Investigations on the mechanism of progesterone in inhibiting endometrial cancer cell cycle and viability via regulation of long noncoding RNA NEAT1/microRNA‐146b‐5p mediated Wnt/β‐catenin signaling

Abstract

Progesterone is often used to protect the endometrium and prevent endometrial cancer. An intensive study on its molecular mechanism in endometrial cancer would contribute to the development of more promising therapies. Relevant lncRNAs and mRNAs expression data in endometrial cancer cell line Ishikawa pretreated and post‐treated with progesterone were derived from Gene Expression Omnibus (accession no. GSE29435), and then we analyzed long noncoding RNAs and mRNAs with differential expressions in two different conditions. The Cytoscape software, TargetScan, miRanda, and Human microRNA Disease Database (HMDD) websites were employed. Gene set enrichment analysis (GSEA) was used to determine related Kyoto Encyclopedia of Genes and Genomes pathways alteration in Ishikawa cells treated with progesterone. In addition to bioinformatics analysis, Reverse Transcription‐Polymerase Chain Reaction (RT‐PCR), Western blot, and dual‐luciferase reporter assays were performed. The impact of progesterone on cell propagation and cell cycle was testified by colony formation and flow cytometry analysis. LncRNA nuclear enriched abundant transcript 1 (NEAT1) was the most significantly downregulated lncRNA in endometrial cancer cells treated with progesterone. Lymphoid enhancing factor 1 (LEF1) was positively associated with NEAT1, and eventually hsa_miR‐146b‐5p was validated to target both LEF1 and NEAT1. Wnt/β‐catenin signaling pathway was identified to involve in endometrial cancer. NEAT1 or LEF1 was overexpressed in endometrial cancer cells while downregulated following post‐treatment with progesterone. Conversely, miR‐146b‐5p was notably decreased in Ishikawa cells while upregulated after treatment with progesterone. Downstream gene c‐myc or MMP9 regulated by upstream gene LEF1 in Wnt/β‐catenin signaling pathway was remarkably increased in Ishikawa cells and positively related with NEAT1. Progesterone inhibited cell cycle and viability through regulating NEAT1/miR‐146b‐5p axis via Wnt/β‐catenin signaling pathway. Progesterone exerted suppressive influence on endometrial cancer progression via regulation of lncRNA NEAT1/miR‐146b‐5p‐mediated Wnt/β‐catenin signaling pathway, which might reveal new strategies for developing more effective therapeutics. © 2018 IUBMB Life, 71(1):223–234, 2019

Ubiquitin C-Terminal Hydrolase L5 (UCHL5) Accelerates the Growth of Endometrial Cancer via Activating the Wnt/β-Catenin Signaling Pathway

“…β-Catenin is a key signal transduction protein in the Wnt/β-catenin pathway, which controls transcription of a wide range of genes involved in embryonic development, cell proliferation and migration, and cell fate (33). Aberrant activation of the Wnt/β-catenin pathway has been reported in EC and associates with the deterioration outcome (34,35). Previous researches documented that deletion of UCHL5 increased the level of the ubiquitinated β-catenin and accelerated the hydrogen peroxide-stimulated degradation of β-catenin in HeLa cells (36).…”

Long noncoding RNA NEAT1 correlates with higher disease risk, worse disease condition, decreased miR‐124 and miR‐125a and predicts poor recurrence‐free survival of acute ischemic stroke

“…MicroRNAs are evolutionarily conserved noncoding RNA oligonucleotides and are involved in the pathology of numerous diseases . According to previous studies, miR‐124, miR‐125a, and miR‐146b, which are frequently investigated miRNAs, are well known as inflammation‐related miRNAs, moreover, they have been identified as direct target genes of lncRNA NEAT1 . Thus, we hypothesized that lncRNA NEAT1 might function via regulating miR‐124, miR‐125a, and miR‐146b in AIS as well.…”

“…26,27 According to previous studies, miR-124, miR-125a, and miR-146b, which are frequently investigated miRNAs, are well known as inflammation-related miRNAs, moreover, they have been identified as direct target genes of lncRNA NEAT1. [18][19][20] Thus, we hypothesized that lncRNA NEAT1 might function via regulating miR-124, miR-125a, and miR-146b in AIS as well. To verify this hypothesis, we assessed the correlation of lncRNA NEAT1 expression with the expression of plasma miR-124, miR-125a, and miR-146b in patients with AIS.…”

“…MiR‐124, miR‐125a, and miR‐146b are reported to be direct target genes of lncRNA NEAT1, which are also well‐known as inflammation‐related miRNAs. Hence, we hypothesized that lncRNA NEAT1 might function via miR‐124, miR‐125a, and miR‐146b in AIS as well, and we detected the relative expression of plasma miR‐124, miR‐125a and miR‐146b in patients with AIS.…”

Exploring lncRNA-Mediated Regulatory Networks in Endometrial Cancer Cells and the Tumor Microenvironment: Advances and Challenges

“…This leads to the downregulation of target genes, such as cyclin D1, c-Myc and MMP-9 [46]. NEAT1 has been suggested to function as an oncogenic sponge in EC where it sequesters several tumor suppressor miRNAs (miR-146b and miR-214) to activate the WNT/β-catenin pathway [47,48]. Moreover, the ectopic expression of MALAT1, a downstream effector of the Wnt/β-catenin pathway [49], promoted EC cell migration and invasion via inhibiting the expression of miR-200c, which suppressed the migration and invasion of EC cells [29].…”