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Abstract Excessive glucocorticoid (GC) action is linked to various metabolic disorders. Recent findings suggest that disrupting skeletal GC signaling prevents bone loss and alleviates metabolic disorders in high-fat diet (HFD)-fed obese mice, underpinning the neglected contribution of skeletal GC action to obesity and related bone loss. Here, we show that the elevated expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), the enzyme driving local GC activation, and GC signaling in osteoblasts, are associated with bone loss and obesity in HFD-fed male mice. Osteoblast-specific 11β-HSD1 knockout male mice exhibit resistance to HFD-induced bone loss and metabolic disorders. Mechanistically, elevated 11β-HSD1 restrains glucose uptake and osteogenic activity in osteoblast. Pharmacologically inhibiting osteoblastic 11β-HSD1 by using bone-targeted 11β-HSD1 inhibitor markedly promotes bone formation, ameliorates glucose handling and mitigated obesity in HFD-fed male mice. Taken together, our study demonstrates that osteoblastic 11β-HSD1 directly contributes to HFD-induced bone loss, glucose handling impairment and obesity.

Sclerostin emerges as a novel target for bone anabolic therapy in bone diseases. Osteogenesis imperfecta (OI) and X-linked hypophosphatemia (XLH) are rare bone diseases in which therapeutic potential of sclerostin inhibition cannot be ignored. In OI, genetic/pharmacologic sclerostin inhibition promoted bone formation of mice, but responses varied by genotype and age. Serum sclerostin levels were higher in young OI-I patients, while lower in adult OI-I/III/IV. It's worth investigating whether therapeutic response of OI to sclerostin inhibition could be clinically predicted by genotype and age. In XLH, preclinical/clinical data suggested factors other than identified FGF23 contributing to XLH. Higher levels of circulating sclerostin were detected in XLH. Sclerostin inhibition promoted bone formation in Hyp mice, while restored phosphate homeostasis in age-/gender-dependent manner. The role of sclerostin in regulating phosphate metabolism deserves investigation. Sclerostin/FGF23 levels of XLH patients with/without response to FGF23-antibody warrants study to develop precise sclerostin/FGF23 inhibition strategy or synergistic/additive strategy. Notably, OI patients were associated with cardiovascular abnormalities, so were XLH patients receiving conventional therapy. Targeting sclerostin loop3 promoted bone formation without cardiovascular risks. Further, blockade of sclerostin loop3-LRP4 interaction while preserving sclerostin loop2-ApoER2 interaction could be a potential precise sclerostin inhibition strategy for OI and XLH with cardiovascular safety.The Translational Potential of this Article.Preclinical data on the molecular understanding of sclerostin inhibition in OI and therapeutic efficacy in mouse models of different genotypes, as well as clinical data on serum sclerostin levels in patients with different phenotypes of OI, were reviewed and discussed. Translationally, it would facilitate to develop clinical prediction strategies (e.g. based on genotype and age, not just phenotype) for OI patients responsive to sclerostin inhibition. Both preclinical and clinical data suggested sclerostin as another factor contributing to XLH, in addition to the identified FGF23. The molecular understanding and therapeutic effects of sclerostin inhibition on both promoting bone anabolism and improving phosphate homostasis in Hyp mice were reviewed and discussed. Translationaly, it would facilitate the development of precise sclerostin/FGF23 inhibition strategy or synergistic/additive strategy for the treatment of XLH. Cardiovascular risk could not be ruled out during sclerostin inhibition treatment, especially for OI and XLH patients with cardiovascular diseases history and cardiovascular abnormalities. Studies on the role of sclerostin in inhiting bone formation and protecting cardiovascular system were reviewed and discussed. Translationaly, blockade of sclerostin loop3-LRP4 interaction while preserving sclerostin loop2-ApoER2 interaction could be a potential precise sclerostin inhibition strategy for OI and XLH with cardiovascular safety.

Osteogenesis imperfecta (OI) is a rare genetic disease characterized by bone fragility and bone formation. Sclerostin could negatively regulate bone formation by antagonizing the Wnt signal pathway, whereas it imposes severe cardiac ischemic events in clinic. Our team has screened an aptamer that could promote bone anabolic potential without cardiovascular risk. However, the affinity of the aptamer is lower and needs to be improved. In the study, hydrophobic quinoline molecule with unique orientations (seven subtypes) were incorporated into key sites of a bone anabolic aptamer against sclerostin to form a modified aptamer library. Among all the quinoline modifications, 5-quinoline modification could shape the molecular recognition of modified aptamers to sclerostin to facilitate enhancing its binding to sclerostin toward the highest affinity by interacting with newly participated binding sites in sclerostin. Further, 5-quinoline modification could facilitate the modified aptamer attenuating the suppressed effect of the transfected sclerostin on both Wnt signaling and bone formation marker expression levels in vitro, promoting bone anabolism in OI mice (Col1a2+/G610C). The proposed quinoline-oriented modification strategy could shape the molecular recognition of modified aptamers to proteins to facilitate enhancing its binding affinity and therapeutic potency.

Abstract Objectives Primary blast lung injury (PBLI) is the main cause of death in blast injury patients, and is often ignored due to the absence of a specific diagnosis. Circular RNAs (circRNAs) are becoming recognized as new regulators of various diseases, but the role of circRNAs in PBLI remain largely unknown. This study aimed to investigate PBLI-related circRNAs and their probable roles as new regulators in PBLI in order to provide new ideas for PBLI diagnosis and treatment. Methods The differentially expressed (DE) circRNA and mRNA profiles were screened by transcriptome high-throughput sequencing and validated by quantitative real-time PCR (qRT-PCR). The GO and KEGG pathway enrichment was used to investigate the potential function of DE mRNAs. The interactions between proteins were analyzed using the STRING database and hub genes were identified using the MCODE plugin. Then, Cytoscape software was used to illustrate the circRNA-miRNA-hub gene network. Results A total of 117 circRNAs and 681 mRNAs were aberrantly expressed in PBLI, including 64 up-regulated and 53 down-regulated circRNAs, and 315 up-regulated and 366 down-regulated mRNAs. GO and KEGG analysis revealed that the DE mRNAs might be involved in the TNF signaling pathway and Fanconi anemia pathway. Hub genes, including Cenpf, Ndc80, Cdk1, Aurkb, Ttk, Aspm, Ccnb1, Kif11, Bub1 and Top2a, were obtained using the MCODE plugin. The network consist of 6 circRNAs (chr18:21008725–21020999 + , chr4:44893533–44895989 + , chr4:56899026–56910247-, chr5:123709382–123719528-, chr9:108528589–108544977 + and chr15:93452117–93465245 +), 7 miRNAs (mmu-miR-3058-5p, mmu-miR-3063-5p, mmu-miR-668-5p, mmu-miR-7038-3p, mmu-miR-761, mmu-miR-7673-5p and mmu-miR-9-5p) and 6 mRNAs (Aspm, Aurkb, Bub1, Cdk1, Cenpf and Top2a). Conclusions This study examined a circRNA-miRNA-hub gene regulatory network associated with PBLI and explored the potential functions of circRNAs in the network for the first time. Six circRNAs in the circRNA-miRNA-hub gene regulatory network, including chr18:21008725–21020999 + , chr4:44893533–44895989 + , chr4:56899026–56910247-, chr5:123709382–123719528-, chr9:108528589–108544977 + and chr15:93452117–93465245 + may play an essential role in PBLI.

This study presents a novel tripartite evolutionary game model within a social-ecological system framework to address the challenge of securing sustainable operational funding for national parks while balancing social and ecological interests. The model engages 3 key stakeholders: government, public welfare organizations, and national park operators, highlighting their complex interdependencies. Findings indicate that cooperative strategies among stakeholders are more likely when appropriate incentives and penalties are applied and decrease with higher associated costs. The study recommends that policymakers implement diversified funding mechanisms, clarify fiscal responsibilities, and promote coordinated efforts between central and local governments. Additionally, reducing operational costs and barriers for public welfare organizations and park operators can enhance cooperative behavior. This research provides valuable insights for optimizing funding mechanisms for national parks and offers an innovative tool for the study of social-ecological systems.

The molecular weight of nucleic acid aptamers (20 kDa) is lower than the cutoff threshold of the renal filtration (30–50 kDa), resulting in a very short half-life, which dramatically limits their druggability. To address this, we utilized 3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-(4-hydroxy-2-oxo-2H-chromen-6-yl)propenamide (HC) and 12-((2,5-dioxopyrrolidin-1-yl)oxy)-12-oxododecanoic acid (DA), two newly designed coupling agents, for synergistic binding to human serum albumin (HSA). Both HC and DA are conjugated to a bone anabolic aptamer (Apc001) against sclerostin to form an Apc001OC conjugate with high binding affinity to HSA. Notably, HC and DA could synergistically facilitate prolonging the half-life of the conjugated Apc001 and promoting its bone anabolic potential. Using the designed blocking peptides, the mechanism studies indicate that the synergistic effect of HC-DA on pharmacokinetics and bone anabolic potential of the conjugated Apc001 is achieved via their synergistic binding to HSA. Moreover, biweekly Apc001OC at 50 mg/kg shows comparable bone anabolic potential to the marketed sclerostin antibody given weekly at 25 mg/kg. This proposed bimolecular modification strategy could help address the druggability challenge for aptamers with a short half-life.

In drug discovery, selecting targeted molecules is crucial as the target could directly affect drug efficacy and the treatment outcomes. As a member of the CCN family, CTGF (also known as CCN2) is an essential regulator in the progression of various diseases, including fibrosis, cancer, neurological disorders, and eye diseases. Understanding the regulatory mechanisms of CTGF in different diseases may contribute to the discovery of novel drug candidates. Summarizing the CTGF-targeting and -inhibitory drugs is also beneficial for the analysis of the efficacy, applications, and limitations of these drugs in different disease models. Therefore, we reviewed the CTGF structure, the regulatory mechanisms in various diseases, and drug development in order to provide more references for future drug discovery.

The burning loss of Al and Ti elements in superalloys during electroslag remelting has become a prevalent issue. And the existing slag system is not suitable for smelting the ATI 718PlusTM alloy. Therefore, it is imperative to develop a new slag system for smelting the ATI 718PlusTM alloy. To mitigate this issue, a thermodynamic model of the oxidation reaction of Al and Ti at the slag and alloy interface was established based on the ion and molecule coexistence theory (IMCT). The thermodynamic model was used to investigate the correlation between the equilibrium content of Al and Ti, slag composition, smelting temperature, and initial Al and Ti content of the electrode. The results indicate that while increasing the smelting temperature can effectively inhibit the burning loss of Al, it will exacerbate the burning loss of Ti. Increasing CaO and Al2O3 contents can inhibit the Al burning loss, while an increase in the TiO2 content can inhibit the Ti burning loss. Although an increase in the MgO content results in the burning loss of Al, its impact on the Al is minimal. The burning loss of Al and Ti was not affected by the change in the CaF2 content. The high Al content in ATI 718PlusTM makes it prone to burning loss of Al during the electroslag remelting. The combustion loss of Al can be reduced by increasing the Ti content in the electrode or adding a suitable amount of aluminum powder to the slag system. The accuracy of the model had been validated through experimental verification.

The interception of one chemical intermediate with another intermediate is very challenging, as intermediates may be incompatible or too reactive, but could result in a streamlined method of organic synthesis. Here, the authors demonstrate enantioselective four-component reactions via the coupling of two intermediates.

Small noncoding RNAs, known as microRNAs (miRNAs), are vital for the regulation of diverse biological processes. miR-223, an evolutionarily conserved anti-inflammatory miRNA expressed in cells of the myeloid lineage, has been implicated in the regulation of monocyte–macrophage differentiation, proinflammatory responses, and the recruitment of neutrophils. The biological functions of this gene are regulated by its expression levels in cells or tissues. In this review, we first outline the regulatory role of miR-223 in granulocytes, macrophages, endothelial cells, epithelial cells and dendritic cells (DCs). Then, we summarize the possible role of miR-223 in chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), coronavirus disease 2019 (COVID-19) and other pulmonary inflammatory diseases to better understand the molecular regulatory networks in pulmonary inflammatory diseases.

Sclerostin, a protein secreted from osteocytes, negatively regulates the WNT signaling pathway by binding to the LRP5/6 co-receptors and further inhibits bone formation and promotes bone resorption. Sclerostin contributes to musculoskeletal system-related diseases, making it a promising therapeutic target for the treatment of WNT-related bone diseases. Additionally, emerging evidence indicates that sclerostin contributes to the development of cancers, obesity, and diabetes, suggesting that it may be a promising therapeutic target for these diseases. Notably, cardiovascular diseases are related to the protective role of sclerostin. In this review, we summarize three distinct types of inhibitors targeting sclerostin, monoclonal antibodies, aptamers, and small-molecule inhibitors, from which monoclonal antibodies have been developed. As the first-in-class sclerostin inhibitor approved by the U.S. FDA, the monoclonal antibody romosozumab has demonstrated excellent effectiveness in the treatment of postmenopausal osteoporosis; however, it conferred high cardiovascular risk in clinical trials. Furthermore, romosozumab could only be administered by injection, which may cause compliance issues for patients who prefer oral therapy. Considering these above safety and compliance concerns, we therefore present relevant discussion and offer perspectives on the development of next-generation sclerostin inhibitors by following several ways, such as concomitant medication, artificial intelligence-based strategy, druggable modification, and bispecific inhibitors strategy.

Nucleic acid aptamers are ssDNA or ssRNA fragments that specifically recognize targets. However, the pharmacodynamic properties of natural aptamers consisting of 4 naturally occurring nucleosides (A, G, C, T/U) are generally restricted for inferior binding affinity than the cognate antibodies. The development of high-affinity modification strategies has attracted extensive attention in aptamer applications. Chemically modified aptamers with stable three-dimensional shapes can tightly interact with the target proteins via enhanced non-covalent bonding, possibly resulting in hundreds of affinity enhancements. This review overviewed high-affinity modification strategies used in aptamers, including nucleobase modifications, fluorine modifications (2′-fluoro nucleic acid, 2′-fluoro arabino nucleic acid, 2′,2′-difluoro nucleic acid), structural alteration modifications (locked nucleic acid, unlocked nucleic acid), phosphate modifications (phosphorothioates, phosphorodithioates), and extended alphabets. The review emphasized how these high-affinity modifications function in effect as the interactions with target proteins, thereby refining the pharmacodynamic properties of aptamers.

Aptamers are short, single-stranded DNA or RNA oligonucleotide sequences that can bind specific targets. The molecular weight of aptamers (

Primary blast lung injury (PBLI), caused by exposure to high-intensity pressure waves from explosions in war, terrorist attacks, industrial production, and life explosions, is associated with pulmonary parenchymal tissue injury and severe ventilation insufficiency. PBLI patients, characterized by diffused intra-alveolar destruction, including hemorrhage and inflammation, might deteriorate into acute respiratory distress syndrome (ARDS) with high mortality. However, due to the absence of guidelines about PBLI, emergency doctors and rescue teams treating PBLI patients rely on experience. The goal of this review is to summarize the mechanisms of PBLI and their cross-linkages, exploring potential diagnostic and therapeutic targets of PBLI. We summarize the pathophysiological performance and pharmacotherapy principles of PBLI. In particular, we emphasize the crosstalk between hemorrhage and inflammation, as well as coagulation, and we propose early control of hemorrhage as the main treatment of PBLI. We also summarize several available therapy methods, including some novel internal hemostatic nanoparticles to prevent the vicious circle of inflammation and coagulation disorders. We hope that this review can provide information about the mechanisms, diagnosis, and treatment of PBLI for all interested investigators.

Dickkopf-1 (DKK1) is a well-characterized Wnt inhibitor and component of the Wnt/β-catenin signaling pathway, whose dysregulation is associated with multiple abnormal pathologies including osteoporosis, Alzheimer’s disease, diabetes, and various cancers. The Wnt signaling pathway has fundamental roles in cell fate determination, cell proliferation, and survival; thus, its mis-regulation can lead to disease. Although DKK1 is involved in other signaling pathways, including the β-catenin-independent Wnt pathway and the DKK1/CKAP4 pathway, the inhibition of DKK1 to propagate Wnt/β-catenin signals has been validated as an effective way to treat related diseases. In fact, strategies for developing DKK1 inhibitors have produced encouraging clinical results in different pathological models, and many publications provide detailed information about these inhibitors, which include small molecules, antibodies, and nucleic acids, and may function at the protein or mRNA level. However, no systematic review has yet provided an overview of the various aspects of their development and prospects. Therefore, we review the DKK1 inhibitors currently available or under study and provide an outlook on future studies involving DKK1 and drug discovery.

The traditional power grid ticket filling method has a large workload, low efficiency, and cannot achieve comprehensive and effective reference of historical tickets. This paper proposes a method of intelligent filling in a power grid working ticket based on a historical ticket knowledge base. Firstly, the historical ticket data are preprocessed, then the historical ticket information is mined by the association rule algorithm, and the method of establishing the historical ticket knowledge base is proposed. Based on the improved word bag model, an intelligent grid work ticket filling model is established based on the historical ticket knowledge base, and the correctness of the method is verified by an example. The results show that the accuracy of the proposed method is at least 18% higher than that of the traditional model, and the matching efficiency is 50% higher than the evaluation results of the three models based on semantic expressions. The method enables the identification and extraction of similar and associated work tickets, improves the efficiency of filling work tickets for power grids, and promotes the intelligence of the safety procedures for power grid operations.

Abstract Background Mucosal melanoma with poor prognosis is a common histopathologic subtype of melanoma among Chinese and other Asian peoples. Regulated microRNAs (miRNAs) have been reported as oncogenes or tumour suppressors in melanoma. However, the roles of specific miRNAs in mucosal melanoma remain largely unknown. Here, we aimed to assess the biological functions, molecular mechanisms and clinical potential of miR-let-7b and miR-let-7c in mucosal melanoma. Methods The expression of miR-let-7b and miR-let-7c in mucosal melanoma was determined by quantitative polymerase chain reaction (qPCR). Cutoff scores for miR-let-7b and miR-let-7c expressions were calculated through receiver operating characteristic (ROC) curve analysis in 106 mucosal melanoma patients according to recurrence. Correlations of miR-let-7b and miR-let-7c expression with clinicopathological characteristics, disease-free survival (DFS) and clinical benefits after treatment were then statistically analysed. The biological functions and molecular mechanisms of miR-let-7b and miR-let-7c were studied in vitro and in vivo. Results The expression of miR-let-7b and miR-let-7c was decreased in 94 cases (88.7%) and 89 cases (84.0%) of 106 mucosal melanoma patients compared with mucosal nevi. A correlation was observed between the expression of miR-let-7b, miR-let-7c and DFS after surgery. In addition, overexpression of miR-let-7b or miR-let-7c inhibited mucosal melanoma cell growth, migration, invasion and metastasis and induced cell apoptosis and cell cycle arrest in vitro and in vivo. Mechanistically, miR-let-7b and miR-let-7c directly targeted metadherin (MTDH) and calumenin (CALU) and suppressed phospho-ERK in mucosal melanoma cells. MTDH and CALU reversed the partial function of miR-let-7b and miR-let-7c in vitro. Furthermore, progression-free survival (PFS) of mucosal melanoma patients upon temozolomide-based and paclitaxel-based chemotherapy was related to miR-let-7b and miR-let-7c expression. Overexpression of miR-let-7b or miR-let-7c in patient-derived xenograft (PDX) models and certain mucosal melanoma cells had better growth inhibition after temozolomide and paclitaxel treatment. MTDH reversed the sensitivity of miR-let-7b and miR-let-7c to paclitaxel in vitro. Conclusions Our results suggested that miR-let-7b and miR-let-7c inhibited the recurrence of mucosal melanoma through inhibiting cell growth, migration, invasion and metastasis, inducing cell apoptosis and cell cycle arrest by targeting MTDH and CALU. In addition, miR-let-7b and miR-let-7c increased sensitivity to chemotherapeutic agents by targeting MTDH.

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is an overactivated inflammatory response caused by direct or indirect injuries that destroy lung parenchymal cells and dramatically reduce lung function. Although some research progress has been made in recent years, the pathogenesis of ALI/ARDS remains unclear due to its heterogeneity and etiology. MicroRNAs (miRNAs), a type of small noncoding RNA, play a vital role in various diseases. In ALI/ARDS, miRNAs can regulate inflammatory and immune responses by targeting specific molecules. Regulation of miRNA expression can reduce damage and promote the recovery of ALI/ARDS. Consequently, miRNAs are considered as potential diagnostic indicators and therapeutic targets of ALI/ARDS. Given that inflammation plays an important role in the pathogenesis of ALI/ARDS, we review the miRNAs involved in the inflammatory process of ALI/ARDS to provide new ideas for the pathogenesis, clinical diagnosis, and treatment of ALI/ARDS.

Paclitaxel (PTX) has been used for cancer treatment for decades and has become one of the most successful chemotherapeutics in the clinic and financially. However, serious problems with its use still exist, owing to its poor solubility and non-selective toxicity. With respect to these issues, recent advances have addressed the water solubility and tumor specificity related to PTX application. Many measures have been proposed to remedy these limitations by enhancing tumor recognition via ligand-receptor-mediated targeting as well as other associated strategies. In this review, we investigated various kinds of ligands that have emerged as PTX tumor-targeting tools. In particular, this article highlights small molecule-, protein-, and aptamer-functionalized conjugates and nanoparticles (NPs), providing a promising approach for PTX-based individualized treatment prospects.

Abstract Background Estrogen receptor alpha (ER alpha) is expressed in the majority of breast cancers and promotes estrogen-dependent cancer progression. ER alpha positive breast cancer can be well controlled by ER alpha modulators, such as tamoxifen. However, tamoxifen resistance is commonly observed by altered ER alpha signaling. Thus, further understanding of the molecular mechanisms, which regulates ER alpha signaling, is important to improve breast cancer therapy. Methods SMURF1 and ER alpha protein expression levels were measured by western blot, while the ER alpha target genes were measured by real-time PCR. WST-1 assay was used to measure cell viability; the xeno-graft tumor model were used for in vivo study. RNA sequencing was analyzed by Ingenuity Pathway Analysis. Identification of ER alpha signaling was accomplished with luciferase assays, real-time RT-PCR and Western blotting. Protein stability assay and ubiquitin assay was used to detect ER alpha protein degradation. Immuno-precipitation based assays were used to detect the interaction domain between ER alpha and SMURF1. The ubiquitin-based Immuno-precipitation based assays were used to detect the specific ubiquitination manner happened on ER alpha. Results Here, we identify the E3 ligase SMURF1 facilitates ER alpha signaling. We show that depletion SMURF1 decreases ER alpha positive cell proliferation in vitro and in vivo. SMURF1 depletion based RNA-sequence data shows SMURF1 is necessary for ER alpha target gene expression in the transcriptomic scale. Immunoprecipitation indicates that SMURF1 associates with the N-terminal of ER alpha in the cytoplasm via its HECT domain. SMURF1 increases ER alpha stability, possibly by inhibiting K48-specific poly-ubiquitination process on ER alpha protein. Interestingly, SMURF1 expression could be induced via estradiol treatment. Conclusions Our study reveals a novel positive feedback between SMURF1 and ER alpha signaling in supporting breast cancer growth. Targeting SMURF1 could be one promising strategy for ER alpha positive breast cancer treatment.

Phosgene (COCl2) was once used as a classic suffocation poison and currently plays an essential role in industrial production. Due to its high toxicity, the problem of poisoning caused by leakage during production, storage, and use cannot be ignored. Phosgene mainly acts on the lungs, causing long-lasting respiratory depression, refractory pulmonary edema, and other related lung injuries, which may cause acute respiratory distress syndrome or even death in severe cases. Due to the high mortality, poor prognosis, and frequent sequelae, targeted therapies for phosgene exposure are needed. However, there is currently no specific antidote for phosgene poisoning. This paper reviews the literature on the mechanism and treatment strategies to explore new ideas for the treatment of phosgene poisoning.

Esophageal cancer is among the most deadly malignant diseases. However, the genetic factors contributing to its occurrence are poorly understood. Multiple studies with large clinic-based cohorts revealed that variations of the phospholipase C epsilon (PLCE1) gene were associated with esophageal cancer susceptibility. However, the causative role of PLCE1 in esophageal cancer is not clear. We inactivated the functional alleles of PLCE1 by CRISPR/Cas9 genome editing technology. The resultant PLCE1 inactivated cells were analyzed both in vitro and in vivo. Our results showed that loss of PLCE1 dramatically decreased the invasion and proliferation capacity of esophageal carcinoma cells in vitro. Moreover, such PLCE1 inactivated tumor grafts exhibited significantly decreased tumor size in mice. We found that PLCE1 was required to maintain protein level of snail a key transcription factor responsible for invasion. Our further transcriptomic data revealed that deficient cells were significantly decreased in expression of genes enriched as targets of Snail. Strikingly, recovery of Snail protein at least partially rescued the invasion and proliferation capacity in PLCE1 inactivated cells. In ESCC clinical specimens, PLCE1 was correlated with tumor stage (P

The ubiquitin binding protein SHAPRIN is highly expressed in human breast cancer, one of the most frequent female malignancies worldwide. Here, we perform SHARPIN depletion in breast cancer cells together with RNA sequencing. The global expression profiling showed p53 signaling as a potential SHARPIN target. SHARPIN depletion decreased cell proliferation, which effect could be rescue by p53 knocking down. Depletion SHARPIN significantly increases p53 protein level and its target genes in multiple breast cancer cell lines. Further experiment revealed that SHARPIN could facilitate p53 poly-ubiquitination and degradation in MDM2 dependent manner. Immuno-precipitation assay showed that SHARPIN associated with MDM2 and prolonged MDM2 protein stability. Analysis of public available database showed SHARPIN correlated with poor prognosis specifically in p53 wild-type breast cancer patients. Together, our finding revealed a novel modifier for p53/MDM2 complex and suggested SHARPIN as a promising target to restore p53 function in breast cancer.