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Dual‐specificity phosphatase 5 (DUSP5) is a novel anti‐inflammatory modulator in many inflammatory diseases. However, the role of DUSP5 in fibroblast‐like synoviocytes (FLS) of rheumatoid arthritis (RA) remains unknown. In this study, we aimed to explore the biological function and regulation of DUSP5 in FLS. We found that lower DUSP5 expression level was detected in collagen‐induced arthritis (CIA) and synoviocyte MH7A. Overexpression of DUSP5 markedly decreased the proliferation, migration, and invasion of MH7A, which correlated with suppressing the phosphorylation of extracellular signal‐regulated kinase (ERK). Moreover, DUSP5 was identified as a novel target gene of miR‐216a‐3p, which was upregulated in FLS. Therefore, DUSP5 expression was negatively regulated by miR‐216a‐3p, and the effect of DUSP5 overexpression on FLS was reversed by miR‐216a‐3p mimics. Overall, our study demonstrates that DUSP5 is a miR‐216a‐3p target gene and its anti‐inflammatory function in FLS via inactivation of ERK. These results revealed that the miR‐216a‐3p/DUSP5 pathway may play a crucial role in the malignant behavior of FLS, which may serve as a new target for the treatment of RA. [ABSTRACT FROM AUTHOR]

Background: Ovarian cancer (OC) is a common gynecologic cancer with high incidence and mortality. We attempted to investigate the role of circular RNA_0000471 (circ_0000471) in OC progression and its associated mechanism. Methods: Reverse transcription‐quantitative polymerase chain reaction (RT‐qPCR) and western blot assay were conducted to measure RNA and protein expression, respectively. Cell proliferation was analyzed by Cell Counting Kit‐8 (CCK8) assay, colony formation assay, and 5‐Ethynyl‐2′‐deoxyuridine (EdU) assay. Cell apoptosis was assessed by flow cytometry. Cell migration and invasion were analyzed by wound healing assay and transwell assay, respectively. Dual‐luciferase reporter assay and RNA immunoprecipitation (RIP) assay were conducted to verify the target relationships. Xenograft tumor model was established to assess the role of circ_0000471 on tumor growth in vivo. Results: Circ_0000471 expression was down‐regulated in OC tissues and cell lines. Circ_0000471 overexpression blocked the proliferation, migration, and invasion and triggered the apoptosis of OC cells. Circ_0000471 served as a molecular sponge for microRNA‐135b‐5p (miR‐135b‐5p), and circ_0000471 overexpression‐mediated anti‐tumor influences in OC cells were largely reversed by the overexpression of miR‐135b‐5p. Dual specificity phosphatase 5 (DUSP5) was a target of miR‐135b‐5p, and miR‐135b‐5p silencing‐induced anti‐tumor effects were largely counteracted by the interference of DUSP5. Circ_0000471 increased DUSP5 expression by sponging miR‐135b‐5p in OC cells. Circ_0000471 overexpression restrained the growth of xenograft tumors in vivo. Conclusion: Overexpression of circ_0000471 inhibited OC development by targeting miR‐135b‐5p/DUSP5 axis, indicating that circ_0000471 may be a new potential target for OC treatment. [ABSTRACT FROM AUTHOR]

Background: Differentiated thyroid cancer involves thyroid follicular carcinoma (FTC) and papillary thyroid carcinoma (PTC). Patients with FTC have a worse prognosis than those with PTC for early metastasis through blood of FTC. However, the mechanism of poor prognosis of FTC is still unclear. Here, we aim to evaluate the role of DUSP5 in the prognostic evaluation of FTC. Method: We searched the Gene Expression Omnibus (GEO) database for the differentially expressed genes (DEGs) between FTC and PTC, and then combined with survival analysis of cBioPortal database to locate the gene significantly related to prognosis. Tissue microarrays and clinical tissues were used to examine DUSP5 expression by immunohistochemical (IHC) staining between FTC and PTC tissues. In vitro experiment, proliferation, migration and invasion of FTC were observed after regulation of DUSP5 by transfection of siRNA and plasmids, respectively. Results: After searching the GEO database, 26 DEGs were found. DUSP5 was significantly associated with prognosis of FTC in combination with survival analysis. Data of IHC staining showed lower expression of DUSP5 in FTC compared to PTC tissues. Furthermore, overexpression of DUSP5 inhibited the proliferation, migration and invasion accompanied with low level of MMP9 and Vimentin and high level of E‐cadherin. Nevertheless, inhibition of DUSP5 ameliorated above damaging effect on the proliferation, migration and invasion. Conclusion: DUSP5 was differentially expressed in FTC and PTC tissues. Low level of DUSP5 in FTC participates in the high frequency of metastasis, and further contributes to poor prognosis of FTC. DUSP5 could be served as a novel therapeutic target for FTC. [ABSTRACT FROM AUTHOR]

This study investigated the role of microRNA‐95 (miR‐95) in gastric cancer (GC) and to elucidate the underlying mechanism. Initially, bioinformatic prediction was used to predict the differentially expressed genes and related miRNAs in GC. miR‐95 and DUSP5 expression was altered in GC cell line (MGC803) to evaluate their respective effects on the epithelial–mesenchymal transition (EMT) process, cellular processes (cell proliferation, migration, invasion, cell cycle, and apoptosis), cancer stem cell (CSC) phenotype, as well as tumor growth ability. It was further predicted in bioinformatic prediction and verified in GC tissue and cell line experiments that miR‐95 was highly expressed in GC. miR‐95 negatively regulated DUSP5, which resulted in the MAPK pathway activation. Inhibited miR‐95 or overexpressed DUSP5 was observed to inhibit the levels of CSC markers (CD133, CD44, ALDH1, and Lgr5), highlighting the inhibitory role in the CSC phenotype. More important, evidence was obtained demonstrating that miR‐95 knockdown or DUSP5 upregulation exerted an inhibitory effect on the EMT process, cellular processes, and tumor growth. Together these results, miR‐95 knockdown inhibited GC development via DUSP5‐dependent MAPK pathway. [ABSTRACT FROM AUTHOR]

Gliomas are the most common central nervous system tumors. They show malignant characteristics indicating rapid proliferation and a high invasive capacity and are associated with a poor prognosis. In our previous study, p68 was overexpressed in glioma cells and correlated with both the degree of glioma differentiation and poor overall survival. Downregulating p68 significantly suppressed proliferation in glioma cells. Moreover, we found that the p68 gene promoted glioma cell growth by activating the nuclear factor‐κB signaling pathway by a downstream molecular mechanism that remains incompletely understood. In this study, we found that dual specificity phosphatase 5 (DUSP5) is a downstream target of p68, using microarray analysis, and that p68 negatively regulates DUSP5. Upregulating DUSP5 in stably expressing cell lines (U87 and LN‐229) suppressed proliferation, invasion, and migration in glioma cells in vitro, consistent with the downregulation of p68. Furthermore, upregulating DUSP5 inhibited ERK phosphorylation, whereas downregulating DUSP5 rescued the level of ERK phosphorylation, indicating that DUSP5 might negatively regulate ERK signaling. Additionally, we show that DUSP5 levels were lower in high‐grade glioma than in low‐grade glioma. These results suggest that the p68‐induced negative regulation of DUSP5 promoted invasion by glioma cells and mediated the activation of the ERK signaling pathway. We found that the function of the DUSP5 gene is to act as the downstream signaling pathway of p68 using global microarray gene expression analysis, and revealed that p68 negatively regulated the DUSP5 gene. Our discovery provides novel insight into the mode of negative regulation in cancer cells and represents a new facet in the complexities of p68 gene tumor‐promoting function. [ABSTRACT FROM AUTHOR]

Abstract: Colorectal cancer (CRC) is a common human malignancy worldwide and increasing studies have attributed its malignant progression to abnormal molecular changes in cancer cells. Nuclear division cycle 80 (NDC80) is a newly discovered oncoprotein that regulates cell proliferation and cycle in numerous malignancies. However, its clinical significance and biological role in CRC remain unclear. Therefore, in this study, we firstly analyze its expression in a retrospective cohort enrolling 224 CRC patients and find its overexpression is significantly correlated with advanced tumor stage and poor prognosis in CRC patients. In addition, our result reveals it is an independent adverse prognostic factor affecting CRC‐specific and disease‐free survival. The subgroup analysis indicates NDC80 expression can stratify the clinical outcome in stage II and III patients, but fails in stage I and IV patients. In cellular assays, we find knockdown of NDC80 dramatically inhibits the proliferative ability, apoptosis resistance, cell cycle progression, and clone formation of CRC cells in vitro. Using xenograft model, we further prove knockdown of NDC80 also inhibits the tumorigenic ability of CRC cells in vivo. Finally, the microarray analysis is utilized to preliminarily clarify the oncogenic molecular mechanisms regulated by NDC80 and the results suggest it may promote CRC progression partly by downregulating tumor suppressors such as dual specificity phosphatase 5 and Forkhead box O1. Taken together, our study provides novel evidences to support that NDC80 is not only a promising clinical biomarker but also a potential therapeutical target for CRC precise medicine. [ABSTRACT FROM AUTHOR]

We recently reported that KO of Dual‐specificity protein phosphatase 5 (Dusp5) enhances myogenic reactivity and blood flow autoregulation in the cerebral and renal circulations in association with increased levels of pPKC and pERK1/2 in the cerebral and renal arteries and arterioles. In the kidney, hypertension‐related renal damage was significantly attenuated in Dusp5 KO rats. Elevations in pPKC and pERK1/2 promote calcium influx in VSMC and facilitate vasoconstriction. However, whether DUSP5 plays a role in altering the passive mechanical properties of cerebral and renal arterioles has never been investigated. In this study, we found that KO of Dusp5 did not alter body weights, kidney and brain weights, plasma glucose, and HbA1C levels. The expression of pERK is higher in the nucleus of primary VSMC isolated from Dusp5 KO rats. Dusp5 KO rats exhibited eutrophic vascular hypotrophy with smaller intracerebral parenchymal arterioles and renal interlobular arterioles without changing the wall‐to‐lumen ratios. These arterioles from Dusp5 KO rats displayed higher myogenic tones, better distensibility, greater compliance, and less stiffness compared with arterioles from WT control rats. VSMC of Dusp5 KO rats exhibited a stronger contractile capability. These results demonstrate, for the first time, that DUSP5 contributes to the regulation of the passive mechanical properties of cerebral and renal arterioles and provide new insights into the role of DUSP5 in vascular function, cancer, stroke, and other cardiovascular diseases. [ABSTRACT FROM AUTHOR]