查看更多>>摘要：Adoptive cell therapies involve infusing engineered immune cells into cancer patients to recognize and eliminate tumor cells.Adoptive cell therapy,as a form of living drug,has undergone explosive growth over the past decade.The recognition of tumor antigens by the T-cell receptor(TCR)is one of the natural mechanisms that the immune system used to eliminate tumor cells.TCR-T cell therapy,which involves introducing exogenous TCRs into patients'T cells,isa novel cell therapy strategy.TCR-T celltherapy can target the entire proteome of cancer cells.Engineering T cells with exogenous TCRs to help patients combat cancer has achieved success in clinical trials,particularly in treating solid tumors.In this review,we examine the progress of TCR-T cell therapy over the past five years.This includes the discovery of new tumor antigens,protein engineering techniques for TCR,reprogramming strategies for TCR-T cell therapy,clinical studies on TCR-T cell therapy,and the advancement of TCR-T cell therapy in China,We also propose several potential directions for the future development of TCR-T cell therapy.
查看更多>>摘要：Benign prostatic hyperplasia(BPH)is the expansion of the prostate gland that results in urinary symptoms.Both the epithelial-to-mesenchymal transition(EMT)and the Wnt signaling pathway are associated with BPH pathology.In this study,we find that miR-1202 is increased in BPH samples.Overexpression of miR-1202 in TGF-β-treated BPH-1 cells enhances cell survival and DNA synthesis and inhibits cell apoptosis,whereas miR-1202 inhibition partially abolishes the effects of TGF-β on BPH-1 cells.miR-1202 overexpression reduces E-cadherin level but elevates vimentin,N-cadherin,and snail levels,whereas miR-1202 inhibition partially attenuates the effects of TGF-β on EMT markers.Regarding the Wnt/β-catenin pathway,miR-1202 overexpression significantly enhances,whereas miR-1202 inhibition partially decreases,the promotive effects of TGF-β on Wnt1,c-Myc,and cyclin D1 proteins.3-Hydroxy-3-methylglutaryl-CoA lyase(HMGCL)is a direct downstream target of miR-1202,and miR-1202 inhibits HMGCL expression through binding to its3'UTR.Overexpression of HMGCL significantly reduces the effect of miR-1202 overexpression on the phenotypes of BPH-1 cells by inhibiting cell survival and promoting apoptosis.Simi-larly,HMGCL overexpression has the opposite effects on EMT markers and the Wnt/β-catenin signaling,and markedly alleviates the effects of miR-1202 overexpression.Finally,in the BPH rat model,Ki67 and vimentin levels are elevated,but E-cadherin and HMGCL levels are reduced.In conclusion,miR-1202 is upregulated in benign prostatic hyperplasia;miR-1202 enhances epithelial cell proliferation,suppresses cell apoptosis,and promotes EMT by targeting HMGCL.The Wnt/β-catenin pathway may participate in the miR-1202/HMGCL axis-mediated regulation of BPH-1 cell phenotypes.
查看更多>>摘要：20(S)-Ginsenoside Rh2 has significant anti-tumor effects in various types of cancers,including human hepatocel-lular carcinoma(HCC).However,its molecular targets and mechanisms of action remain largely unknown.Here,we aim to elucidate the potential mechanisms by which Rh2 suppresses HCC growth.We first demonstrate the role of Rh2 in inhibiting angiogenesis.We observe that Rh2 effectively suppresses cell proliferation and induces apoptosis in HUVECs.Furthermore,Rh2 significantly inhibits HepG2-stimulated HUVEC proliferation,migration and tube formation,accompanied by the downregulation of VEGF and MMP-2 expressions.We also reveal that Rh2 inhibits HCC growth through the down regulation of glypican-3-mediated activation of the Wnt/β-catenin pathway.We observe a dose-dependent inhibition of proliferation and induction of apoptosis in HepG2 cells upon Rh2 treatment,which is mediated by the inhibition of glypican-3/Wnt/β-catenin signaling.Moreover,downregulation of glypican-3 expression enhances the effects of Rh2 on the glypican-3/Wnt/β-catenin signaling pathway,resulting in greater suppression of tumor growth in HepG2 cells.Collectively,our findings shed light on the molecular mechanisms through which Rh2 modulates HCC growth,which involve the regulation of angiogenesis and the glypican-3/Wnt/β-catenin pathway.These insights may pave the way for the development of novel therapeutic strategies targeting these pathways for the treatment of HCC.
查看更多>>摘要：Hepatocellular carcinoma(HCC)is one of the most prevalent and deadly cancers in the world,which is frequently diagnosed at a late stage.HCC patients have a poor prognosis due to the lack of an efficacious therapeutic strategy.Approved drug repurposing is a way for accelerating drug discovery and can significantly reduce the cost of drug development.Carfilzomib(CFZ)is a second-generation proteasome inhibitor,which is highly efficacious against multiple myeloma and has been reported to possess potential antitumor activities against multiple cancers.However,the underlying mechanism of CFZ on HCC is still unclear.Here,we show that CFZ inhibits the proliferation of HCC cells through cell cycle arrest at the G2/M phase and suppresses the migration and invasion of HCC cells by inhibiting epithelial-mesenchymal transition.We also find that CFZ promotes reactive oxygen species production to induce endoplasmic reticulum(ER)stress and activate JNK/p38 MAPK signaling in HCC cells,thus inducing cell death in HCC cells.Moreover,CFZ significantly inhibits HCC cell growth in a xenograft mouse model.Collectively,our study elucidates that CFZ impairs mitochondrial function and activates ER stress and JNK/p38 MAPK signaling,thus inhibiting HCC cell and tumor growth.This indicates that CFZ has the potential as a therapeutic drug for HCC.
查看更多>>摘要：SLC45A1 encodes a glucose transporter protein highly expressed in the brain.Mutations in SLC45A1 may lead to neurological diseases and developmental disorders,but its exact role is poorly understood.DNA G-quadruplexes(DNA G4s)are stable structures formed by four guanine bases and play a role in gene regulation and genomic stability.Changes in DNA G4s may affect brain development and function.The mechanism linking alterations in DNA G-quadruplex structures to SLC45A1 pathogenicity remains unknown.In this study,we identify a functional DNA G-quadruplex and its key binding site on SLC45A1(NM_001080397.3:exon 2:c.449 G＞A:p.R150K).This variant results in the upregulation of mRNA and protein expression,which may lead to intellectual developmental disorder with neuropsychiatric features.Mechanistically,the mutation is found to disrupt DNA G-quadruplex structures on SLC45A1,leading to transcriptional enhancement and a gain-of-function mutation,which further causes increased expression and function of the SLC45A1 protein.The identification of the functional DNA G-quadruplex and its effects on DNA G4s may provide new insights into the genetic basis of SLC45A1 pathogenicity and highlight the importance of DNA G4s of SLC45A1 in regulating gene expression and brain development.
查看更多>>摘要：The epicardium is integral to cardiac development and facilitates endogenous heart regeneration and repair.While miR-194-3p is associated with cellular migration and invasion,its impact on epicardial cells remains uncharted.In this work we use gain-of-function and loss-of-function methodologies to investigate the function of miR-194-3p in cardiac development.We culture embryonic epicardial cells in vitro and subject them to transforming growth factorβ(TGF-β)treatment to induce epithelial-mesenchymal transition(EMT)and monitor miR-194-3p expression.In addition,the effects of miR-194-3p mimics and inhibitors on epicardial cell development and changes in EMT are investigated.To validate the binding targets of miR-194-3p and its ability to recover the target gene-phenotype,we produce a mutant vector p120-catenin-3'UTR-MUT.In epicardial cells,TGF-β-induced EMT results in a notable overexpression of miR-194-3p.The administration of miR-194-3p mimics promotes EMT,which is correlated with elevated levels of mesenchymal markers.Conversely,miR-194-3p inhibitor attenuates EMT.Further investigations reveal a negative correlation between miR-194-3p and p120-catenin,which influences β-catenin level in the cell adhesion pathway.The suppression of EMT caused by the miR-194-3p inhibitor is balanced by silencing of p120-catenin.In conclusion,miR-194-3p directly targets p120-catenin and modulates its expression,which in turn alters β-catenin expression,critically influencing the EMT process in the embryonic epicardial cells via the cell adhesion mechanism.
查看更多>>摘要：Bronchial thermoplasty(BT),an effective treatment for severe asthma,requires heat to reach the airway to reduce the mass of airway smooth muscle cells(ASMCs).Autophagy is involved in the pathological process of airway remodeling in patients with asthma.However,it remains unclear whether autophagy participates in controlling airway remodeling induced by BT.In this study,we aim to elucidate the autophagy-mediated molecular mechan-isms in BT.Our study reveal that the number of autophagosomes and the level of alpha-smooth muscle actin(α-SMA)fluorescence are significantly decreased in airway biopsy tissues after BT.As the temperature increased,BT causes a decrease in cell proliferation and a concomitant increase in the apoptosis of human airway smooth muscle cells(HASMCs).Furthermore,increase in temperature significantly downregulates cellular autophagy,autophagosome accumulation,the LC3Ⅱ/LC3I ratio,and Beclin-1 expression,upregulates p62 expression,and in-hibits the AMPK/mTOR pathway.Furthermore,cotreatment with AICAR(an AMPK agonist)or RAPA(an mTOR antagonist)abolishes the inhibition of autophagy and attenuates the increase in the apoptosis rate of HASMCs induced by the thermal effect.Therefore,we conclude that BT decreases airway remodeling by blocking autophagy induced by the AMPK/mTOR signaling pathway in HASMCs.
查看更多>>摘要：Dysregulation of microRNA(miRNA)expression in cancer is a significant factor contributing to the progression of chemoresistance.The objective of this study is to explore the underlying mechanisms by which miR-34b-3p reg-ulates chemoresistance in cervical cancer(CC).Previous findings have demonstrated low expression levels of miR-34b-3p in both CC chemoresistant cells and tissues.In this study,we initially characterize the behavior of SiHa/DDP cells which are CC cells resistant to the chemotherapeutic drug cisplatin(DDP).Subsequently,miR-34b-3p mimics are transfected into SiHa/DDP cells.It is observed that overexpression of miR-34b-3p substantially inhibits the proliferation,migration,and invasion abilities of SiHa/DDP cells and also enhances their sensitivity to DDP-induced cell death.Quantitative RT-PCR and western blot analysis further reveal elevated expression levels of STC2and FN1 in SiHa/DDP cells,contrary to the expression pattern of miR-34b-3p.Moreover,STC2 and FN1 contribute to DDP resistance,proliferation,migration,invasion,and decreased apoptosis in CC cells.Through dual-luciferase assay analysis,we confirm that STC2 and FN1 are direct targets of miR-34b-3p in CC.Finally,rescue experiments de-monstrate that overexpression of either STC2 or FN1 can partially reverse the inhibitory effects of miR-34b-3p overexpression on chemoresistance,proliferation,migration and invasion in CC cells.In conclusion,our findings support the role of miR-34b-3p as a tumor suppressor in CC.This study indicates that targeting the miR-34b-3p/STC2 or FN1 axis has potential therapeutic implications for overcoming chemoresistance in CC patients.
查看更多>>摘要：Adhesion molecules play critical roles in maintaining the structural integrity of the airway epithelium in airways under stress.Previously,we reported that catenin alpha-like 1(CTNNAL1)is downregulated in an asthma animal model and upregulated at the edge of human bronchial epithelial cells(HBECs)after ozone stress.In this work,we explore the potential role of CTNNAL1 in the structural adhesion of HBECs and its possible mechanism,We con-struct a CTNNAL1-/-mouse model with CTNNAL1-RNAi recombinant adeno-associated virus(AAV)in the lung and a CTNNAL1-silencing cell line stably transfected with CTNNAL1-siRNA recombinant plasmids.Hematoxylin and eosin(HE)staining reveals that CTNNAL1-/-mice have denuded epithelial cells and structural damageto the airway.Silencing of CTNNAL1 in HBECs inhibits cell proliferation and weakens extracellular matrix adhesion and inter-cellular adhesion,possibly through the action of the cytoskeleton.We also find that the expressions of the structural adhesion-related molecules E-cadherin,integrin β1,and integrin β4 are significantly decreased in ozone-treated cells than in vector control cells.In addition,our results show that the expression levels of RhoA/ROCK1 are decreased after CTNNAL1 silencing.Treatment with Y27632,a ROCK inhibitor,abolished the expressions of ad-hesion molecules induced by ozone in CTNNAL1-overexpressing HBECs.Overall,the findings of the present study suggest that CTNNAL1 plays a critical role in maintaining the structural integrity of the airway epithelium under ozone challenge,and is associated with epithelial cytoskeleton dynamics and the expressions of adhesion-related molecules via the RhoA/ROCK1 pathway.
查看更多>>摘要：Traditional Chinese medicine(TCM)has been used to treat triple-negative breast cancer(TNBC),a breast cancer subtype with poor prognosis.Clinical studies have verified that the Sanyingfang formula(SYF),a TCM prescription,has obvious effects on inhibiting breast cancer recurrence and metastasis,prolonging patient survival,and redu-cing clinical symptoms.However,its active ingredients and molecular mechanisms are still unclear.In this study,the active ingredients of each herbal medicine composing SYF and their target proteins are obtained from the Traditional Chinese Medicine Systems Pharmacology database.Breast cancer-related genes are obtained from the GeneCards database.Major targets and pathways related to SYF treatment in breast cancer are identified by analyzing the above data.By conducting molecular docking analysis,we find that the active ingredients quercetin and luteolin bind well to the key targets KDR1,PPARG,SOD1,and VCAM1.In vitro experiments verify that SYF can reduce the proliferation,migration,and invasion ability of TNBC cells.Using a TNBC xenograft mouse model,we show that SYF could delay tumor growth and effectively inhibit the occurrence of breast cancer lung metastasis in vivo.PPARG,SOD1,KDR1,and VCAM1 are all regulated by SYF and may play important roles in SYF-mediated inhibition of TNBC recurrence and metastasis.
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