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MiR-20a-5p inhibits endometrial cancer progression by targeting janus kinase 1.

ABSTRACT: Endometrial cancer (EC) is a multi-factorial disease of which pathogenesis has not been fully elucidated. The function and underlying mechanism of microRNA-20a-5p (miR-20a-5p) in EC remain poorly understood. The present study aimed to analyze the association between miR-20a-5p expression and the clinicopathological characteristics of patients with EC. Whether miR-20a-5p could inhibit EC progression by targeting janus kinase 1 (Jak1) was subsequently investigated. To do so, human EC tissues and paracancerous tissues were collected from 47 patients with EC. miR-20a-5p and Jak1 mRNA and protein expression was determined by reverse transcription quantitative PCR and western blotting, respectively. Cell proliferation, invasive ability and adhesion were investigated by MTT, Matrigel invasion and cell adhesion assays, respectively. Dual luciferase reporter assay was used to verify whether miR-20a-5p could directly target Jak1. The results demonstrated that miR-20a-5p was downregulated and that Jak1 was upregulated in EC tissues compared with paracancerous tissues. In addition, miR-20a-5p expression and Jak1 expression level were negatively correlated in EC tissues. miR-20a-5p expression was also significantly associated with the depth of myometrial invasion, FIGO stage, histologic grade and lymph node metastasis in patients with EC. Furthermore, Jak1 was identified as a new direct target of miR-20a-5p, and Jak1 overexpression was demonstrated to reverse the effects of miR-20a-5p-mimic on EC cell proliferation, invasive ability and adhesion. Taken together, the results from this study revealed for the first time that miR-20a-5p expression was significantly associated with the clinicopathological characteristics of patients with EC. These findings suggested that miR-20a-5p may act as a tumor suppressor in EC, in part through decreasing Jak1 expression. miR-20a-5p and Jak1 may therefore serve as potential therapeutic targets in EC.

SUBMITTER: He Y

PROVIDER: S-EPMC8025135 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Circular RNAs (circRNAs) are a new class of single-stranded RNAs that form a continuous loop with crucial role in regulation of gene expression. Because their circular conformation conforms numerous properties, circRNAs have been investigated recently to demonstrate their important role in the development and progression of various cancers. However, the function of circRNAs and their regulatory outcomes in cervical cancer (CC) have rarely been explored. In this study, the role and molecular mechanism of hsa_circ_0107593 in cervical cancer are demonstrated. Quantitative polymerase chain reaction (qRT-PCR) was used to determine the expression of hsa_circ_0107593 and three miRNAs (hsa-miR-20a-5p, 93-5p, and 106b-5p) in paired CC tissues (tumor tissue vs. adjacent normal cervical tissue), CC cell lines, and human normal cervical epithelial immortalized cell line. A series of functional experiments were conducted to assess the function of hsa_circ_0107593 in CC development. The Receiver Operating Characteristic (ROC) curve was plotted to estimate the diagnostic value of hsa_circ_0107593 in CC. The dual-luciferase reporter assay was used to explore the interaction between hsa_circ_0107593 and hsa-miR-20a-5p/93-5p/106b-5p. Bioinformatic analysis was conducted to predict the target mRNAs, pathways, and functional enrichment. The results revealed that hsa_circ_0107593 has low expression in CC tissues and CC cell lines. Moreover, negative correlations of hsa_circ_0107593 expression were found against tumor diameter, FIGO stage, and myometrial invasion. Also, hsa_circ_0107593 impedes CC cell proliferation, migration, and invasion. Based on ROC curve analysis, hsa_circ_0107593 could serve as a diagnostic biomarker. Its low expression may indicate increased patient's risk to developing cervical cancer. Mechanistically, hsa_circ_0107593 serves as a sponge of hsa-miR-20a-5p, hsa-miR-93-5p, and hsa-miR-106b-5p. Collectively, our study implies that hsa_circ_0107593 has tumor-suppressing activity in CC by physically binding with hsa-miR-20a-5p, hsa-miR-93-5p, and hsa-miR-106b-5p.

Project description:BackgroundThis study evaluated the clinical relevance of a set of five serum-derived circulating microRNAs (miRNAs) in colorectal cancer (CRC). Additionally, we investigated the role of miR-20a-5p released by exosomes derived from cancer-associated fibroblasts (CAFs) in the context of CRC.MethodsThe expression levels of five circulating serum-derived miRNAs (miR-20a-5p, miR-122-5p, miR-139-3p, miR-143-5p, and miR-193a-5p) were quantified by real-time quantitative PCR (RT-qPCR), and their associations with clinicopathological characteristics in CRC patients were assessed. The diagnostic accuracy of these miRNAs was determined through Receiver Operating Characteristic (ROC) curve analysis. CAFs and normal fibroblasts (NFs) were isolated from tissue samples, and subsequently, exosomes derived from these cells were isolated and meticulously characterized using electron microscopy and Western blotting. The cellular internalization of fluorescent-labeled exosomes was visualized by confocal microscopy. Gain- and loss-of-function experiments were conducted to elucidate the oncogenic role of miR-20a-5p transferred by exosomes derived from CAFs in CRC progression. The underlying mechanisms were uncovered through luciferase reporter assay, Western blotting, enzyme-linked immunosorbent assays, as well as proliferation and migration assays.ResultsThe expression levels of serum-derived circulating miR-20a-5p and miR-122-5p were significantly higher in CRC and were positively correlated with advanced stages of tumorigenesis and lymph node metastasis (LNM). In contrast, circulating miR-139-3p, miR-143-5p, and miR-193a-5p were down-regulated in CRC and associated with early tumorigenesis. Except for miR-139-3p, they showed a negative correlation with LNM status. Among the candidate miRNAs, significantly elevated levels of miR-20a-5p were observed in both cellular and exosomal fractions of CAFs. Our findings indicated that miR-20a-5p induces the expression of EMT markers, partly by targeting PTEN. Exosomal miR-20a secreted by CAFs emerged as a key factor enhancing the proliferation and migration of CRC cells. The inhibition of miR-20a impaired the proliferative and migratory potential of CAF-derived exosomes in SW480 CRC cells, suggesting that the oncogenic effects of CAF-derived exosomes are mediated through the exosomal transfer of miR-20a. Furthermore, exosomes originating from CAFs induced increased nuclear translocation of the NF-kB p65 transcription factor in SW480 CRC cells, leading to increased interleukin-6 (IL-6) production.ConclusionsWe established a set of five circulating miRNAs as a non-invasive biomarker for CRC diagnosis. Additionally, our findings shed light on the intricate mechanisms underpinning the oncogenic impacts of CAF-derived exosomes and underscore the pivotal role of miR-20a-5p in CRC progression.

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MiR-20a-5p inhibits endometrial cancer progression by targeting janus kinase 1.

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