| Psycho-social stress has been suggested to affect the development of tumor,while positive psychology remains largely unknown whether and how to influence the progress of tumor and regulate cancer-related therapeutic responses.In this study,we used environmental eustress mice living in an enriched environment to simulate psychological stress,and explored the mechanism of protection against transplantable syngeneic of hepatocellular carcinoma.Firstly,Hepa1-6 and H22 subcutaneous tumor transplantation models were constructed to evaluate the effect of environmental eustress on the development of mice hepatocellular carcinoma.Then,through vivo experiments,CD8+ T cells,CD4+ T cells,tumor-associated macrophage,Myeloid-derived suppressor cells and Chemokine ligand2(CCL2)neutralization antibody,beta adrenergic receptor(?-ARs)blockers,6-Hydroxydopamine hydrochloride,Beta-adrenoceptor agonists: Epinephrine(EPI)and Norepinephrine(NE)were used to intervene mice to ensure their effect and function in tumor inhibition.In vitro experiments,Beta-adrenoceptor agonists EPI and NE were incubated with human hepatocytes/hepatic stellate cells organoid and mice hepatocellular carcinoma cells.Last,anti-PD-L1 treatment combined with environmental eustress were used to intervene transplantable syngeneic liver tumors.It was found that environmental stress could inhibit the development of liver cancer and improve the immune microenvironment in tumor tissues.Specifically,the number of CD8+T infiltrated inside the tumor was increased,while the number of immunosuppressive cells such as MDSCs and TAM were decreased significantly.Besides,the level of CCL2 in serum,tumor tissue and immunosuppressive cells were decreased.Through further research,we found that knocking out CCL2 of tumor origin and host origin could relieve the anti-tumor effect of environmental eustress-mediated,and environmental eustress induced antitumor immunity required CCL2/CCR2 signaling.In addition,environmental eustress moderately increased the levels of NE and EPI in peripheral blood,activated peripheral SNS/?-ARs,inhibited the expression of CCL2,and reshaped the immune microenvironment of tumor tissues to achieve better immunotherapy.Finally,we found that environmental eustress could sensitize anti-PDL immune checkpoint therapy,and increase the infiltration and immune response of tumor specific T cell.Overall,we determined that environmental benign stress exerts an anti-tumor effect through a peripheral neuro-endocrine-immune pathway: SNS/?-ARs-CCL2 axis.Tyrosine kinase(TKs),mediated in phospho-tyrosine signal transduction is one of the few conservative signal transduction pathways in the whole metazoan.It mainly involves the regulation process of multicellular organisms,including tissue differentiation,growth and development,immune response,cell adhesion,movement and apoptosis.More importantly,the mutation or overexpression of about half of the members of the TKs family is associated with tumor progression.We combined evolutionary analysis and data mining technology to analyze the motif and structural domain composition of TKs family,phylogenetic analysis of multiple metazoan species,and conducted functional divergence studies on the ABL subfamily,using public databases to find mutation sites and prognostic relationship in pan-cancer.It was found that the phylogenetic position of TKs is consistent with the core structural domain sequence,but the structure among subfamilies is complex.The difference in structural domain motif composition and structural domain composition reflects the diversity of protein functions among TKs subfamilies.The phylogenetic analysis of the TKs of 31 metazoans found that the functional conservatism and germline-specific expansion of the TKs family: it tends to evolutionary conservation in subfamily species,and species-specific expansion occurred.Some species(such as electrophorus electricus)may achieve unique diversification through the creation of TK members with different structures in the evolution process,which is related to their specific organizational functions.Through functional divergence and tumor data mining analysis of the ABL family,it was found that the two genes had significant type I functional divergence,and three amino acid sites related to type I functional divergence were predicted for the two genes.In addition,we analyzed the pan-cancer mutations of the ABL family in the tumor public database,and found that ABL1 had significant fusion mutations related to hematological tumors,while ABL2 mutations mainly occurred in solid tumors,we also found that the high expression of ABL2 was unfavourable prognosis in kidney renal papillary cell carcinoma.In this study,bioinformatics analysis was used to explore the conservation and functional diversity of TKs,and functional divergence analysis was used to predict the amino acid sites related to functional divergence,so as to provide a theoretical basis for finding tumor drug design,tumor related mutations and prognosis targets. |
PDF Full Text Request