Calcium saccharate/DUSP6 suppresses renal cell carcinoma glycolytic metabolism and boosts sunitinib efficacy via the ERK-AKT pathway.

Current therapeutic options for renal cell carcinoma (RCC) are very limited, which is largely due to inadequate comprehension of molecular pathological mechanisms as well as RCC's resistance to chemotherapy. Dual-specificity phosphatase 6 (DUSP6) has been associated with numerous human diseases. However, its role in RCC is not well understood. Here, we show that diminished DUSP6 expression is linked to RCC progression and unfavorable prognosis. Mechanistically, DUSP6 serves as a tumor suppressor in RCC by intervening the TAF10 and BSCL2 via the ERK-AKT pathway. Further, DUSP6 is also transcriptionally regulated by HNF-4a. Moreover, docking experiments have indicated that DUSP6 expression is enhanced when bound by Calcium saccharate, which also inhibits RCC cell proliferation, metabolic rewiring, and sunitinib resistance. In conclusion, our study identifies Calcium saccharate as a prospective pharmacological therapeutic approach for RCC.

Stable knockdown of Drp1 improves retinoic acid-BDNF-induced neuronal differentiation through global transcriptomic changes and results in reduced phosphorylation of ERK1/2 independently of DUSP1 and 6.

Background: Dynamin-related protein Drp1 -a major mitochondrial fission protein- is widely distributed in the central nervous system and plays a crucial role in regulating mitochondrial dynamics, specifically mitochondrial fission and the organelle's shaping. Upregulated Drp1 function may contribute to the pathological progression of neurodegenerative diseases by dysregulating mitochondrial fission/ fusion. The study aims to investigate the effects of Drp1 on retinoic acid-BDNF-induced (RA-BDNF) neuronal differentiation and mitochondrial network reorganization in SH-SY5Y neuroblastoma cells. Methods: We generated an SH-SY5Y cell line with stably depleted Drp1 (shDrp1). We applied RNA sequencing and analysis to study changes in gene expression upon stable Drp1 knockdown. We visualized the mitochondria by transmission electron microscopy and used high-content confocal imaging to characterize and analyze cell morphology changes and mitochondrial network reorganization during neuronal differentiation. Results: shDrp1 cells exhibited fused mitochondrial ultrastructure with perinuclear clustering. Stable knockdown of Drp1 resulted in the upregulation of genes involved in nervous system development. High content analysis showed improved neurite outgrowth, segmentation, and extremities in differentiated shDrp1 cells. Neuronal differentiation was associated with a significant reduction in ERK1/2 phosphorylation, and ERK1/2 phosphorylation was independent of the dual specificity phosphatases DUSP1/6 in shDrp1 cells. Differentiated control underwent mitochondrial morphology remodeling, whereas differentiated shDrp1 cells retained the highly fused mitochondria and developed long, elongated structures. The shDrp1 cells responded to specific apoptotic stimuli like control in vitro, suggesting that Drp1 is not a prerequisite for apoptosis in SH-SY5Y cells. Moreover, Drp1 downregulation reduced the formation of toxic mHtt aggregates in vitro. Discussion: Our results indicate that Drp1 silencing enhances RA-BDNF-induced neuronal differentiation by promoting transcriptional and mitochondrial network changes in undifferentiated cells. We also demonstrate that the suppression of Drp1 reduces toxic mHtt aggregate formation in vitro, suggesting protection against neurotoxicity. Thus, Drp1 may be an attractive target for further investigation in future strategies to combat neurodegenerative diseases.

Critical Role of miR-130b-5p in Cardiomyocyte Proliferation and Cardiac Repair in Mice After Myocardial Infarction.

Poor proliferative capacity of adult cardiomyocytes is the primary cause of heart failure after myocardial infarction (MI), thus exploring the molecules and mechanisms that promote the proliferation of adult cardiomyocytes is crucially useful for cardiac repair after MI. Here, we found that miR-130b-5p was highly expressed in mouse embryonic and neonatal hearts and able to promote cardiomyocyte proliferation both in vitro and in vivo. Mechanistic studies revealed that miR-130b-5p mainly promoted the cardiomyocyte proliferation through the MAPK-ERK signaling pathway, and the dual-specific phosphatase 6 (Dusp6), a negative regulator of the MAPK-ERK signaling, was the direct target of miR-130b-5p. Moreover, we found that overexpression of miR-130b-5p could promote the proliferation of cardiomyocytes and improve cardiac function in mice after MI. These studies thus revealed the critical role of miR-130b-5p and its targeted MAPK-ERK signaling in the cardiomyocyte proliferation of adult hearts and proved that miR-130b-5p could be a potential target for cardiac repair after MI.

Dual-Specificity Phosphatase 6 Deficiency Attenuates Arterial-Injury-Induced Intimal Hyperplasia in Mice.

In response to injury, vascular smooth muscle cells (VSMCs) of the arterial wall dedifferentiate into a proliferative and migratory phenotype, leading to intimal hyperplasia. The ERK1/2 pathway participates in cellular proliferation and migration, while dual-specificity phosphatase 6 (DUSP6, also named MKP3) can dephosphorylate activated ERK1/2. We showed that DUSP6 was expressed in low baseline levels in normal arteries; however, arterial injury significantly increased DUSP6 levels in the vessel wall. Compared with wild-type mice, Dusp6-deficient mice had smaller neointima. In vitro, IL-1ß induced DUSP6 expression and increased VSMC proliferation and migration. Lack of DUSP6 reduced IL-1ß-induced VSMC proliferation and migration. DUSP6 deficiency did not affect IL-1ß-stimulated ERK1/2 activation. Instead, ERK1/2 inhibitor U0126 prevented DUSP6 induction by IL-1ß, indicating that ERK1/2 functions upstream of DUSP6 to regulate DUSP6 expression in VSMCs rather than downstream as a DUSP6 substrate. IL-1ß decreased the levels of cell cycle inhibitor p27 and cell-cell adhesion molecule N-cadherin in VSMCs, whereas lack of DUSP6 maintained their high levels, revealing novel functions of DUSP6 in regulating these two molecules. Taken together, our results indicate that lack of DUSP6 attenuated neointima formation following arterial injury by reducing VSMC proliferation and migration, which were likely mediated via maintaining p27 and N-cadherin levels.

Alcohol Consumption During Adolescence Alters the Cognitive Function in Adult Male Mice by Persistently Increasing Levels of DUSP6.

Binge alcohol drinking during adolescence has long-term effects on the adult brain that alter brain structure and behaviors, but the underlying mechanisms remain poorly understood. Extracellular signal-regulated kinase (ERK) is involved in the synaptic plasticity and pathological brain injury by regulating the expression of cyclic adenosine monophosphate response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF). Dual-specificity phosphatase 6 (DUSP6) is a critical effector that dephosphorylates ERK1/2 to control the basal tone, amplitude, and duration of ERK signaling. To explore DUSP6 as a regulator of ERK signaling in the mPFC and its impact on long-term effects of alcohol, a male mouse model of adolescent intermittent alcohol (AIA) exposure was established. Behavioral experiments showed that AIA did not affect anxiety-like behavior or sociability in adulthood, but significantly damaged new object recognition and social recognition memory. Molecular studies further found that AIA reduced the levels of pERK-pCREB-BDNF-PSD95/NR2A involved in synaptic plasticity, while DUSP6 was significantly increased. Intra-mPFC infusion of AAV-DUSP6-shRNA restored the dendritic spine density and postsynaptic density thickness by reversing the level of p-ERK and its downstream molecular expression, and ultimately repaired adult cognitive impairment caused by chronic alcohol exposure during adolescence. These findings indicate that AIA exposure inhibits ERK-CREB-BDNF-PSD95/NR2A by increasing DUSP6 in the mPFC in adulthood that may be associated with long-lasting cognitive deficits.

LncRNA SPRY4-IT1 regulates 16HBE cell malignant transformation induced by particulate matter through DUSP6-ERK1/2-Chk1 signaling pathway.

Particulate matter (PM), one of the most serious air contaminants, could easily pass through the airway and deposit at the deep alveoli. Thus, it might trigger respiratory diseases like inflammation, asthma and lung cancer on human. Long non-coding RNAs (lncRNAs) are considered as important regulator in promotion and progression of diverse cancers. However, the molecular mechanism of lncRNAs mediating PM-induced lung carcinogenesis remains unclear. In this study, we established a 16HBE malignant transformed cell induced by PM (Cells were treated with 20 µg/ml PM, which named PM-T cells) and explored the roles and mechanisms of lncRNAs in the malignant transformation induced by PM. Compared with 16HBE cells, various biological functions were changed in PM-T cells, such as cell proliferation, migration, cell cycle and apoptosis. LncRNA SPRY4-IT1 was significant down-regulated expression and associated with these biological effects. Our results showed that lncRNA SPRY4-IT1 overexpression reversed these functional changes mentioned above. The further studies indicated that lncRNA SPRY4-IT1 involved in PM-induced cell transformation by modulating Chk1 expression via negative regulation of DUSP6-ERK1/2. In conclusion, our studies suggested that lncRNA SPRY4-IT1 played the role as a tumor suppressor gene and might mediate 16HBE cells malignant transformation induced by PM through regulating DUSP6-ERK1/2-Chk1 signaling pathway.

In Vitro and In Silico Investigation of BCI Anticancer Properties and Its Potential for Chemotherapy-Combined Treatments.

BACKGROUND: DUSP6 phosphatase serves as a negative regulator of MAPK kinases involved in numerous cellular processes. BCI has been identified as a potential allosteric inhibitor with anticancer activity. Our study was designed to test the anticancer properties of BCI in colon cancer cells, to characterize the effect of this compound on chemotherapeutics such as irinotecan and oxaliplatin activity, and to identify potential molecular targets for this inhibitor. METHODS: BCI cytotoxicity, proapoptotic activity, and cell cycle distribution were investigated in vitro on three colon cancer cell lines (DLD1, HT-29, and Caco-2). In silico investigation was prepared to assess BCI drug-likeness and identify potential molecular targets. RESULTS: The exposure of colorectal cancer cells with BCI resulted in antitumor effects associated with cell cycle arrest and induction of apoptosis. BCI exhibited strong cytotoxicity on DLD1, HT-29, and Caco-2 cells. BCI showed no significant interaction with irinotecan, but strongly attenuated the anticancer activity of oxaliplatin when administered together. Analysis of synergy potential further confirmed the antagonistic interaction between these two compounds. In silico investigation indicated CDK5 as a potential new target of BCI. CONCLUSIONS: Our studies point to the anticancer potential of BCI but note the need for a precise mechanism of action.

BOP1 Promotes Prostate Cancer through the DUSP6/MAPK Pathway.

BACKGROUND: Nucleolar prominence is a biomarker of prostate cancer (CaP), and the nucleolar protein block of proliferation 1 (BOP1) participates in the development of CaP, which has great significance for CaP therapy. Thus, this study explored the mechanism of BOP1 in CaP development. METHODS: BOP1 expression levels in the tumor tissues of CaP patients and in PC3 tumor cells were determined. The viability, apoptosis rate of PC3 cells, and apoptosis-related proteins levels were determined to explore the effect of BOP1 on tumor-cell growth in vitro. BOP1 function in the metastasis of PC3 cells was further assessed by Transwell experiment. We also studied the influence of BOP1 on the expression of mitogen-activated protein kinase (MAPK) pathway-related proteins and investigated the regulatory effect of BOP1 on dual-specificity phosphatase 6 (DUSP6). RESULTS: BOP1 expression was upregulated in the tumor tissues and PC3 cells of CaP patients. BOP1 knockout reduced the activity of PC3 cells and induced apoptosis, significantly inhibiting the metastasis of PC3 cells. DUSP6 was overexpressed in tumor tissues and PC3 cells. BOP1 knockout inhibited DUSP6 expression and the MAPK pathway. DUSP6 overexpression reversed the inhibition of BOP1 siRNA (si-BOP1) on PC3 cells and the activated MAPK signaling pathway. CONCLUSIONS: This finding demonstrated that BOP1 promoted CaP progression by regulating the DUSP6/MAPK pathway.

BOP1 Promotes Prostate Cancer through the DUSP6/MAPK Pathway

Background: Nucleolar prominence is a biomarker of prostate cancer (CaP), and the nucleolar protein block of proliferation 1 (BOP1) participates in the development of CaP, which has great significance for CaP therapy. Thus, this study explored the mechanism of BOP1 in CaP development. Methods: BOP1 expression levels in the tumor tissues of CaP patients and in PC3 tumor cells were determined. The viability, apoptosis rate of PC3 cells, and apoptosis-related proteins levels were determined to explore the effect of BOP1 on tumor-cell growth in vitro. BOP1 function in the metastasis of PC3 cells was further assessed by Transwell experiment. We also studied the influence of BOP1 on the expression of mitogen-activated protein kinase (MAPK) pathway-related proteins and investigated the regulatory effect of BOP1 on dual-specificity phosphatase 6 (DUSP6). Results: BOP1 expression was upregulated in the tumor tissues and PC3 cells of CaP patients. BOP1 knockout reduced the activity of PC3 cells and induced apoptosis, significantly inhibiting the metastasis of PC3 cells. DUSP6 was overexpressed in tumor tissues and PC3 cells. BOP1 knockout inhibited DUSP6 expression and the MAPK pathway. DUSP6 overexpression reversed the inhibition of BOP1 siRNA (si-BOP1) on PC3 cells and the activated MAPK signaling pathway. Conclusions: This finding demonstrated that BOP1 promoted CaP progression by regulating the DUSP6/MAPK pathway (AU)

DUSP6 inhibits the proliferation of hair follicle stem cells (HFSCs) in vitro.

RNA-seq has shown that the DUSP6 and MAPK signaling pathways are associated with the production of high-quality brush hair (type III hair) in Yangtze River Delta white goats. However, there are few reports on the regulatory effects of DUSP6 expression on hair follicle stem cells (HFSCs) and cellular processes, as well as the underlying mechanism. Here, we investigated the effect of DUSP6 level in HFSCs and the molecular mechanism underlying the functional regulation of HFSCs by DUSP6. Overexpression of DUSP6 significantly suppressed the proliferation of HFSCs by inducing cell cycle arrest in the G1 phase and by promoting apoptosis. Transcriptome analysis revealed a total of 217 differentially expressed genes between DUSP6-overexpressing and control HFSCs, of which 33 (15.2%) were upregulated in DUSP6-overexpressing cells. The two pathways with the most significant enrichment of differentially expressed genes were the TNF signaling pathway and cytokine-cytokine receptor interaction pathway, and the significantly enriched terms in the GO enrichment analysis involved cell attachment and cytokines. These results indicate that DUSP6 can function as an inhibitory factor in HFSCs through the induction of cell cycle arrest in the G1 phase and can promote apoptosis by mediating crosstalk among several pathways and cytokines.HighlightsWe constructed DUSP6 overexpression vectors to detect mRNA and protein expression levels related to high-quality brush hair in MAPK signaling pathway.We found that high expression level of DUSP6 can inhibit the proliferation of hair follicle stem cells (HFSCs) and promote cell apoptosis of HFSCs.DUSP6 may be involved in the growth regulation of HFSCs like Other studies in cancer, tumors by regulating the expression of cytokines, changing the transmission of signals between cells, activating or suppressing immune-related pathways.

miR-101-5p suppresses trophoblast cell migration and invasion via modulating the DUSP6-ERK1/2 axis in preeclampsia.

PURPOSE: Dysregulated behaviors of trophoblast cells leading to defective placentation are considered the main cause of preeclampsia (PE). Abnormal miRNA expression profiles have been observed in PE placental tissue, indicating the significant role of miRNAs in PE development. This study aimed to investigate the expression of miR-101-5p in PE placental tissue and its biological functions. METHODS: The expression of miR-101-5p in placental tissue was detected by quantitative real-time PCR (qRT-PCR). The localization of miR-101-5p in term placental tissue and decidual tissue was determined by the fluorescence in situ hybridization (FISH)-immunofluorescence (IF) double labeling assay. The effect of miR-101-5p on the migration, invasion, proliferation, and apoptosis of the HTR8/SVneo trophoblast cells was investigated. Online databases combined with transcriptomics were used to identify potential target genes and related pathways of miR-101-5p. Finally, the interaction between miR-101-5p and the target gene was verified by qRT-PCT, WB, dual-luciferase reporter assay, and rescue experiments. RESULTS: The study found that miR-101-5p was upregulated in PE placental tissue compared to normal controls and was mainly located in various trophoblast cell subtypes in placental and decidual tissues. Overexpression of miR-101-5p impaired the migration and invasion of HTR8/SVneo cells. DUSP6 was identified as a potential downstream target of miR-101-5p. The expression of miR-101-5p was negatively correlated with DUSP6 expression in HTR8/SVneo cells, and miR-101-5p directly bound to the 3' UTR region of DUSP6. DUSP6 upregulation rescued the migratory and invasive abilities of HTR8/SVneo cells in the presence of miR-101-5p overexpression. Additionally, miR-101-5p downregulated DUSP6, resulting in enhanced ERK1/2 phosphorylation. CONCLUSION: This study revealed that miR-101-5p inhibits the migration and invasion of HTR8/SVneo cells by regulating the DUSP6-ERK1/2 axis, providing a new molecular mechanism for the pathogenesis of PE.

DUSP6 Deficiency Attenuates Neurodegeneration after Global Cerebral Ischemia.

Transient global cerebral ischemia (tGCI) resulting from cardiac arrest causes selective neurodegeneration in hippocampal CA1 neurons. Although the effect is clear, the underlying mechanisms directing this process remain unclear. Previous studies have shown that phosphorylation of Erk1/2 promotes cell survival in response to tGCI. DUSP6 (also named MKP3) serves as a cytosolic phosphatase that dephosphorylates Erk1/2, but the role of DUSP6 in tGCI has not been characterized. We found that DUSP6 was specifically induced in the cytoplasm of hippocampal CA1 neurons 4 to 24 h after tGCI. DUSP6-deficient mice showed normal spatial memory acquisition and retention in the Barnes maze. Impairment of spatial memory acquisition and retention after tGCI was attenuated in DUSP6-deficient mice. Neurodegeneration after tGCI, revealed by Fluoro-Jade C and H&E staining, was reduced in the hippocampus of DUSP6-deficient mice and DUSP6 deficiency enhanced the phosphorylation and nuclear translocation of Erk1/2 in the hippocampal CA1 region. These data support the role of DUSP6 as a negative regulator of Erk1/2 signaling and indicate the potential of DUSP6 inhibition as a novel therapeutic strategy to treat neurodegeneration after tGCI.

Missense polymorphisms potentially involved in mandibular prognathism.

Objective: The current study aimed to identify and analyze missense single nucleotide polymorphisms (SNPs) that can potentially cause mandibular prognathism. Methods: After reviewing the articles, 56 genes associated with mandibular prognathism were identified and their missense SNPs were retrieved from the NCBI website. Several web-based tools including CADD, PolyPhen-2, PROVEAN, SNAP2, PANTHER, FATHMM, and PON-P2 were used to filter out harmful SNPs. Additionally, ConSurf determined the level of evolutionary conservation at positions where SNPs occur. I-Mutant2 and MUpro predicted the effect of SNPs on protein stability. Furthermore, to investigate the structural and functional changes of proteins, HOPE and LOMETS tools were utilized. Results: Based on predictions in at least four web-based tools, the results indicated that PLXNA2-rs4844658, DUSP6-rs2279574, and FBN3-rs33967815 are harmful. These SNPs are located at positions with variable or average conservation and have the potential to reduce the stability of their respective proteins. Moreover, they may impair protein activity by causing structural and functional changes. Conclusions: In this study, we identified PLXNA2-rs4844658, DUSP6-rs2279574, and FBN3-rs33967815 as potential risk factors for mandibular prognathism using several web-based tools. According to the possible roles of PLXNA2, DUSP6, and FBN3 proteins in ossification pathways, we recommend that these SNPs be investigated further in experimental research. Through such studies, we hope to gain a better understanding of the molecular mechanisms involved in mandible formation.

LncTUG1 ameliorates renal tubular fibrosis in experimental diabetic nephropathy through the miR-145-5p/dual-specificity phosphatase 6 axis.

The renal interstitial fibrosis contributes to the progression and deterioration of diabetic nephropathy (DN). Long noncoding RNA taurine-up-regulated gene 1 (TUG1) in kidneys may be down-regulated by hyperglycemia. We aim to explore its role in tubular fibrosis caused by high glucose and the possible target genes of TUG1. In this study, a streptozocin-induced accelerated DN mouse model and a high glucose-stimulated HK-2 cells model was established to evaluate TUG1 expression. Potential targets of TUG1 were analyzed by online tools and confirmed by luciferase assay. A rescue experiment and gene silencing assay were used to investigate whether TUG1 plays its regulation role via miR-145-5p/dual-specificity phosphatase 6 (DUSP6) in HK2 cells. The effects of TUG1 on inflammation and fibrosis in high glucose treated tubular cells were evaluated by in vitro study, as well as in vivo DN mice model through AAV-TUG1 delivery. Results showed TUG1was downregulated in HK2 cells incubated with high glucose while miR-145-5p was upregulated. Overexpression of TUG1 alleviated renal injury by suppressing inflammation and fibrosis in vivo. Overexpression of TUG1 inhibited HK-2 cell fibrosis and relieved the inflammation. A mechanism study demonstrated that TUG1 directly sponged to miR-145-5p, and DUSP6 was identified as a target downstream of miR-145-5p. In addition, miR-145-5 overexpression and DUSP6 inhibition countervailed the impacts of TUG1. Our findings revealed that TUG1 overexpression alleviates kidney injury in DN mice and decreases the inflammatory response and fibrosis of high glucose-stimulated HK-2 cells via miR-145-5p/DUSP6 axis.

Aging and obesity prime the methylome and transcriptome of adipose stem cells for disease and dysfunction.

The epigenome of stem cells occupies a critical interface between genes and environment, serving to regulate expression through modification by intrinsic and extrinsic factors. We hypothesized that aging and obesity, which represent major risk factors for a variety of diseases, synergistically modify the epigenome of adult adipose stem cells (ASCs). Using integrated RNA- and targeted bisulfite-sequencing in murine ASCs from lean and obese mice at 5- and 12-months of age, we identified global DNA hypomethylation with either aging or obesity, and a synergistic effect of aging combined with obesity. The transcriptome of ASCs in lean mice was relatively stable to the effects of age, but this was not true in obese mice. Functional pathway analyses identified a subset of genes with critical roles in progenitors and in diseases of obesity and aging. Specifically, Mapt, Nr3c2, App, and Ctnnb1 emerged as potential hypomethylated upstream regulators in both aging and obesity (AL vs. YL and AO vs. YO), and App, Ctnnb1, Hipk2, Id2, and Tp53 exhibited additional effects of aging in obese animals. Furthermore, Foxo3 and Ccnd1 were potential hypermethylated upstream regulators of healthy aging (AL vs. YL), and of the effects of obesity in young animals (YO vs. YL), suggesting that these factors could play a role in accelerated aging with obesity. Finally, we identified candidate driver genes that appeared recurrently in all analyses and comparisons undertaken. Further mechanistic studies are needed to validate the roles of these genes capable of priming ASCs for dysfunction in aging- and obesity-associated pathologies.

miR-133a-3p regulates the growth of hair follicle stem cells in white goats from the Yangtze River Delta.

The Yangtze River Delta white goats are the sole goat breed producing brush hair of high quality. Owing to the particularities of its wool production, a higher demand is placed on breeding efforts for this animal. Studies on the developmental mechanisms of the aligned hair follicle stem cells (HFSCs) provide a theoretical basis for molecular breeding. In the present study, HFSCs were isolated using the technique of immunohistochemistry from the cervical spinal skin tissue samples from the fetal sheep, and the miR-133a-3p expression was confirmed using quantitative reverse-transcription PCR (RT-qPCR) and western blotting experiments from the isolated HFSCs. Additionally, the effects on the proliferation and apoptosis of HFSCs were detected using flow cytometry and 5-ethynyl-2'-deoxyuridine assays, along with other methods, following the overexpression of miR-133a-3p or its inhibition. The experimental results revealed that miR-133a-3p overexpressed could inhibit the proliferation of HFSCs and promote apoptosis by specifically targeting DUSP6. While the miR-133a-3p knockdown could promote the proliferation but inhibit the apoptosis of the HFSCs. Meanwhile, the miR-133a-3p knockdown experiments showed opposite outcomes. These results illustrate the presence of a relevant network between DUSP6 and miR-133a-3p, which regulates the production of superior-quality brush hair.

A DUSP6 inhibitor suppresses inflammatory cardiac remodeling and improves heart function after myocardial infarction.

Acute myocardial infarction (MI) results in loss of cardiomyocytes and abnormal cardiac remodeling with severe inflammation and fibrosis. However, how cardiac repair can be achieved by timely resolution of inflammation and cardiac fibrosis remains incompletely understood. Our previous findings have shown that dual-specificity phosphatase 6 (DUSP6) is a regeneration repressor from zebrafish to rats. In this study, we found that intravenous administration of the DUSP6 inhibitor (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one (BCI) improved heart function and reduced cardiac fibrosis in MI rats. Mechanistic analysis revealed that BCI attenuated macrophage inflammation through NF-κB and p38 signaling, independent of DUSP6 inhibition, leading to the downregulation of various cytokines and chemokines. In addition, BCI suppressed differentiation-related signaling pathways and decreased bone-marrow cell differentiation into macrophages through inhibiting DUSP6. Furthermore, intramyocardial injection of poly (D, L-lactic-co-glycolic acid)-loaded BCI after MI had a notable effect on cardiac repair. In summary, BCI improves heart function and reduces abnormal cardiac remodeling by inhibiting macrophage formation and inflammation post-MI, thus providing a promising pro-drug candidate for the treatment of MI and related heart diseases. This article has an associated First Person interview with the first author of the paper.

Identification of upregulated genes in glioblastoma and glioblastoma cancer stem cells using bioinformatics analysis.

Glioblastoma (GBM) is the most common malignant brain tumor among adults. Cancer stem cells (CSCs) are known to drive treatment resistance and recurrence. However, a few CSC markers have been identified as therapeutic targets for GBM. This study aimed to show highly coexpressed genes in GBM CSCs and TCGA GBM samples and to identify possible therapeutic targets for GBM. The gene expression profiles of GBM CSCs were obtained from Gene Expression Omnibus database. After the differentially upregulated genes were screened, functional enrichment analyses were performed using DAVID and Reactome databases. For upregulated genes, biological processes were mainly associated with the regulation of transcription. Subsequently, a protein-protein interaction network was constructed for upregulated genes through STRING, in which DUSP6, FGFR3, EGFR, SOX2, NES, and PLP1 were further identified as hub genes via MCC and MNC methods. Expression profiles of hub genes and their association with survival were examined in TCGA GBM dataset using GEPIA2 platform. The expression levels of four hub genes were found to be increased in TCGA GBM samples. Of these, DUSP6 and SOX2 had prognostic value for patients with GBM. Molecular compounds targeting DUSP6 were searched through PubChem database. (E/Z)-BCI and BCI were found to be inhibitors of DUSP6. The molecular docking was performed using Autodock vina 1.02. The compounds showed strong binding capacities by forming various interactions with the ERK2 binding domain of DUSP6. Hence, the current study unravels the potential of (E/Z)-BCI and BCI compounds as possible anti-cancer molecules for GBM treatment.

SKA1 promotes tumor metastasis via SAFB-mediated transcription repression of DUSP6 in clear cell renal cell carcinoma.

The most hostile form of urologic cancer, clear cell renal cell carcinoma (ccRCC), has a high fatality rate and poor prognosis due to tumor metastasis at initial presentation. The complex process driving ccRCC metastasis is still unknown, though. In this study, we demonstrate that Spindle and kinetochore-associated protein 1 (SKA1) expression is significantly upregulated in ccRCC tissues and associated with aggressive clinicopathologic characteristics. Functionally, SKA1 knockdown on ccRCC cells reduced cancer cell motility both in vivo and in vitro research. These bioactivities of SKA1 may be brought on by its specific interaction with scaffold attachment factor B, according to the proposed mechanism (SAFB), which could further depress the transcription of dual specificity phosphatase 6 (DUSP6). Our findings may provide a new way of researching SKA1-regulated tumor metastasis, and indicate that SKA1 is a prospective therapeutic target for renal carcinoma.

CIC-Rearranged Sarcomas: An Intriguing Entity That May Lead the Way to the Comprehension of More Common Cancers.

Capicua transcriptional repressor (CIC)-rearranged sarcoma, belonging to the undifferentiated round cells sarcoma family, is characterized by high metastatic rate and poor chemo response. CIC sarcoma represents a new entity harboring the recurrent chromosomal translocation between CIC and, in most of the cases, DUX4. CIC-DUX4 imposes a CIC-specific transcriptional signature, which drives cell transformation, proliferation, and migration. While the discovery of the fusion represented the first evidence of a role of CIC in cancer, a complete comprehension of CIC-rearranged activity is still required before providing new potential avenues for therapy. To date, a specific and effective treatment for CIC sarcoma has yet to be defined. In this review, we initially highlight the clinical features and pathogenesis of CIC-rearranged sarcomas along with current therapeutic approaches and then focus on the specific oncogenic mechanisms driven by the CIC-rearrangement. We discuss novel therapeutic options evoked by the aberrant relations of CIC-DUX4 with the IGF system, DUSP6, P300/CBP, and CCNE1. We also discuss how different mutations involving CIC might converge on a common upregulation of CIC-target genes across human cancers. A deeper understanding of the oncogenic mechanisms driven by the chimera CIC-DUX4 might provide novel therapeutic opportunities with a general impact in cancer.