Correction to: Sunitinib-suppressed miR-452-5p facilitates renal cancer cell invasion and metastasis through modulating SMAD4/SMAD7 signals.
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ABSTRACT:
SUBMITTER: Zhai W
PROVIDER: S-EPMC8985374 | biostudies-literature | 2022 Apr
REPOSITORIES: biostudies-literature
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Correction to: Sunitinib-suppressed miR-452-5p facilitates renal cancer cell invasion and metastasis through modulating SMAD4/SMAD7 signals.
Zhai Wei W Li Saiyang S Zhang Jin J Chen Yonghui Y Ma Junjie J Kong Wen W Gong Dongkui D Zheng Junhua J Xue Wei W Xu Yunfei Y
Molecular cancer 20220406 1
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Project description:PurposeAlthough microRNAs (miRNAs) were revealed as crucial modulators in tumor metastasis and target therapy, our understanding of their roles in metastatic renal cell carcinoma (mRCC) and Sunitinib treatment was limited. Here we sought to identify human miRNAs that acted as key regulators in renal cancer metastasis and Sunitinib treatment.Experimental designWe focused on 2 published microarray data to select out our anchored miRNA and then explored the roles of miR-452-5p both in vitro and in vivo, which was downregulated after Sunitinib treatment while upregulated in metastasis renal cell carcinoma (RCC) tissues.ResultsHere, we discovered that treating with Sunitinib, the targeted receptor tyrosine kinase inhibitor (TKI), inhibited renal cancer cell migration and invasion via attenuating the expression of miR-452-5p. The novel identified miR-452-5p was upregulated and associated with poor prognosis in RCC. Preclinical studies using multiple RCC cells and xenografts model illustrated that miR-452-5p could promote RCC cell migration and invasion in vitro and in vivo. Mechanistically, P65 could directly bind to the miR-452-5p promoter and thus transcriptionally induce miR-452-5p expression, which led to post-transcriptionally abrogate SMAD4 expression, thus inhibition of its downstream gene SMAD7.ConclusionOur study presented a road map for targeting this newly identified miR-452-5p and its SMAD4/SMAD7 signals pathway, which imparted a new potential therapeutic strategy for mRCC treatment.
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Project description:The mutated SCN5A gene encoding defective Nav1.5 protein causes arrhythmic ailments and is associated with enhanced cardiac fibrosis. This study investigated whether SCN5A mutation directly affects cardiac fibroblasts and explored how defective SCN5A relates to cardiac fibrosis. SCN5A knockdown (SCN5AKD) human cardiac fibroblasts (HCF) had higher collagen, α-SMA, and fibronectin expressions. Micro-RNA deep sequencing and qPCR analysis revealed the downregulation of miR-452-5p and bioinformatic analysis divulged maladaptive upregulation of transforming growth factor β (TGF-β) signaling in SCN5AKD HCF. Luciferase reporter assays validated miR-452-5p targets SMAD4 in SCN5AKD HCF. Moreover, miR-452-5p mimic transfection in SCN5AKD HCF or AAV9-mediated miR-452-5p delivery in isoproterenol-induced heart failure (HF) rats, resulted in the attenuation of TGF-β signaling and fibrogenesis. The exogenous miR-452-5p significantly improved the poor cardiac function in HF rats. In conclusion, miR-452-5p regulates cardiac fibrosis progression by targeting the TGF-β/SMAD4 axis under the loss of the SCN5A gene.
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Project description:SCN5A coding for sodium channels in the heart and its reduced activity implicated various biological processes including fibrogenesis. However, the mechanistic interplay between loss of SCN5A activity and cardiac fibrosis pertinence remains elusive. In-vitro knockdown of the SCN5A gene activates fibroblasts and increases TGF-β signaling with small-RNA sequencing indicating its impact on miR-452-5P expression in human cardiac fibroblasts (HCF). Mechanistically, miR-452-5p acts as a direct regulator of TGF-β signaling by inhibiting SMAD4 expression, maintaining cellular homeostasis in normal physiological conditions. SCN5A knockdown limits miR-452-5p regulatory function on SMAD4, which further promotes cardiac fibrosis (CF). These results clarify the significant involvement of miR-452-5p in CF development and propose a promising target for potential therapeutic intervention.
2024-06-20 | GSE261598 | GEO
Project description:Osteoblast differentiation is a complex process that is essential for normal bone formation. A growing number of studies have shown that microRNAs (miRNAs) are key regulators in a variety of physiological and pathological processes, including osteogenesis. In this study, BMP2 was used to induce MC3T3-E1 cells to construct osteoblast differentiation cell model. Then, we investigated the effect of miR-452-3p on osteoblast differentiation and the related molecular mechanism by RT-PCR analysis, Western blot analysis, ALP activity, and Alizarin Red Staining. We found that miR-452-3p was significantly downregulated in osteoblast differentiation. Overexpression miR-452-3p (miR-452-3p mimic) significantly inhibited the expression of osteoblast marker genes RUNX2, osteopontin (OPN), and collagen type 1 a1 chain (Col1A1), and decreased the number of calcium nodules and ALP activity. In contrast, knockdown miR-452-3p (miR-452-3p inhibitor) produced the opposite effect. In terms of mechanism, we found that Smad4 may be the target of miR-452-3p, and knockdown Smad4 (si-Smad4) partially inhibited the osteoblast differentiation enhanced by miR-452-3p. Our results suggested that miR-452-3p plays an important role in osteoblast differentiation by targeting Smad4. Therefore, miR-452-3p is expected to be used in the treatment of bone formation and regeneration.
| S-EPMC8485836 | biostudies-literature
Project description:BackgroundMicroRNAs (miRNAs) as the subtype of non-coding RNAs are revealed to be crucial players in cellular activities. It has been reported that miR-3619-5p functions as a tumor inhibitor in several cancers. However, the connection between miR-3619-5p and stomach adenocarcinoma (STAD) remains to be discovered.Aim of the studyThe purpose of the study is to figure out the role and molecular regulation mechanism of miR-3619-5p in STAD.MethodsThe expression of miR-3619-5p was evaluated via qRT-PCR analysis. Gain-of-function experiments demonstrated the effects of miR-3619-5p on cellular functions. The upper-stream transcription factor STAT4 and downstream target gene TBC1D10B of miR-3619-5p were identified by bioinformatic analysis. The binding and interaction between the indicated molecules were verified by RNA pull-down and luciferase reporter assays.ResultsThe expression of miR-3619-5p was prominently down-regulated in STAD cells and tissues. MiR-3619-5p suppresses cell proliferation, migration, invasion and tumor growth in STAD. Further, STAT4 bound with miR-3619-5p promoter and inhibited its transcription. MiR-3619-5p was also recognized to modulate STAD progression through the regulation of downstream target gene TBC1D10B.ConclusionSTAT4-mediated miR-3619-5p controls STAD carcinogenesis and progression through modulating TBC1D10B expression, which may provide a novel insight for researching the STAD-related molecular mechanism.
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Project description:BackgroundLINC01140 has been known to be involved in various cancers. However, its underlying molecular mechanism in breast cancer (BC) needs further exploration.MethodsThe LINC01140, miR-452-5p, and RGS2 levels in BC cells and tissues were evaluated by means of RT-qPCR and western blotting. The variations in the biological functions of BC cells were analyzed through CCK-8, transwell, western blotting, and xenograft experiments to observe cell viability, migration, levels of apoptosis-related proteins (Bax and Bcl-2), and tumor growth. The correlations existing among LINC01140, miR-452-5p, and RGS2 were validated through luciferase reporter and RIP assays.ResultsLINC01140 and RGS2 were remarkably downregulated in BC cells and tissues, whereas miR-452-5p was upregulated. LINC01140 overexpression diminished BC cell viability, migration, and tumor growth and facilitated apoptosis. MiR-452-5p upregulation enhanced cell viability and migration and suppressed apoptosis. Nevertheless, the additional upregulation of LINC01140 could reverse the promotive effects of miR-452-5p upregulation. Additionally, RGS2 overexpression inhibited the malignant phenotypes of BC cells, but miR-452-5p upregulation abolished this effect. In terms of mechanisms, LINC01140 acted as a miR-452-5p sponge. Moreover, RGS2 was determined to be miR-452-5p's downstream target gene in BC.ConclusionLINC01140 functioned as an antitumor agent in BC by sponging miR-452-5p to release RGS2. This hints that LINC01140 is a promising therapeutic target for BC.
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Project description:Fibrosis after skeletal muscle injury is common in sports and can cause irreversible damage to the biomechanical properties of skeletal muscle. Long non-coding RNAs (lncRNAs) have been validated to act as important modulators in the fibrosis of various organs. Here, we reported a novel lncRNA (the skeletal muscle fibrosis-associated transcript 1, lnc-MFAT1), which was highly expressed in skeletal muscle fibrosis. We demonstrate that lnc-MFAT1 knockdown can reduce TGFβ-induced fibrosis in vitro and attenuate skeletal muscle fibrosis after acute contusion in mice. Further study showed that lnc-MFAT1 acted as a competitive endogenous RNA of miR-135a-5p. Besides, the miR-135a-5p inhibition obviously promoted TGFβ-induced fibrosis in vitro via enhancing its target genes Tgfbr2/Smad4. Moreover, we discovered that lnc-MFAT1 regulates Tgfbr2/Smad4 expression by sponging miR-135a-5p to exert competing endogenous RNA function, resulting in TGFβ pathway activation. In conclusion, our study identified a crucial role of lnc-MFAT1-miR-135a-Tgfbr2/Smad4 axis in skeletal muscle fibrosis, providing a promising treatment option against skeletal muscle fibrosis.
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Project description:Dysregulation of long non-coding RNAs (lncRNAs) confirm that it plays a crucial role in tumourigenesis and malignant progression of glioma. The present study demonstrated that LncRNA secretory carrier membrane protein 1 (SCAMP1) was up-regulated and functioned as an oncogene in glioma cells. In addition, miR-499a-5p was down-regulated meanwhile exerted tumour-suppressive function in glioma cells. Subsequently, inhibition of SCAMP1 significantly restrained the cell proliferation, migration and invasion, as well as promoted apoptosis by acting as a molecular sponge of miR-499a-5p. Transcription factor LIM homeobox transcription factor 1, alpha (LMX1A) was overexpressed in glioma tissues and cells. Moreover, miR-499a-5p targeted LMX1A 3'-UTR in a sequence-specific manner. Hence, down-regulation of SCAMP1 remarkably reduced the expression level of LMX1A, indicating that LMX1A participated in miR-499a-5p-induced tumour-suppressive effects on glioma cells. Furthermore, knockdown of LMX1A decreased NLR family, CARD domain containing 5 (NLRC5) mRNA and protein expression levels through directly binding to the NLRC5 promoter region. Down-regulation of NLRC5 obviously inhibited malignant biological behaviours of glioma cells through attenuating the activity of Wnt/β-catenin signalling pathway. In conclusion, our study clarifies that SCAMP1/miR-499a-5p/LMX1A/NLRC5 axis plays a critical role in modulating malignant progression of glioma cells, which provide a novel therapeutic strategy for glioma treatment.
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Project description:Objective: The pancreatic endocrinal system dominates the regulation of blood glucose levels in vivo, and the dysfunction of pancreatic endocrine β-cells is a major cause of the occurrence and development of Type 2 diabetes (T2D). Although microRNA (miRNA) have been found to be key regulators of pancreatic β-cells proliferation, differentiation and apoptosis, the underlying mechanism remains enigmatic. The aim of this study was to identify several novel miRNAs which might be involved in the etiopathogenesis of diabetic β-cells dysfunction. Methods: The miRNA expression profiles in the pancreas of high-fat diet (HFD) fed Zucker diabetic fatty (ZDF) rats and Zucker lean (ZL) rats feed with normal-fat diet (NFD) were detected by using miRNA microarray chip, and individually verified the most significant factors by quantitative real-time polymerase chain reaction (qRT-PCR) assay. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to predict the target genes related to each of the identified miRNAs and the functions of these target genes in different metabolic signaling pathways. Results: Compared with the ZL rats, a total of 24 differentially expressed miRNAs were detected in ZDF rats. Among which miR-34a-5p and miR-452-5p were the most significantly up-regulated and down-regulated respectively. These miRNAs have not been reported in rats' pancreas before. By GO and KEGG enrichment analyses, we found that miR-34a-5p could negatively regulate pancreatic β-cell proliferation through the involvement of Wnt signaling pathway. In addition, it was also found to regulate insulin secretion through the insulin signaling pathway to modulate blood glucose levels. At the same time, miR-452-5p was found to positively regulate the activity of the key rate-limiting enzyme branched-chain α-keto acid dehydrogenase-β (BCKDHB) in the catabolism of branched chain amino acids (BCAA), leading to mitochondrial dysfunction in pancreatic β-cells. Conclusions: miR-34a-5p and miR-452-5p were identified as the novel regulators of pancreatic endocrine dysfunction. These miRNAs might have the potential to be utilized as the new predictive biomarkers for the diagnosis of the occurrence and development of T2D, as well as the therapeutic targets for T2D treatment.
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Project description:Cell division cycle associated 7 (CDCA7) is a copy number amplification gene that contributes to the metastasis and invasion of tumors, including esophageal squamous cell carcinoma (ESCC). This present study aimed at clarifying whether high expression of CDCA7 promotes the metastasis and invasion of ESCC cell lines and exploring the underlying mechanisms implicated in epithelial-mesenchymal transition (EMT) of ESCC. The role of CDCA7 in the regulation of ESCC metastasis and invasion was evaluated using ESCC cell lines. Expression of EMT-related markers including E-cadherin, N-cadherin, Vimentin, Snail, and Slug, transforming growth factor β (TGF-β) signaling pathway including Smad2/3, p-Smad2/3, Smad4, and Smad7 were detected in CDCA7 knockdown and overexpressed cell lines. Dual-luciferase reporter assay and rescue assay were used to explore the underlying mechanisms that CDCA7 contributed to the metastasis and invasion of ESCC. High CDCA7 expression significantly promoted the metastasis and invasion of ESCC cell lines both in vivo and in vitro. Additionally, the expression of CDCA7 positively correlated with the expression of N-cadherin, Vimentin, Snail, Slug, TGF-β signaling pathway and negatively correlated with the expression of E-cadherin. Furthermore, CDCA7 transcriptionally regulated the expression of Smad4 and Smad7. Knockdown of CDCA7 inhibited the TGF-β signaling pathway and therefore inhibited EMT. Our data indicated that CDCA7 was heavily involved in EMT by regulating the expression of Smad4 and Smad7 in TGF-β signaling pathway. CDCA7 might be a new therapeutic target in the suppression of metastasis and invasion of ESCC.
| S-EPMC9807500 | biostudies-literature