Retraction: MicroRNA-182 downregulates Wnt/ß-catenin signaling, inhibits proliferation, and promotes apoptosis in human osteosarcoma cells by targeting HOXA9.

[This retracts the article DOI: 10.18632/oncotarget.21167.].

Retraction Notice to: Bone Marrow Mesenchymal Stem Cell-Derived Exosomal MicroRNA-126-3p Inhibits Pancreatic Cancer Development by Targeting ADAM9.

[This retracts the article DOI: 10.1016/j.omtn.2019.02.022.].

Retraction: MicroRNA-433 inhibits oral squamous cell carcinoma cells by targeting FAK.

[This retracts the article DOI: 10.18632/oncotarget.22151.].

Diastereo- and Enantioselective Construction of Biologically Important Chiral 1,3-Dioxolochroman Frameworks via Catalytic Asymmetric [4+2] Cycloaddition.

A diastereo- and enantioselective construction of biologically important chiral 1,3-dioxolochroman frameworks has been established via chiral phosphoric acid (CPA)-catalyzed asymmetric [4+2] cycloaddition of ortho-quinone methides with 3-methyl-2-vinylindoles. By using this approach, a series of indole-based chiral 1,3-dioxolochromans were synthesized with structural diversity in generally good yields, excellent diastereoselectivities and high enantioselectivities (up to 98% yields, >95:5 dr, 97% ee). The evaluation on the cytotoxic activity of some selected products indicated that this class of chiral 1,3-dioxolochroman derivatives had some extent of anti-cancer activity. This reaction not only provides an efficient synthetic method for accessing chiral 1,3-dioxolochroman derivatives with structural diversity and optical purity but also will enrich the research contents of catalytic asymmetric [4+2] cycloadditions involving ortho-quinone methides. In addition, the bioassay of these compounds will cast a light on discovering useful bioactivities of chiral 1,3-dioxolochroman derivatives, which will be helpful for finding lead compounds.

2, 2', 4, 4'-tetrabromodiphenyl ether (BDE-47) induces mitochondrial dysfunction and related liver injury via eliciting miR-34a-5p-mediated mitophagy impairment.

2,2',4,4'-Tetrabromodiphenyl ether (BDE-47) is associated with various adverse human health effects; however, the knowledge of its toxicity is still very limited. Mitochondrial injury has been observed in liver cells exposed to BDE-47 in vitro. Mitophagy impairment causes the accumulation of dysfunctional mitochondria, contributing to the pathological mechanisms of liver injury. The aim of this study was to investigate whether BDE-47 impairs mitophagy to trigger mitochondrial dysfunction-related liver injury and the underlying mechanisms. This study revealed that BDE-47 elicited mitochondrial dysfunction and related oxidative liver injury by impairing mitophagy. Moreover, our results showed that NAD+ insufficiency is responsible for BDE-47-mediated mitophagy defect and mitochondrial dysfunction in mouse livers, which was associated with suppression of Sirt3/FoxO3a/PINK1 signaling. Furthermore, our results indicated a potential role of miR-34a-5p in the hepatotoxicity of BDE-47. Mechanistically, BDE-47 dramatically upregulated miR-34a-5p expression in mouse livers. The data from AAV-sponge-mediated miR-34a-5p inhibition suggested that miR-34a-5p diminished NAD+ level by directly targeting NAMPT expression in BDE-47-treated mouse livers, which was confirmed by luciferase reporter assay. Consequently, miR-34a-5p markedly abated Sirt3/FoxO3a/PINK1 signaling-mediated mitophagy to promote mitochondrial dysfunction in BDE-47-treated mouse livers. The present study provided in vivo evidence to reveal a potential mechanism for BDE-47-induced mitochondrial dysfunction and related liver injury and indicated that miR-34a-5p-mediated mitophagy impairment might be a therapeutic target for BDE-47 toxicity.

LncRNA AB209371 up-regulated Survivin gene by down-regulating miR-203 in ovarian carcinoma.

AB209371 gene has been characterized as an oncogenic lncRNA in liver cancer. However, its involvement in ovarian carcinoma (OC) is unknown. In the present study, we analyzed the roles of AB209371 in OC. We found that AB209371 gene and Survivin gene were up-regulated in OC and positively correlated with OC development. AB209371 over-expression led to up-regulated Survivin in OC cells, while Survivin over-expression failed to affect AB209371. In addition, AB209371 over-expression led to down-regulated miR-203. However, miR-203 over-expression failed to affect AB209371, but down-regulated the expression of Survivin. In addition, over-expressions of AB209371 and Survivin resulted in the increased proliferation rate of OC cells. Over-expression MiR-203 played the opposite role and attenuated the effects of AB209371 over-expression. Therefore, AB209371 may down-regulate miR-203 to up-regulate Survivin, thereby promoting OC cell proliferation. Our study provided novel insights into the pathogenesis of OC.

Down-regulated lncRNA DLX6-AS1 inhibits tumorigenesis through STAT3 signaling pathway by suppressing CADM1 promoter methylation in liver cancer stem cells.

BACKGROUND: Liver cancer stem cells (LCSCs) are a small subset of cells characterized by unlimited self-renewal, cell differentiation, and uncontrollable cellular growth. LCSCs are also resistant to conventional therapies and are thus believed to be held responsible for causing treatment failure of hepatocellular carcinoma (HCC). It has been recently found that long non-coding RNAs (lncRNAs) are important regulators in HCC. This present study aims to explore the underlying mechanism of how lncRNA DLX6-AS1 influences the development of LCSCs and HCC. METHODS: A microarray-based analysis was performed to initially screen differentially expressed lncRNAs associated with HCC. We then analyzed the lncRNA DLX6-AS1 levels as well as CADM1 promoter methylation. The mRNA and protein expression of CADM1, STAT3, CD133, CD13, OCT-4, SOX2, and Nanog were then detected. We quantified our results by evaluating the spheroid formation, proliferation, and tumor formation abilities, as well as the proportion of tumor stem cells, and the recruitment of DNA methyltransferase (DNMT) in LCSCs when lncRNA DLX6-AS1 was either overexpressed or silenced. RESULTS: LncRNA DLX6-AS1 was upregulated in HCC. The silencing of lncRNA DLX6-AS1 was shown to reduce and inhibit spheroid formation, colony formation, proliferation, and tumor formation abilities, as well as attenuate CD133, CD13, OCT-4, SOX2, and Nanog expression in LCSCs. Furthermore, downregulation of lncRNA DLX6-AS1 contributed to a reduction in CADM1 promoter methylation via suppression of DNMT1, DNMT3a, and DNMT3b in LCSCs and inactivating the STAT3 signaling pathway. CONCLUSION: This study demonstrated that down-regulated lncRNA DLX6-AS1 may inhibit the stem cell properties of LCSCs through upregulation of CADM1 by suppressing the methylation of the CADM1 promoter and inactivation of the STAT3 signaling pathway.

FBXW7 suppresses HMGB1-mediated innate immune signaling to attenuate hepatic inflammation and insulin resistance in a mouse model of nonalcoholic fatty liver disease.

BACKGROUND: Innate immune dysfunction contributes to the development and progression of nonalcoholic fatty liver disease (NAFLD), however, its pathogenesis is still incompletely understood. Identifying the key innate immune component responsible for the pathogenesis of NAFLD and clarifying the underlying mechanisms may provide therapeutic targets for NAFLD. Recently, F-box- and WD repeat domain-containing 7 (FBXW7) exhibits a regulatory role in hepatic glucose and lipid metabolism. This study aims to investigate whether FBXW7 controls high-mobility group box 1 protein (HMGB1)-mediated innate immune signaling to improve NAFLD and the mechanism underlying this action. METHODS: Mice were fed a high-fat diet (HFD) for 12 or 20 weeks to establish NAFLD model. Hepatic overexpression or knockdown of FBXW7 was induced by tail-vein injection of recombinant adenovirus. Some Ad-FBXW7-injected mice fed a HFD were injected intraperitoneally with recombinant mouse HMGB1 to confirm the protective role of FBXW7 in NAFLD via inhibition of HMGB1. RESULTS: FBXW7 improves NAFLD and related metabolic parameters without remarkable influence of body weight and food intake. Moreover, FBXW7 markedly ameliorated hepatic inflammation and insulin resistance in the HFD-fed mice. Furthermore, FBXW7 dramatically attenuated the expression and release of HMGB1 in the livers of HFD-fed mice, which is associated with inhibition of protein kinase R (PKR) signaling. Thereby, FBXW7 restrains Toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE) signaling in HFD-fed mouse livers. In addition, exogenous HMGB1 treatment abolished FBXW7-mediated inhibition of hepatic inflammation and insulin resistance in HFD-fed mouse livers. CONCLUSIONS: Our results demonstrate a protective role of FBXW7 in NAFLD by abating HMGB1-mediated innate immune signaling to suppress inflammation and consequent insulin resistance, suggesting that FBXW7 is a potential target for therapeutic intervention in NAFLD development.

Bone Marrow Mesenchymal Stem Cell-Derived Exosomal MicroRNA-126-3p Inhibits Pancreatic Cancer Development by Targeting ADAM9.

Pancreatic cancer is a lethal malignancy with relatively few effective therapies. Recent investigations have highlighted the role of microRNAs (miRNAs) as crucial regulators in various tumor processes including tumor progression. Hence the current study aimed to investigate the role of bone marrow mesenchymal stem cell (BMSC)-derived exosomal microRNA-126-3p (miR-126-3p) in pancreatic cancer. Initially, miRNA candidates and related genes associated with pancreatic cancer were screened. PANC-1 cells were transfected with miR-126-3p or silenced a disintegrin and a metalloproteinase-9 (ADAM9) to examine their regulatory roles in pancreatic cancer cells. Additionally, exosomes derived from BMSCs were isolated and co-cultured with pancreatic cancer cells to elucidate the effects of exosomes in pancreatic cancer. Furthermore, the effects of overexpressed miR-126-3p derived from BMSCs exosomes on proliferation, migration, invasion, apoptosis, tumor growth, and metastasis of pancreatic cancer cells were analyzed in connection with lentiviral packaged miR-126-3p in vivo. Restored miR-126-3p was observed to suppress pancreatic cancer through downregulating ADAM9. Notably, overexpressed miR-126-3p derived from BMSCs exosomes inhibited the proliferation, invasion, and metastasis of pancreatic cancer cells, and promoted their apoptosis both in vitro and in vivo. Taken together, the key findings of the study indicated that overexpressed miR-126-3p derived from BMSCs exosomes inhibited the development of pancreatic cancer through the downregulation of ADAM9, highlighting the potential of miR-126-3p as a novel biomarker for pancreatic cancer treatment.

Roles of ß-catenin, TCF-4, and survivin in nasopharyngeal carcinoma: correlation with clinicopathological features and prognostic significance.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a common malignant tumor of the head and neck region with poorly understood progression and prognosis. The present study aims at exploring whether the expression of ß-catenin, TCF-4, and survivin affects clinicopathological features and prognostic significance in NPC. METHODS: We enrolled 164 patients with NPC and 70 patients with chronic nasopharyngitis (CNP) in this study. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC) were conducted to evaluate the expression of ß-catenin, TCF-4, and survivin. Spearman's rank correlation analysis and Pearson correlation analysis were used to measure the correlation of ß-catenin, TCF-4, and survivin. Risk factors for prognosis and survival conditions of NPC patients were analyzed by Cox proportional hazards model and Kaplan-Meier curves. RESULTS: The results obtained revealed that mRNA and protein expression of ß-catenin, TCF-4, and survivin was higher in NPC tissues than in CNP tissues. Positive correlations amongst ß-catenin, TCF-4, and survivin were identified by Spearman's rank correlation analysis and Pearson correlation analysis. There was a significant correlation in expression of ß-catenin, TCF-4, and survivin with EBV DNA, EBV-VCA-IgA, EBV-EA-IgA, T stage, N stage, and clinicopathological stages. Lower overall survival (OS), distant metastasis-free survival (DMFS), local recurrence-free survival (LRFS), and disease-free survival (DFS) rates were detected in NPC patients with positive expression of ß-catenin, TCF-4, and survivin, in contrast to those with negative expression. Cox proportional hazards model demonstrated that ß-catenin, TCF-4, and survivin protein positive expression were independent risk factors for OS and DFS of NPC prognosis; there was an evident correlation between clinicopathological stages, TCF-4, and EBV-EA-IgA and OS, DMFS, LRFS, and DFS of NPC. CONCLUSIONS: The aforementioned results indicate that ß-catenin, TCF-4, and survivin proteins are highly expressed in NPC, which can be used as factors to predict the malignancy of NPC. In addition, positive expression of ß-catenin, TCF-4, and survivin are potential risk factors that lead to an unfavorable prognosis of OS and DFS in NPC patients.

High-throughput screening of novel pyruvate dehydrogenase kinases inhibitors and biological evaluation of their in vitro and in vivo antiproliferative activity.

Overexpression of pyruvate dehydrogenase kinases (PDKs) has been widely noticed in a variety of human solid tumors, which could be regarded as an attractive therapeutic target for cancer therapy. In this paper, we present an enzymatic screening assay and multiple biological evaluations for the identification of potential PDKs, especially PDK1 inhibitors. We identified 9 potential PDKs inhibitors from the screening of an in-house small molecule library, all of the identified inhibitors reduced pyruvate dehydrogenase (PDH) complex phosphorylation. Among which, 4, 5, and 9 displayed the most potent PDKs inhibitory activities, with EC50 values of 0.34, 1.4, and 1.6 µM in an enzymatic assay, respectively. A kinase inhibition assay suggested that 4, 5, and 9 were pan-isoform PDK inhibitors, but more sensitive to PDK1. Meanwhile, the three compounds inhibited HSP90, with IC50 values of 0.78, 3.58, and 2.70 µM, respectively. The cell viability assay indicated that 4 inhibited all of the tested cancer cells proliferation, with a GC50 value of 2.3 µM against NCIH1975 cell, but has little effect on human normal lung cell BEAS-2B cell. In the NCIH1975 xenograft models, 4 displayed strong antitumor activities at a dose of 10 and 20 mg/kg, but with no negative effect on the mice weight. In addition, 4 decreased the ECAR and lactate formation, increased OCR and ROS level in NCIH1975 cancer cell, which could be used as a promising modulator to reprogram the glucose metabolic pathways in NCIH1975 cancer cells.

MCL1 gene silencing promotes senescence and apoptosis of glioma cells via inhibition of the PI3K/Akt signaling pathway.

Glioma is known to be the most prevalent primary brain tumor. In recent years, there has been evidence indicating myeloid cell leukemia-1 (MCL1) plays a role in brain glioblastoma. Therefore, the present study was conducted with aims of exploring the ability of MCL1 silencing to influence glioma cell senescence and apoptosis through the mediation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. Glioma and tumor-adjacent tissues were collected in order to detect the presence of higher levels of MCL1 protein expression. Next, the mRNA and protein expression of MCL1, PI3K, Akt, B cell lymphoma 2 (Bcl2), Bcl2-associated X (Bax), B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1), and phosphatase and tensin homolog (PTEN) were determined. Cell counting kit-8 assay was applied to detect cell proliferation, ß-galactosidase staining for cell senescence, and flow cytometry for cell cycle entry and apoptosis. Initially, the results revealed higher positive expression rate of MCL1 protein, increased mRNA and protein expression of MCL1, PI3K, Akt, Bmi-1, and Bcl-2 and decreased that of Bax and PTEN in human glioma tissues. The silencing of MCL1 resulted in a decrease in mRNA and protein expression of PI3K, Akt, Bmi-1, and Bcl-2 and an increase in Bax and PTEN expressions in glioma cells. Moreover, silencing of MCL1 also inhibited cell proliferation and cell cycle entry in glioma cells, and promoted glioma cell senescence and apoptosis. In conclusion, the aforementioned results collectively suggested that the silencing of MCL1 promotes senescence and apoptosis in glioma cells through inhibiting the PI3K/Akt signaling pathway. Thus, decreasing the expression of MCL1 might have therapeutic functions in glioma. © 2018 IUBMB Life, 71(1):81-92, 2019.

Micro-RNA-143 inhibits proliferation and promotes apoptosis of thymocytes by targeting CXCL13 in a myasthenia gravis mouse model.

Myasthenia gravis (MG) is an autoimmune neuromuscular disorder, affecting the quality of life of millions of people worldwide. The present study aims to determine the relationship between micro-RNA-143 (miR-143) and C-X-C motif chemokine 13 (CXCL13) and whether it influences the pathogenesis of myasthenia gravis (MG). Thymus specimens were resected from patients with thymic hyperplasia combined with MG and then infused into normal mouse cavities to establish MG mouse models. Immunohistochemistry, reverse transcription-quantitative PCR, in situ hybridization detection, and Western blot analysis were employed to identify the expression of miR-143 and CXCL13 in MG and normal mice. The obtained thymocytes were cultured in vitro and transfected with a series of miR-143 mimic, miR-143 inhibitor, overexpression of CXCL13, or siRNA against CXCL13. MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] and flow cytometry assays were employed to assess cell viability, cycle entry, and apoptosis of the thymocytes. Dual-luciferase reporter assay provided verification, confirming that CXCL13 was the target gene of miR-143. Low miR-143 expression in the thymus tissues of the MG mice was detected, which presented with a reciprocal relationship with the expression rate of CLCX13. Observations in relation to the interactions between miR-143 mimic or siRNA-CXCL13 exposure showed reduced cell viability, with a greater number of cells arrested at the G0/G1 phase and a greater rate of induced apoptosis. Furthermore, overexpression of CXCL13 rescued miR-143 mimic-induced apoptosis. The findings have identified the potential role of miR-143 as a MG development mediator by targeting CXCL13. The key results obtained provide a promising experimental basis for targeted intervention treatment with miR-143.

Suppression of microRNA-342-3p increases glutamate transporters and prevents dopaminergic neuron loss through activating the Wnt signaling pathway via p21-activated kinase 1 in mice with Parkinson's disease.

Development of effective therapeutic drugs for Parkinson's disease (PD) is of great importance. Aberrant microRNA (miRNA) expression has been identified in postmortem human PD brain samples, in vitro and in vivo PD models. However, the role of miR-342-3p in PD has been understudied. The study explores the effects of miR-342-3p on expression of glutamate (Glu) transporter, and dopaminergic neuron apoptosis and proliferation by targeting p21-activated kinase 1 (PAK1) through the Wnt signaling pathway in PD mice. After establishment of PD mouse models, gain- or loss-of-function assay was performed to explore the functional role of miR-342-3p in PD. Number of apoptotic neurons and Glu concentration was then determined. Subsequently, PC12 cells were treated with miR-342-3p mimic, miR-342-3p inhibitor, dickkopf-1 (DKK1), and miR-342-3p inhibitor + DKK1. The expression of miR-342-3p, PAK1, the Wnt signaling pathway-related and apoptosis-related genes, Glutamate transporter subtype 1 (GLT-1), l-glutamate/ l-aspartate transporter (GLAST), tyrosine hydroxylase (TH) was measured. Also, cell viability and apoptosis were evaluated. PD mice exhibited increased miR-342-3p, while decreased expression of PAK1, GLT-1, GLAST, TH, and the Wnt signaling pathway-related and antiapoptosis genes. miR-342-3p downregulation could promote expression of PAK1, the Wnt signaling pathway-related and antiapoptosis genes. GLT-1, GLAST, and TH as well as cell viability, but reduce cell apoptosis rate. The results indicated that suppression of miR-342-3p improves expression of Glu transporter and promotes dopaminergic neuron proliferation while suppressing apoptosis through the Wnt signaling pathway by targeting PAK1 in mice with PD.

Long noncoding RNA nuclear enriched abundant transcript 1 impacts cell proliferation, invasion, and migration of glioma through regulating miR-139-5p/ CDK6.

AIMS: We aimed to explore the impact of long noncoding RNA (lncRNA) nuclear enriched abundant transcript 1 (NEAT1) on cell proliferation, invasion, and migration of glioma. METHODS: Differentially expressed genes were screened out from Gene Expression Omnibus data set based on the microarray analysis. The expression levels of lncRNA NEAT1, miR-139-5p, and CDK6 in glioma cells and tissues were examined by quantitative reverse transcription polymerase chain reaction, and the protein level of CDK6 in glioma cells was determined by western blot and immunohistochemistry. Glioma cell viability, cell cycle, and apoptosis were detected by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) and flow cytometry, respectively, whereas cell invasion and migration were analyzed by transwell assay. The target relationships among NEAT1, miR-139-5p, and CDK6 were confirmed by dual-luciferase reporter gene assay. The effects of lncRNA NEAT1 on tumor growth were further testified through glioma xenografts in nude mice. RESULTS: LncRNA NEAT1 and CDK6 were highly expressed in glioma tissues and cells, whereas miR-139-5p was lowly expressed. There were target relationships and correlations on expressions between miR-139-5p and NEAT1/ CDK6. NEAT1 and CDK6 could promote cell proliferation and metastasis of glioma cells and impeded cell apoptosis, whereas miR-139-5p exerted suppressive effects on the biological functions of glioma cells. NEAT1 regulated CDK6 to affect glioma growth through sponging miR-139-5p. CONCLUSIONS: LncRNA NEAT1 promotes cell proliferation, invasion, and migration of glioma through regulating miR-139-5p/CDK6 pathway.

ZNF300 stimulates fatty acid oxidation and alleviates hepatosteatosis through regulating PPARα.

ZNF300 plays an important role in the regulation of HBV-related hepatocellular carcinoma. However, little is known about the role of ZNF300 in lipid metabolism and NAFLD. In the present study, we observed that ZNF300 expression was markedly decreased in free fatty acid (FFA)-induced fatty liver. Overexpressed ZNF300 alleviated hepatic lipid accumulation, whereas knockdown of ZNF300 enhanced the FFA-induced lipid accumulation. Investigations of the underlying mechanisms revealed that ZNF300 directly binds to and regulates the PPARα expression, thus promoting fatty acid oxidation. Furthermore, bisulfite pyrosequencing PCR (BSP) analysis identified the hypermethylation status of ZNF300 gene in FFA-treated hepatocytes. Importantly, the suppression of ZNF300 could be blocked by DNA methyltransferase inhibitor (5-azadC) or DNMT3a-siRNA. These results suggested that ZNF300 plays an important role in hepatic lipid metabolism via PPARα promoting fatty acid oxidation and this effect might be blocked by DNMT3a-mediated methylation of ZNF300. Therefore, in addition to ZNF300 expression levels, the methylation status of this gene also has a potential as a prognostic biomarker.