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MiR-340-5p inhibits pancreatic acinar cell inflammation and apoptosis via targeted inhibition of HMGB1.

ABSTRACT: Acute pancreatitis (AP) is a common gastrointestinal disease that affects 1 million individuals worldwide. Inflammation and apoptosis are considered to be important pathogenic mechanisms of AP, and high mobility group box 1 (HMGB1) has been shown to play a particularly important role in the etiology of this disease. MicroRNAs (miRs) are emerging as critical regulators of gene expression and, as such, they represent a promising area of therapeutic target identification and development for a variety of diseases, including AP. Using the online database query (microRNA.org), the current study identified a site in the 3' untranslated region of HMGB1 mRNA that was a viable target for miR-340-5p. The present study aimed to investigate the association between miR-340-5p and HMGB1 expression in pancreatic acinar cells following lipopolysaccharide (LPS) treatment by performing luciferase, western blotting and reverse transcription-quantitative PCR assays. The results suggest that miR-340-5p attenuates the induction of HMGB1 by LPS, thereby inhibiting inflammation and apoptosis via blunted activation of Toll-like receptor 4 and enhanced AKT signaling. Thus, the therapeutic application of miR-340-5p may be a useful strategy in AP via upregulation of HMGB1 and subsequent promotion of inflammation and apoptosis.

SUBMITTER: Gao Y

PROVIDER: S-EPMC8756431 | biostudies-literature |

REPOSITORIES: biostudies-literature

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CircSmox knockdown alleviates PC12 cell apoptosis and inflammation in spinal cord injury by miR-340-5p/Smurf1 axis.

Project description:BackgroundSpinal cord injury (SCI) is a traumatic central nervous system disorder that leads to irreversible neurological dysfunction. Emerging evidence has shown that differentially expressed circular RNAs (circRNAs) after SCI is closely associated with the pathophysiological process. Herein, the potential function of circRNA spermine oxidase (circSmox) in functional recovery after SCI was investigated.MethodsDifferentiated PC12 cells stimulated with lipopolysaccharide (LPS) were employed as an in vitro model for neurotoxicity research. Levels of genes and proteins were detected by quantitative real-time PCR and Western blot analysis. Cell viability and apoptosis were determined by CCK-8 assay and flow cytometry. Western blot analysis was used to detect the protein level of apoptosis-related markers. The levels of interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor (TNF)-α. Dual-luciferase reporter, RIP, and pull-down assays were used to confirm the target relationship between miR-340-5p and circSmox or Smurf1 (SMAD Specific E3 Ubiquitin Protein Ligase 1).ResultsLPS elevated the levels of circSmox and Smurf1, but decreased the levels of miR-340-5p in PC12 cells in a dose-dependent manner. Functionally, circSmox silencing alleviated LPS-induced apoptosis and inflammation in PC12 cells in vitro. Mechanistically, circSmox directly sponged miR-340-5p, which targeted Smurf1. Rescue experiments showed that miR-340-5p inhibition attenuated the neuroprotective effect of circSmox siRNA in PC12 cells. Moreover, miR-340-5p suppressed LPS-triggered neurotoxicity in PC12 cells, which was reversed by Smurf1 overexpression.ConclusionCircSmox enhances LPS-induced apoptosis and inflammation via miR-340-5p/Smurf1 axis, providing an exciting view of the potential involvement of circSmox in SCI pathogenesis.

| S-EPMC10091371 | biostudies-literature

Knockdown of LINC01694 inhibits growth of gallbladder cancer cells via miR-340-5p/Sox4.

Project description:PURPOSE:The indispensable role of long non-coding RNAs (lncRNAs) in tumorigenesis has been increasingly reported. In the present study, LINC01694 was found to regulate the proliferation, invasion, as well as apoptosis in gallbladder cancer (GBC) cells through sponging miR-340-5p. METHODS:LINC01694 level in GBC cells was quantified by quantitative real-time polymerase chain reaction (qRT-PCR). The proliferation, invasion, and apoptosis were determined by Cell Counting Kit-8 (CCK-8), Transwell, and flow cytometry, respectively. The expression of Sry-related high-mobility group box 4 (Sox4) was detected by Western blot (WB). The interaction between LINC01694 and miR-340-5p was measured by dual-luciferase reporter (DLR) assay, RNA immunoprecipitation (RIP) test, and RNA pull-down. Tumor formation was examined by in vivo experiment. RESULTS:qRT-PCR illustrated that cancerous tissues had higher LINC01694 than normal tissues. Survival analysis demonstrated that the prognosis of patients with high LINC01694 was significantly poorer than those with low LINC01694. Down-regulation of LINC01694 slowed down the proliferation and invasion in GBC cells and accelerated the apoptosis. DLR assay indicated that LINC01694 elevated Sox4 expression by regulating miR-340-5p. LINC01694 functioned as miR-340-5p sponge to inhibit Sox4 expression. CONCLUSION:LINC01694 level is elevated in GBC by regulating miR-340-5p/Sox4 axis, which indicates the poor prognosis of the patients.

| S-EPMC7182660 | biostudies-literature

Paeonol attenuates inflammation by targeting HMGB1 through upregulating miR-339-5p.

Project description:Sepsis is a life-threatening disease caused by infection. Inflammation is a key pathogenic process in sepsis. Paeonol, an active ingredient in moutan cortex (a Chinese herb), has many pharmacological activities, such as anti-inflammatory and antitumour actions. Previous studies have indicated that paeonol inhibits the expression of HMGB1 and the transcriptional activity of NF-κB. However, its underlying mechanism is still unknown. In this study, microarray assay and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) results confirmed that paeonol could significantly up-regulate the expression of miR-339-5p in RAW264.7 cells stimulated by LPS. Dual-luciferase assays indicated that miR-339-5p interacted with the 3' untranslated region (3'-UTR) of HMGB1. Western blot, immunofluorescence and enzyme-linked immunosorbent assay (ELISA) analyses indicated that miR-339-5p mimic and siHMGB1 both negatively regulated the expression and secretion of inflammatory cytokines (e.g., HMGB1, IL-1β and TNF-α) in LPS-induced RAW264.7 cells. Studies have confirmed that IKK-β is targeted by miR-339-5p, and we further found that paeonol could inhibit IKK-β expression. Positive mutual feedback between HMGB1 and IKK-β was observed when we silenced HMGB1 or IKK-β. These results indicated that paeonol could attenuate the inflammation mediated by HMGB1 and IKK-β by upregulating miR-339-5p expression. In addition, we constructed CLP model mice by cecal ligation and puncture. Paeonol was used to intervene to investigate its anti-inflammatory effect in vivo. The results showed that paeonol could improve the survival rate of sepsis mice and protect the kidney of sepsis mice.

| S-EPMC6920373 | biostudies-literature

LINC00501 Inhibits the Growth and Metastasis of Lung Cancer by Mediating miR-129-5p/HMGB1.

Project description:Background:The function of LINC00501, a long-non-coding RNA (lncRNA), is unclear at present. According to the Cancer Genome Atlas (TCGA), LINC00501 is highly expressed in lung cancer (LC), but whether it can be adopted as a potential therapy target for LC still needs further research. Methods:The expression of LINC00501 in LC was analyzed based on the TCGA, and a real-time fluorescent quantitative PCR assay was carried out to quantify LINC00501 in non-small-cell lung cancer (NSCLC). Additionally, bioinformatics analysis, luciferase reporter gene technique, and RNA immunoprecipitation (RIP) were employed to analyze the direct interaction between LINC00501 and miR-129-5p, and CCK-8 and Transwell assays and flow cytometry were employed to analyze the effects of LINC00501 on cell proliferation, invasion, and apoptosis. Furthermore, a Western blot assay was carried out to determine the protein level of HMGB1. Results:LINC00501 was highly expressed in LC according to the database, and it was found that LINC00501 was upregulated in NSCLC specimens and cells, and the up-regulation indicated an unfavorable prognosis. Besides, knockdown of LINC00501 hindered the proliferation and invasion of NSCLC cells and intensified their apoptosis, and LINC00501 could be adopted as competitive endogenous RNA to regulate HMGB1 and tumorigenesis through miR-129-5p. Conclusion:LINC00501 is overexpressed in LC and the overexpression indicates poor prognosis of patients. In addition, LINC00501 can inhibit the invasion and migration of LC by mediating miR-129-5p/HMGB1.

| S-EPMC7386808 | biostudies-literature

Overexpression of miR-340 inhibits cell proliferation and induces apoptosis of human bladder cancer via targeting Glut-1.

Project description:BackgroundBladder cancer (BC) has high mortality due to distant metastasis. Previous works suggested that microRNA (miRNA)-340 is a critical regulator for the development and progression of various cancers. The specific biological function of miR-340 in BC is little known.MethodsIn the present study, RT-qPCR was performed to measure the expression of miR-340 in paired BC tissues and adjacent non-tumor tissues. Next, the target gene of miR-340 was identified using dual-luciferase reporter assay and its level was also tested in tissues. Moreover, cell proliferation and apoptosis were analyzed by CCK-8 and flow cytometry. Finally, the expression of PCNA, Bax was detected by RT-qPCR and western blotting, as well as PI3K/AKT signaling measured by western blotting.ResultThe results demonstrated that miR-340 expression was downregulated and its target Glut-1 level was upregulated in BC tissues. Functionally, overexpression of miR-340 suppressed the proliferation and induced apoptosis in BC cells, while Glut-1 reversed the suppression of proliferation or induction of apoptosis induced by miR-340. Additionally, miR-340 repressed PCNA, p-PI3K and p-AKT levels but enhanced Bax level, while Glut-1 rescued the effects.ConclusionIn conclusion, miR-340 functions as a tumor suppressor of BC, which inhibited proliferation and induced apoptosis by targeting Glut-1 partly through regulating PCNA, Bax expression and PI3K/AKT pathway. This study suggested that miR-340 is a potential target for the treatment of BC.

| S-EPMC8641194 | biostudies-literature

MiR-374b-5p inhibits KDM5B-induced epithelial-mesenchymal transition in pancreatic cancer.

Project description:Micro(mi)RNAs play a critical regulatory role in the progression and metastasis of pancreatic cancer (PC). In this study, we aimed to reveal the mechanisms of miR-374b-5p in regulating epithelial-mesenchymal transition (EMT) in PC. Gene Expression Omnibus datasets (GSE24279 and GSE71533) and the pancreatic ductal adenocarcinoma (PDAC) cohort of The Cancer Genome Atlas were employed to screen for potential prognostic miRNAs. The expression of miR-374b-5p was measured by quantitative real-time polymerase chain reaction (qRT-PCR) in 78 paired PDAC tissue samples. The biological effects of miR-374b-5p were investigated using in vitro and in vivo assays. Luciferase reporter assays and immunohistochemical tests were conducted to verify the interaction between miR-374b-5p and its predicted direct target, KDM5B. MiR-374b-5p was downregulated in PC tissues, and a low level of miR-374b-5p was associated with poor overall survival, greater tumor size, and more lymph node metastasis in PC. In vitro assays indicated that overexpression of miR-374b-5p suppressed the proliferation, migration, and invasion of PC cells. Mechanistically, miR-374b-5p suppressed the expression of KDM5B, which inhibited E-cadherin expression but promoted N-cadherin and vimentin expression. Finally, in vivo assays demonstrated that miR-374b-5p overexpression suppressed tumor growth and lung metastasis in PANC-1 cells. Thus, our findings indicate that miR-374b-5p could be a potential prognostic biomarker and therapeutic target for KDM5B-induced EMT in PC.

| S-EPMC8414380 | biostudies-literature

MicroRNA-340-5p inhibits colon cancer cell migration via targeting of RhoA.

Project description:Colon cancer is the third most common cancer and a significant cause of cancer-related deaths worldwide. Metastasis is the most insidious aspect of cancer progression. Convincing data suggest that microRNAs (miRs) play a key function in colon cancer biology. We examined the role of miR-340-5p in regulating RhoA expression as well as cell migration and invasion in colon cancer cells. Levels of miR-340-5p and RhoA mRNA varied inversely in serum-free and serum-grown HT-29 and AZ-97 colon cancer cells. It was found transfection with miR-340-5p not only decreased expression of RhoA mRNA and protein levels in HT-29 cells but also reduced colon cancer cell migration and invasion. Bioinformatics analysis predicted one putative binding sites at the 3'-UTR of RhoA mRNA. Targeting this binding site with a specific blocker reversed mimic miR-340-5p-induced inhibition of RhoA activation and colon cancer cell migration and invasion. These novel results suggest that miR-340-5p is an important regulator of colon cancer cell motility via targeting of RhoA and further experiments are warranted to evaluate the role of miR-340-5p in colon cancer metastasis.

| S-EPMC7547089 | biostudies-literature

Baicalin suppresses lung cancer growth phenotypes via miR-340-5p/NET1 axis.

Project description:As a malignant disease, lung cancer has a high morbidity and mortality rate. Baicalin is derived from Radix Scutellariae and has anti-tumor effects, however, its role in lung cancer remains unknown. Here, functional assays suggested baicalin suppressed in vitro lung cancer phenotypes. We used micro (mi)RNA array analysis to explore baicalin effects on miRNA expression. We observed baicalin increased miR-340-5p expression, whereas inhibition of this expression abolished anti-tumor effects of baicalin. Furthermore, neuroepithelial cell transforming 1 (NET1) functioned as a miR-340-5p target, and acted in a baicalin-dependent manner to regulate lung cancer progression. Thus, baicalin elicited antitumor activities by affecting the miR-340-5p/NET1 axis, suggesting a new approach to lung cancer clinical management.

| S-EPMC8806212 | biostudies-literature

miR-146a-5p mediates inflammation-induced β cell mitochondrial dysfunction and apoptosis.

Project description:We previously showed that miR-146a-5p is upregulated in pancreatic islets treated with pro-inflammatory cytokines. Others have reported that miR-146a-5p overexpression is associated with β cell apoptosis and impaired insulin secretion. However, the molecular mechanisms mediating these effects remain elusive. To investigate the role of miR-146a-5p in β cell function, we developed stable MIN6 cell lines to either overexpress or inhibit the expression of miR-146a-5p. Monoclonal cell populations were treated with pro-inflammatory cytokines (IL-1β, IFNγ, and TNFα) to model T1D in vitro. We found that overexpression of miR-146a-5p increased cell death under conditions of inflammatory stress, whereas inhibition of miR-146a-5p reversed these effects. Additionally, inhibition of miR-146a-5p increased mitochondrial DNA copy number, respiration rate, and ATP production. Further, RNA sequencing data showed enrichment of pathways related to insulin secretion, apoptosis, and mitochondrial function when the expression levels of miR-146a-5p were altered. Finally, a temporal increase in miR-146a-5p expression levels and a decrease in mitochondria function markers was observed in islets derived from NOD mice. Collectively, these data suggest that miR-146a-5p may promote β cell dysfunction and death during inflammatory stress by suppressing mitochondrial function.

| S-EPMC10983918 | biostudies-literature

Pancreatic Inflammation Redirects Acinar to β Cell Reprogramming.

Project description:Using a transgenic mouse model to express MafA, Pdx1, and Neurog3 (3TF) in a pancreatic acinar cell- and doxycycline-dependent manner, we discovered that the outcome of transcription factor-mediated acinar to β-like cellular reprogramming is dependent on both the magnitude of 3TF expression and on reprogramming-induced inflammation. Overly robust 3TF expression causes acinar cell necrosis, resulting in marked inflammation and acinar-to-ductal metaplasia. Generation of new β-like cells requires limiting reprogramming-induced inflammation, either by reducing 3TF expression or by eliminating macrophages. The new β-like cells were able to reverse streptozotocin-induced diabetes 6 days after inducing 3TF expression but failed to sustain their function after removal of the reprogramming factors.

| S-EPMC5131369 | biostudies-literature

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