JARID2 coordinates with the NuRD complex to facilitate breast tumorigenesis through response to adipocyte-derived leptin

Background Proteins containing the Jumonji C(JmjC)domain participated in tumorigenesis and cancer progression.However,the mechanisms underlying this effect are still poorly understood.Our objective was to investigate the role of Jumonji and the AT-rich interaction domain-containing 2(JARID2)—a JmjC family protein—in breast cancer,as well as its latent association with obesity.Methods Immunohistochemistry,The Cancer Genome Atlas,Gene Expression Omnibus,and other databases were used to analyze the expression of JARID2 in breast cancer cells.Growth curve,5-ethynyl-2-deoxyuridine(EdU),colony formation,and cell invasion experiments were used to detect whether JARID2 affected breast cancer cell proliferation and invasion.Spheroidization-based experiments and xenotumor transplantation in NOD/SCID mice were used to examine the association between JARID2 and breast cancer stemness.RNA-sequencing,Kyoto Encyclopedia of Genes and Genomes,and Gene Set Enrichment Analysis were used to identify the cell processes in which JARID2 participates.Immunoaffinity purification and silver staining mass spectrometry were conducted to search for proteins that might interact with JARID2.The results were further verified using co-immunoprecipitation and glutathione S-transferase(GST)pull-down experiments.Using chromatin immunoprecipitation(ChIP)sequencing,we sought the target genes that JARID2 and metastasis-associated protein 1(MTA1)jointly regulated;the results were validated by ChIP-PCR,quantitative ChIP(qChIP)and ChIP-reChIP assays.A coculture experiment was used to explore the interactions between breast cancer cells and adipocytes.Results In this study,we found that JARID2 was highly expressed in multiple types of cancer including breast cancer.JARID2 promoted glycolysis,lipid metabolism,proliferation,invasion,and stemness of breast cancer cells.Furthermore,JARID2 physically interacted with the nucleosome remodeling and deacetylase(NuRD)complex,transcriptionally repressing a series of tumor suppressor genes such as BRCA2 DNA repair associated(BRCA2),RB transcriptional corepressor 1(RB1),and inositol polyphosphate-4-phosphatase type II B(INPP4B).Additionally,JARID2 expression was regulated by the obesity-associated adipokine leptin via Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3)pathway in the breast cancer microenvironment.Analysis of various online databases also indicated that JARID2/MTA1 was associated with a poor prognosis of breast cancer.Conclusion Our data indicated that JARID2 promoted breast tumorigenesis and development,confirming JARID2 as a target for cancer treatment.

Notch signaling pathway:architecture,disease,and therapeutics

The NOTCH gene was identified approximately 110 years ago.Classical studies have revealed that NOTCH signaling is an evolutionarily conserved pathway.NOTCH receptors undergo three cleavages and translocate into the nucleus to regulate the transcription of target genes.NOTCH signaling deeply participates in the development and homeostasis of multiple tissues and organs,the aberration of which results in cancerous and noncancerous diseases.However,recent studies indicate that the outcomes of NOTCH signaling are changeable and highly dependent on context.In terms of cancers,NOTCH signaling can both promote and inhibit tumor development in various types of cancer.The overall performance of NOTCH-targeted therapies in clinical trials has failed to meet expectations.Additionally,NOTCH mutation has been proposed as a predictive biomarker for immune checkpoint blockade therapy in many cancers.Collectively,the NOTCH pathway needs to be integrally assessed with new perspectives to inspire discoveries and applications.In this review,we focus on both classical and the latest findings related to NOTCH signaling to illustrate the history,architecture,regulatory mechanisms,contributions to physiological development,related diseases,and therapeutic applications of the NOTCH pathway.The contributions of NOTCH signaling to the tumor immune microenvironment and cancer immunotherapy are also highlighted.We hope this review will help not only beginners but also experts to systematically and thoroughly understand the NOTCH signaling pathway.

Early assessment of the safety and immunogenicity of a third dose(booster)of COVID-19 immunization in Chinese adults

Inducing durable and effective immunity against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)via vaccination is essential to combat the current pandemic of coronavirus disease 2019(COVID-19).It has been noticed that the strength of anti-COVID-19 vaccination-induced immunity fades over time,which calls for an additional vaccination regime,as known as booster immunization,to restore immunity among previously vaccinated populations.Here we report a pilot open-label trial of a third dose of BBIBP-CorV,an inactivated SARS-CoV-2 vaccine(Vero cell),on 136 participants aged between 18 to 63 years.Safety and immunogenicity in terms of neutralizing antibody titers and cytokine/chemokine responses were analyzed as the main endpoint until day 28.While systemic reactogenicity was either absent or mild,SARS-CoV-2-specific neutralizing antibody titers rapidly arose in all participants within 4 weeks,surpassing the peak antibody titers elicited by the initial two-dose immunization regime.Broad increases of cellular immunity-associated cytokines and chemokines were also detected in the majority of participants after the third vaccination.Furthermore,in an exploratory study,a newly developed recombinant protein vaccine,NVSI-06-08(CHO Cells),was found to be safe and even more effective than BBIBP-CorV in eliciting humoral immune responses in BBIBP-CorV-primed individuals.Together,these results indicate that a third immunization schedule with either homologous or heterologous vaccine showed favorable safety profiles and restored potent SARS-CoV-2-specific immunity,providing support for further trials of booster vaccination in larger populations.

Generated SecPen_NY-ESO-1_ubiquitin-pulsed dendritic cell cancer vaccine elicits stronger and specific T cell immune responses

Dendritic cell-based cancer vaccines(DC vaccines)have been proved efficient and safe in immunotherapy of various cancers,including melanoma,ovarian and prostate cancer.However,the clinical responses were not always satisfied.Here we proposed a novel strategy to prepare DC vaccines.In the present study,a fusion protein SNU containing a secretin-penetratin(SecPen)peptide,NY-ESO-1 and ubiquitin was designed and expressed.To establish the DC vaccine(DC-SNU),the mouse bone marrowderived DCs(BMDCs)were isolated,pulsed with SNU and maturated with cytokine cocktail.Then peripheral blood mononuclear cells(PBMCs)from C57 BL/6 mice inoculated intraperitoneally with DCSNU were separated and cocultured with MC38/MC38NY-ESO-1 tumor cells or DC vaccines.The results show that SNU was successfully expressed.This strategy made NY-ESO-1 entering cytoplasm of BMDCs more efficiently and degraded mainly by proteasome.As we expected,mature BMDCs expressed higher CD40,CD80 and CD86 than immature BMDCs.Thus,the PBMCs released more IFN-γand TNF-αwhen stimulated with DC-SNU in vitro again.What’s more,the PBMCs induced stronger and specific cytotoxicity towards MC38NY-ESO-1 tumor cells.Given the above,it demonstrated that DC-SNU loaded with SecPen and ubiquitin-fused NY-ESO-1 could elicit stronger and specific T cell immune responses.This strategy can be used as a platform for DC vaccine preparation and applied to various cancers treatment.