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Decreased expression of miR-184 restrains the growth and invasion of endometrial carcinoma cells through CDC25A-dependent Notch signaling pathway.

ABSTRACT: Endometrial carcinoma (EC) is one of the most common malignancies of female reproductive tract in developed countries. MicroRNA is frequently dysregulated in human cancers and acts a key regulator role in tumor cell growth and metastasis. The aims of this study were to investigate the roles of microRNA-184 (miR-184) in EC cells and to identify its potential molecular mechanism. Here, the data revealed that miR-184 was significantly downregulated in human EC tissue compared with normal endometrial tissue, and the level of miR-184 expression was associated with lymph node metastasis and prognosis in patients with EC. In vitro assays, overexpression of miR-184 could suppress the proliferation and invasion of HEC-1B and RL95-2 cells. Moreover, bioinformatics analysis showed that cell division cycle 25A (CDC25A) was a putative target gene of miR-184. Dual luciferase reporter assay confirmed that miR-184 significantly downregulated CDC25A expression via directly interaction with the putative binding site in the 3'-untranslated region (3'-UTR) of CDC25A mRNA. Interestingly, knockdown of CDC25A resulted in inhibition of HEC-1B and RL95-2 cells growth and invasion. Mechanistic investigation revealed that downregulation of the Notch receptors (NOTCH1, NOTCH2, NOTCH3 and NOTCH4) and target gene HES1 by miR-184 could be reversed by CDC25A overexpression. In summary, our data demonstrate that CDC25A is a target gene of miR-184 in EC cells, and decreased expression of miR-184 suppresses the growth and invasion of EC cells via CDC25A-dependent Notch signaling pathway, suggesting that miR-184 may be a promising target for a new therapeutic strategy against EC.

SUBMITTER: Chen Z

PROVIDER: S-EPMC6413266 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Decreased expression of miR-184 restrains the growth and invasion of endometrial carcinoma cells through CDC25A-dependent Notch signaling pathway.

Chen Zhen Z Zhu Yingjun Y Fan Xiaodong X Liu Yabo Y Feng Qingqing Q

American journal of translational research 20190215 2

Endometrial carcinoma (EC) is one of the most common malignancies of female reproductive tract in developed countries. MicroRNA is frequently dysregulated in human cancers and acts a key regulator role in tumor cell growth and metastasis. The aims of this study were to investigate the roles of microRNA-184 (miR-184) in EC cells and to identify its potential molecular mechanism. Here, the data revealed that miR-184 was significantly downregulated in human EC tissue compared with normal endometria ...[more]

PMID: 30899377

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Project description:A-kinase-interacting protein 1 (AKIP1), as a recently discovered oncoprotein, promotes cell malignant behaviors in gynecological malignancies. To the best of our knowledge, no study reports its clinical value in patients with endometrial carcinoma. The present study aimed to explore the association between AKIP1 expression and clinical features and survival in patients with endometrial carcinoma, and to assess the effect of AKIP1 knockdown on the regulation of chemosensitivity in vitro. The tumor and adjacent tissue specimens from 101 patients with endometrial carcinoma were retrieved for AKIP1 protein expression analysis using an immunohistochemistry (IHC) assay. Meanwhile, specimens from 54 patients with endometrial carcinoma were analyzed for AKIP1 mRNA expression using reverse transcription-quantitative PCR. Furthermore, an in vitro experiment was conducted in the Ishikawa cell line to determine the effect of AKIP1 modification on the chemosensitivity of cisplatin and paclitaxel. AKIP1 IHC score (P<0.001) and mRNA expression levels (P<0.001) were increased in tumor tissues compared with those in adjacent tissues. Moreover, increased AKIP1 IHC score was associated with lymphovascular invasion (P=0.007), advanced International Federation of Gynecology and Obstetrics (FIGO) stage (P=0.002) and shorter overall survival (OS) time (P=0.035) in the patients with endometrial carcinoma. Meanwhile, upregulated AKIP1 mRNA expression levels were associated with lymphovascular invasion (P=0.020) and advanced FIGO stage (P=0.027) in the patients with endometrial carcinoma. Multivariate Cox regression showed that tumor AKIP1 protein expression (high vs. low) independently predicted a shorter OS time (P=0.036). Silencing of AKIP1 decreased Ishikawa cell viability when treated with 5, 10, 20 and 40 µM cisplatin (all P<0.05) and decreased the half maximal inhibitory concentration value of cisplatin (P=0.003), whereas its effect on paclitaxel chemosensitivity was less obvious. Overall, elevated AKIP1 expression was associated with tumor invasion, shorter survival time and decreased chemosensitivity in endometrial carcinoma.

Project description:BackgroundWe previously identified TrkB as an oncogene involved in promoting metastasis in endometrial carcinoma (EC). Here, we sought to delineate the effect of changes in TrkB expression on the global profile of microRNAs (miRNAs) in EC cells and further investigated the correlation between the expression of certain miRNA and TrkB in the clinicopathologic characteristics of EC patients.Methods and resultsUsing quantitative reverse transcription-PCR (qRT-PCR), we found that expression of TrkB mRNA has no significant difference in transcript levels between normal endometrium and EC cells captured by laser capture microdissection, while immunohistochemistry results demonstrated a markedly higher expression of TrkB protein in EC tissues. The microRNA array showed that ectopic overexpression and knockdown of TrkB expression caused global changes in miRNA expression in EC cells. qRT-PCR results showed that elevated TrkB repressed miR-204-5p expression in EC cells. Furthermore, immunoblotting assays revealed that TrkB overexpression in IshikawaTrkB cells noticeably increased JAK2 and STAT3 phosphorylation, which, however, was aborted by TrkB knockdown in HEC-1BshTrkB cells. Moreover, ChIP assays showed that phospho-STAT3 could directly bind to STAT3-binding sites near the TRPM3 promoter region upstream of miR-204-5p. Interestingly, using bioinformatics analysis and luciferase assays, we identified TrkB was a novel target of miR-204-5p. Functionally, the MTT assays, clonogenic and Transwell assays showed that miR-204-5p significantly suppressed the clonogenic growth, migration and invasion of EC cells. Furthermore, miR-204-5p also inhibited the growth of tumor xenografts bearing human EC cells. Importantly, we found lower miR-204-5p expression was associated with advanced FIGO stages, lymph node metastasis and probably a lower chance for survival in EC patients.ConclusionsThis study uncovers a new regulatory loop involving TrkB/miR-204-5p that is critical to the tumorigenesis of EC and proposes that reestablishment of miR-204-5p expression could be explored as a potential new therapeutic target for this disease.

Project description:This study was aimed to explore the effects of miR-29a-5p expression and its target gene TPX2 (target protein for Xenopus kinesin-like protein 2) on endometrial cancer (EC) devel on EC development and to assess the prognostic impacts of TPX2. Microarray-based GEO and TCGA (the Cancer Genome Atlas) EC expression data were used to identify differentially expressed miRNAs and mRNAs. The observed potential target relationship between miR-29a-5p and TPX2 was verified using TargetScan and luciferase reporter assays. The mRNA and protein expression levels of miR-29a-5p and TPX2 were confirmed by qRT-PCR and western blot, respectively. Associations between TPX2 expression and patient prognosis were assessed using Kaplan-Meier and log-rank assays. Changes in EC-derived cell proliferation, invasion and apoptosis after exogenous miR-29a-5p and TPX2 over-expression and/or silencing were assessed using CCK-8 (cell counting kit-8), colony formation, Transwell and flow cytometry assays, respectively. We found that in primary EC tissues the expression of miR-29a-5p was down-regulated and the expression of TPX2 was up-regulated. We also found that low expression of TPX2 were associated with a better prognosis, and vice versa. Subsequent exogenous miR-29a-5p over-expression and TPX2 silencing could inhibit EC-derived cell proliferation and invasion, and to induce apoptosis. We also found that miR-29a-5p might target and repress TPX2, thereby inhibiting EC-derived cell proliferation and invasion and enhancing apoptosis. We conclude that miR-29a-5p could inhibit the proliferation and invasion of EC-derived cells and enhance the apoptosis of EC-derived cells via TPX2 down-regulation. A high TPX2 expression in primary EC tissues was found to be associated with a poor prognosis. As such, these biomarkers may serve as promising prognostic indicators.AbbreviationsEC: Endometrial cancer; 3'-UTR: 3'-untranslated regions; TPX2: target protein for Xenopus kinesin-like protein 2; TCGA: the Cancer Genome Atlas; UCEC: uterine corpus endometrial carcinoma; CCK-8: cell counting kit-8; OD: optical density; FCM: flow cytometry; EMT: epithelial-mesenchymal transition.

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Decreased expression of miR-184 restrains the growth and invasion of endometrial carcinoma cells through CDC25A-dependent Notch signaling pathway.

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Decreased expression of miR-184 restrains the growth and invasion of endometrial carcinoma cells through CDC25A-dependent Notch signaling pathway.

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