Taqman low density arrays in EECs and normal endometriums. Candidate differentially expressed miRNAs were validated by quantitative real-time PCR. Expression of highly dysregulated miRNAs was examined in vitro through the effect of anti-/pre-miRNA transfection on the malignant phenotype. We identified 16 significantly dysregulated miRNAs in EEC and 7 of these are novel findings with respect to EEC. Antagonizing the function of miR-7, miR-194 and miR-449b, or overexpressing miR-204, repressed migration, invasion and extracellular matrix-adhesion in HEC1A endometrial cancer cells. FOXC1 was determined as a target gene of miR-204, and two binding sites in the 3 0 -untranslated region were validated by dual luciferase reporter assay. FOXC1 expression was inversely related to miR-204 expression in EEC. Functional analysis revealed the involvement of FOXC1 in migration and invasion of HEC1A cells. Our results present dysfunctional miRNAs in endometrial cancer and identify a crucial role for miR-204-FOXC1 interaction in endometrial cancer progression. This miRNA signature offers a potential biomarker for predicting EEC outcomes, and targeting of these cancer progression-and metastasis-related miRNAs offers a novel potential therapeutic strategy for the disease.Endometrial cancer is a common cause of gynecological cancer death. The most dominant subtype, endometrioid endometrial cancer (EEC), accounts for >80% of this cancer. Menopause and unopposed estrogenic stimulation are typical risk factors. Patients are generally treated with surgery, radiation, chemotherapy or hormone therapy. Patients with early stage disease have 5-year survival rates over 80%, however, about 15-20% develop metastasis. 1 These patients and those with advanced stage disease or recurrence have poor prognosis due to limitation of effective treatment. 2 Understanding the pathogenesis of this disease may provide insights for the development of novel therapeutic strategies.MicroRNAs (miRNAs) are small noncoding RNA molecules of 19-24 nucleotides that regulate gene expression posttranscriptionally through imperfect base pairing with the 3 0 -untranslated region (3 0 UTR) of target mRNAs, causing transcript degradation and translational inhibition. 3 Approximately 20-30% of all genes are targeted by miRNAs and a single miRNA may target as many as 200 genes. 4 In human cancers, >50% of the miRNA genes are located in chromosomal fragile sites, minimal regions containing loss of heterozygosity, minimal amplicons or common breakpoint regions. 5 DNA ...

Diagnostic and prognostic significance of miRNA signatures in tissues and plasma of endometrioid endometrial carcinoma patients

“…These results correspond with observations presented in other EEC studies and implicate oncogenic roles of miR-183, miR-96, miR-182 and miR-9 in EEC. 17,19,36 Decreased expression of miR-410, which was revealed in our set of EEC samples, was previously reported in only one study. 30 Interestingly, Ratner et al observed downregulation of miR-487b, which occupies the same locus on chromosome 14 (14q32.31).…”

“…16 Although a number of studies suggested miRNAs involvement in EEC pathogenesis, only few of them involved large groups of patients and addressed issues concerning the influence of clinicopathological features on miRNAs expression. [17][18][19][20] Similarly, diagnostic or prognostic accuracy of miRNA signatures in tissue and plasma of EEC patients has not been systematically studied. Thus, the aim of our study was to define tissue and plasma miRNA signatures, which could potentially serve as diagnostic and prognostic markers in EEC and to investigate miRNA profiles in regard to EEC clinicopathological characteristics.…”

Transformer 2β and miR-204 regulate apoptosis through competitive binding to 3′ UTR of BCL2 mRNA

“…In addition, downregulation of miR-204 has been documented in several types of cancers. [37][38][39][40][41] Decreased expression of miR-204 results in overexpression of its target, myeloid cell leukemia sequence 1 (Mcl-1) mRNA, and induces anti-apoptotic signaling in pancreatic cancers. 42 miR-204 also regulates expression of an oncogene, neurotrophic receptor tyrosine kinase B, and promotes metastasis in endometrial carcinoma.…”

MicroRNAs in endometrial cancer

“…miR-7 is also upregulated in endometrial cancer, and invasion and cancer cell migration are inhibited by downregulation of miR-7 using an anti-miRNA antibody (Chung et al, 2012). In endometrioid adenocarcinoma, upregulation of miR-27 expression is surgical stage-dependent.…”