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The KMT2D variant–caused Kabuki syndrome (KS) is characterized by short stature as a prominent clinical characteristic. The initiation and progression of body growth are fundamentally influenced by chondrocyte proliferation. Uncertainty persists regarding the possibility that KMT2D deficiency affects growth by impairing chondrocyte proliferation. In this study, we used the CRISPR/Cas13d technique to knockdown kmt2d in zebrafish embryos and lentivirus to create a stable Kmt2d gene knockdown cell line in chondrocytes (ATDC5 cells). We also used CCK8 and flow cytometric studies, respectively, to determine proliferation and cell cycle state. The relative concentrations of phosphorylated Akt (ser473), phosphorylated β-catenin (ser552), and cyclin D1 proteins in chondrocytes and zebrafish embryos were determined by using western blots. In addition, Akt inhibition was used to rescue the phenotypes caused by kmt2d deficiency in chondrocytes, as well as a zebrafish model that was generated. The results showed that a knockdown of kmt2d significantly decreased body length and resulted in aberrant cartilage development in zebrafish embryos. Furthermore, the knockdown of Kmt2d in ATDC5 cells markedly increased proliferation and accelerated the G1/S transition. In addition, the knockdown of Kmt2d resulted in the activation of the Akt/β-catenin signaling pathway in ATDC5 cells. Finally, Akt inhibition could partly rescue body length and chondrocyte development in the zebrafish model. Our study demonstrated that KMT2D modulates bone growth conceivably via regulation of the Akt/β-catenin pathway. [ABSTRACT FROM AUTHOR]

Abstract Background Pathological cardiac hypertrophy is associated with cardiac dysfunction and is a key risk factor for heart failure and even sudden death. This study investigates the function of Mycn in cardiac hypertrophy and explores the interacting molecules. Methods A mouse model of cardiac hypertrophy was induced by isoproterenol (ISO). The cardiac dysfunction was assessed by the heart weight-to-body weight ratio (HW/BW), echocardiography assessment, pathological staining, biomarker detection, and cell apoptosis. Transcriptome alteration in cardiac hypertrophy was analyzed by bioinformatics analysis. Gain- or loss-of-function studies of MYCN proto-oncogene (Mycn), ubiquitin specific peptidase 2 (USP2), and junction plakoglobin (JUP) were performed. The biological functions of Mycn were further examined in ISO-treated cardiomyocytes. The molecular interactions were verified by luciferase assay or immunoprecipitation assays. Results Mycn was poorly expressed in ISO-treated mice, and its upregulation reduced HW/BW, cell surface area, oxidative stress, and inflammation while improving cardiac function of mice. It also reduced apoptosis of cardiomyocytes in mice and those in vitro induced by ISO. Mycn bound to the USP2 promoter to activate its transcription. USP2 overexpression exerted similar myocardial protective functions. It stabilized JUP protein by deubiquitination modification, which blocked the Akt/β-catenin pathway. Knockdown of JUP restored phosphorylation of Akt and β-catenin protein level, which negated the protective effects of USP2. Conclusion This study demonstrates that Mycn activates USP2 transcription, which mediates ubiquitination and protein stabilization of JUP, thus inactivating the Akt/β-catenin axis and alleviating cardiac hypertrophy-induced heart failure.

Background: Pathological cardiac hypertrophy is associated with cardiac dysfunction and is a key risk factor for heart failure and even sudden death. This study investigates the function of Mycn in cardiac hypertrophy and explores the interacting molecules. Methods: A mouse model of cardiac hypertrophy was induced by isoproterenol (ISO). The cardiac dysfunction was assessed by the heart weight-to-body weight ratio (HW/BW), echocardiography assessment, pathological staining, biomarker detection, and cell apoptosis. Transcriptome alteration in cardiac hypertrophy was analyzed by bioinformatics analysis. Gain- or loss-of-function studies of MYCN proto-oncogene (Mycn), ubiquitin specific peptidase 2 (USP2), and junction plakoglobin (JUP) were performed. The biological functions of Mycn were further examined in ISO-treated cardiomyocytes. The molecular interactions were verified by luciferase assay or immunoprecipitation assays. Results: Mycn was poorly expressed in ISO-treated mice, and its upregulation reduced HW/BW, cell surface area, oxidative stress, and inflammation while improving cardiac function of mice. It also reduced apoptosis of cardiomyocytes in mice and those in vitro induced by ISO. Mycn bound to the USP2 promoter to activate its transcription. USP2 overexpression exerted similar myocardial protective functions. It stabilized JUP protein by deubiquitination modification, which blocked the Akt/β-catenin pathway. Knockdown of JUP restored phosphorylation of Akt and β-catenin protein level, which negated the protective effects of USP2. Conclusion: This study demonstrates that Mycn activates USP2 transcription, which mediates ubiquitination and protein stabilization of JUP, thus inactivating the Akt/β-catenin axis and alleviating cardiac hypertrophy-induced heart failure. [ABSTRACT FROM AUTHOR]

Neuroblastoma and glioblastoma are primary malignant tumors of the nervous system, with frequent relapse and limited clinical therapeutic drugs. The failure of their treatment is due to the tumor cells exhibiting cancer stem‐like cells (CSLCs) properties. Octamer binding transcription factor 4 (Oct4) is involved in mediating CSLCs, our previous work found that Oct4‐driven reprogramming of astrocytes into induced neural stem cells was potentiated with continuous sonic hedgehog (Shh) stimulation. In this study, we aimed to study the importance of Oct4 and Shh combination in the stemness properties induction of neuroblastoma and glioblastoma cells, and evaluate the anti‐stemness effect of dauricine (DAU), a natural product of bis‐benzylisoquinoline alkaloid. The effect of Oct4 and Shh co‐activation on cancer stemness was evaluated by tumor spheres formation model and flow cytometry analysis. Then the effects of DAU on SH‐SY5Y and T98‐G cells were assessed by the MTT, colony formation, and tumor spheres formation model. DAU acts on Oct4 were verified using the Western blotting, MTT, and so on. Mechanistic studies were explored by siRNA transfection assay, Western blotting, and flow cytometry analysis. We identified that Shh effectively improved Oct4‐mediated generation of stemness in SH‐SY5Y and T98‐G cells, and Oct4 and Shh co‐activation promoted cell growth, the resistance of apoptosis. In addition, DAU, a natural product, was found to be able to attenuate Oct4/Shh co‐activated stemness and induce cell cycle arrest and apoptosis via blocking AKT/β‐catenin signaling in neuroblastoma and glioblastoma, which contributed to the neuroblastoma and glioblastoma cells growth inhibition by DAU. In summary, our results indicated that the treatment of DAU may be served as a potential therapeutic method in neuroblastoma and glioblastoma. [ABSTRACT FROM AUTHOR]

Aberrant protocadherins (PCDHs) expression trigger tumor invasion and metastasis. PCDH20 anti-tumor functions in various tumor have been identified. Tumor suppression is due to Wnt/b-catenin pathway antagonism and may be suppressed caused by PCDH20 downregulation through promotor methylation, whereas PCDH20 effects and regulation mechanism in esophageal squamous cell carcinoma (ESCC) remains elusive. We analyzed PCDH20 effects on ESCC and underlying action mechanisms for PCDH20. We test PCDH20 expression in ESCC tissues and cells by semi-quantitative PCR (RT-PCR) and q-PCR (real-time quantitative polymerase chain reaction). MSP (methylation-specific PCR) was carried out to assess the methylation of PCDH20 in ESCC cells and tissues. Anti-tumor effects of PCDH20 in vitro were assessed by clone formation assay, CCK8 assay, Transwell assay, and flow cytometry. Nude mice tumorigenicity was used to assess PCDH20 anti-tumor effect in vivo. Online database, qPCR, and Western blotting were used to identify the downregulation of MAP3K9 by PCDH20, associated with AKT/βcatenin signaling inactivation. We found that PCDH20 expression was dramatically attenuated in esophageal cancer tissues and cells, maybe due to promotor methylation, and ectopic PCDH20 expression suppressed ESCC malignant biological phenotypes. PCDH20 exerted anti-tumor effects by MAP3K9 downregulation, which suppressed AKT/β-catenin signaling in ESCC cells. Conclusion: PCDH20 was a tumor suppressor gene, which antagonized AKT/β-catenin signaling pathway in ESCC by decreasing MAP3K9. [ABSTRACT FROM AUTHOR]

Synovial mesenchymal stem cells (SMSCs) have been discussed as promising tools for protecting chondrocytes from loss and inhibiting osteoarthritis (OA). This work infocuses on the function of SMSC-derived extracellular vesicles (EVs) in chondrocytes during OA and the molecular mechanism. EVs were extracted from SMSCs and identified. Chondrocytes were treated with interleukin (IL)-1β to induce an OA-like condition in vitro and then treated with EVs. The proliferation, apoptosis, migration, extracellular matrix (ECM) degradation and inflammation in chondrocytes were examined. Key microRNAs (miRNAs) carried by EVs were screened using a microarray analysis, and the downstream molecules involved were explored using bioinformatic analysis. Rescue experiments were performed to validate the involvements of these molecules in EV-mediated events. EVs restored proliferation and migration while reduced apoptosis, ECM degradation and the secretion of pro-inflammatory cytokines in chondrocytes induced by IL-1β. miR-130b-3p was significantly elevated in chondrocytes after EVs treatment. Knockdown of miR-130b-3p blocked the protective roles of EVs against IL-1β-induced damage to chondrocytes. miR-130b-3p was found to target LDL receptor related protein 12 (LRP12) mRNA in chondrocytes. Overexpression of LRP12 counteracted the effects of EVs as well and activated the AKT/β-catenin signaling pathway. This study provided evidence that EVs alleviate chondrocyte damage during OA through miR-130b-3p-mediated inhibition of the LRP12/AKT/β-catenin axis. This study may offer novel thoughts into the protection of chondrocytes and the management of OA. [ABSTRACT FROM AUTHOR]

The natural and synthetic organodiselenides have garnered much research attention due to their chemotherapeutic and chemopreventive activities. Herein, we describe the synthesis of a series of benzylic diselenides, which were synthesized by coupling the in situ generated disodium diselenide with the corresponding benzylic halides. The diselenides were evaluated for their anticancer activities in the highly aggressive triple-negative breast cancer cells. Preliminary anti-proliferative activities indicated 4-cyano-substituted diselenide 7 to be most potent with an IC50 value of 1.9 ± 0.3 μM. Detailed mechanistic investigations showed that diselenide 7 induces apoptosis and causes G1 phase arrest of the cell cycle. It exhibits anticancer activity by suppressing the Akt/β-catenin signaling pathway. Further control experiments with LiCl (inhibitor of GSK-3β) revealed that down-regulation of β-catenin was promoted by GSK-3β-induced phosphorylation of β-catenin and its subsequent proteasomal degradation. Moreover, the intracellular ROS was found to act as an upstream mediator for the inactivation of the Akt/β-catenin signaling pathway. The present study describing the efficient anticancer activity of a synthetic benzylic diselenide towards triple-negative breast cancer cells through the modulation of ROS-dependent Akt/β-catenin signaling pathway would certainly be helpful in the future towards the development of small-molecule organoselenium compounds for the treatment of cancer., (© 2024 Wiley‐VCH GmbH.)

Hepatocellular carcinoma (HCC) is one of the most lethal cancer worldwide, characterized with high heterogeneity and inclination to metastasize. Emerging evidence suggests that BAP31 gets involved in cancer progression with different kinds. It still remains unknown whether and how BAP31 plays a role in HCC metastasis. Epithelial–mesenchymal transition (EMT) has been a common feature in tumor micro-environment, whose inducer TGF-β increased BAP31 expression in this research. Elevated expression of BAP31 was positively correlated with tumor size, vascular invasion and poor prognosis in human HCC. Ectopic expression of BAP31 promoted cell migration and invasion while BAP31 knockdown markedly attenuated metastatic potential in HCC cells and mice orthotopic xenografts. BAP31 induced EMT process, and enhanced the expression level of EMT-related factor Snail and decreased contents and membrane distribution of E-cadherin. BAP31 also activated AKT/β-catenin pathway, which mediated its promotional effects on HCC metastasis. AKT inhibitor further counteracted the activated AKT/β-catenin/Snail upon BAP31 over-expression. Moreover, silencing Snail in BAP31-overexpressed cells impaired enhanced migratory and invasive abilities of HCC cells. In HCC tissues, BAP31 expression was positively associated with Snail. In conclusion, BAP31 promotes HCC metastasis by activating AKT/β-catenin/Snail pathway. Thus, our study implicates BAP31 as potential prognostic biomarker, and provides valuable information for HCC prognosis and treatment.

Kaempferol (KFL), the major constituent of various fruits and vegetables, could attenuate oxidaitve stress and inflammation. The aims of the present study were to explore the ameliorative abilities of KFL on the depressive-like behaviors in a chronic social defeat stress (CSDS) mouse model, and to determine the potential mechanisms on oxidative stress, neuroinflammation, and AKT/β-catenin signaling pathway. Three behavioral tests, sucrose preference test (SPT), social interaction test (SIT), and tail suspension test (TST), were used to evaluate the antidepressive effects of KFL in CSDS mice. Activity levels of antioxidant enzyme, superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), glutathione s-transferase (GST), and concentrations of malonaldehyde (MDA) and protein carbonylation in the prefrontal cortex were assessed by commercial kits, respectively. Elisa was used to detect the levels of interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α). Q-PCR was used to determine the mRNA level of CD-11b. Furthermore, activity level of AKT/β-catenin signaling in the prefrontal cortex of CSDS mice was investigated by western blot. In addition, LY294002, a PI3-K inhibitor, was used to investigate the role of AKT/β-catenin signaling in the antidepressant effects of KFL. Social defeat stress reduced the bodyweights, sucrose consumptions, social interaction times, and the tail suspension mobility times in mice. CSDS mice were also exhibited remarkablely increased levels in oxidative stress markers, inflammatory mediators, and decreased activity of AKT/β-catenin cascade in the prefrontal cortex, which were reversed by treatment with KFL. Interestingly, LY294002 appeared to partly inhibit the overall KFL-mediated protective effects in the CSDS mice. These results confirmed that KFL exerted antidepressive effects, which might be mediated, at least in part, by enhanced antioxidant abilities and anti-inflammation effects via up-regulation AKT/β-catenin cascade activity in the prefrontal cortex of CSDS mice. Thus, KFL might be a promising, effective, and safe food medicine for depression treatment. [ABSTRACT FROM AUTHOR]

Aberrant protocadherins (PCDHs) expression trigger tumor invasion and metastasis. PCDH20 anti-tumor functions in various tumor have been identified. Tumor suppression is due to Wnt/β-catenin pathway antagonism and may be suppressed caused by PCDH20 downregulation through promotor methylation, whereas PCDH20 effects and regulation mechanism in esophageal squamous cell carcinoma (ESCC) remains elusive. We analyzed PCDH20 effects on ESCC and underlying action mechanisms for PCDH20. We test PCDH20 expression in ESCC tissues and cells by semi-quantitative PCR (RT-PCR) and q-PCR (real-time quantitative polymerase chain reaction). MSP (methylation-specific PCR) was carried out to assess the methylation of PCDH20 in ESCC cells and tissues. Anti-tumor effects of PCDH20 in vitro were assessed by clone formation assay, CCK8 assay, Transwell assay, and flow cytometry. Nude mice tumorigenicity was used to assess PCDH20 anti-tumor effect in vivo. Online database, qPCR, and Western blotting were used to identify the downregulation of MAP3K9 by PCDH20, associated with AKT/β-catenin signaling inactivation. We found that PCDH20 expression was dramatically attenuated in esophageal cancer tissues and cells, maybe due to promotor methylation, and ectopic PCDH20 expression suppressed ESCC malignant biological phenotypes. PCDH20 exerted anti-tumor effects by MAP3K9 downregulation, which suppressed AKT/β-catenin signaling in ESCC cells., Conclusion: PCDH20 was a tumor suppressor gene, which antagonized AKT/β-catenin signaling pathway in ESCC by decreasing MAP3K9., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ning, Deng, Li, Peng, Yan, Ran, Chen, Liu, Xia, Ye, Wei and Xiang.)

Hepatocellular carcinoma (HCC) is one of the most lethal cancer worldwide, characterized with high heterogeneity and inclination to metastasize. Emerging evidence suggests that BAP31 gets involved in cancer progression with different kinds. It still remains unknown whether and how BAP31 plays a role in HCC metastasis. Epithelial-mesenchymal transition (EMT) has been a common feature in tumor micro-environment, whose inducer TGF-β increased BAP31 expression in this research. Elevated expression of BAP31 was positively correlated with tumor size, vascular invasion and poor prognosis in human HCC. Ectopic expression of BAP31 promoted cell migration and invasion while BAP31 knockdown markedly attenuated metastatic potential in HCC cells and mice orthotopic xenografts. BAP31 induced EMT process, and enhanced the expression level of EMT-related factor Snail and decreased contents and membrane distribution of E-cadherin. BAP31 also activated AKT/β-catenin pathway, which mediated its promotional effects on HCC metastasis. AKT inhibitor further counteracted the activated AKT/β-catenin/Snail upon BAP31 over-expression. Moreover, silencing Snail in BAP31-overexpressed cells impaired enhanced migratory and invasive abilities of HCC cells. In HCC tissues, BAP31 expression was positively associated with Snail. In conclusion, BAP31 promotes HCC metastasis by activating AKT/β-catenin/Snail pathway. Thus, our study implicates BAP31 as potential prognostic biomarker, and provides valuable information for HCC prognosis and treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Liu, Yu, Ge, Zhao, Miao, Jin, Su, Geng, Chen, Xie, Cui, Yao, Li, Hou and Li.)

Various epidemiology studies showed the correlation between Alzheimer's disease (AD) and low incidence of cancer. However, the etiology underlying etiology of AD-related carcinogenesis remains largely elusive. Our study focused on characterizing the role of TM2D1 (TM2 domain containing 1) in hepatocellular carcinoma. TM2D1 is also known as β-amyloid peptide binding protein and is critical to the pathogenesis of AD. We found that TM2D1 is increasingly expressed in HCC tumors relative to the peritumoral tissues of the matched tumors and high TM2D1 expression predicts unfavorable clinical outcomes. TM2D1 overexpression induced HCC cell proliferation, migration and invasion, which was related to the epithelial-mesenchymal transition (EMT) observed in these cells. Conversely, TM2D1 depletion led to opposite phenotype in HCC. Mechanistically, we found that TM2D1 promoted Akt and β-catenin hyper-activation, which corresponded with molecular marker change in EMT signaling pathway. Taken together, our results indicated that TM2D1 played an important role in the EMT process in HCC cells by activating AKT and β-catenin signaling and may become a promising therapeutic target in HCC., Competing Interests: None., (AJCR Copyright © 2021.)

Rationale : Compelling evidence suggests that Lgr5+ hepatocytes repair liver damage by promoting the regeneration of hepatocytes and ductal cells in the case of liver injury. The PTEN-mediated AKT/β-catenin signaling plays a key role in the regulation of innate immune regulation in the liver. However, the signaling pathways that control Lgr5+ hepatocyte proliferation in the liver remain unclear. Methods : In order to assess the involvement of PTEN-mediated AKT/β-catenin signaling in the expansion of Lgr5+ hepatocytes upon liver injuries, the Lgr5-CreER; Rosa-mTmG lineage tracing system was used to target Lgr5+ hepatocytes. Results: The tracing of Lgr5+ hepatocytes showed that PTEN deletion and β-catenin activation significantly promoted the proliferation of Lgr5+ hepatocytes. In converse, the simultaneous inhibition of PTEN and β-catenin limited Lgr5+ hepatocyte proliferation in the liver. Our findings provide an insight into understanding how PTEN-mediated AKT/β-catenin signaling regulates the proliferation of Lgr5+ hepatocytes. Conclusion: The outcomes can improve the application potential of Lgr5+ hepatocytes in the treatment of liver injury diseases and provide a new treatment option for liver cancer., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)