BACKGROUND Although transmembrane protein 106C(TMEM106C)has been elucidated to be overexpressed in cancers,its underlying mechanisms have not yet been fully understood.AIM To investigate the expression levels and mole...BACKGROUND Although transmembrane protein 106C(TMEM106C)has been elucidated to be overexpressed in cancers,its underlying mechanisms have not yet been fully understood.AIM To investigate the expression levels and molecular mechanisms of TMEM106C across 34 different cancer types,including liver hepatocellular carcinoma(LIHC).METHODS We analyzed TMEM106C expression patterns in pan-cancers using microenvironment cell populations counter to evaluate its association with the tumor microenvironment.Gene set enrichment analysis was conducted to identify molecular pathways related to TMEM106C.Chromatin immunoprecipitation followed by sequencing(ChIP-seq)analysis was conducted to identify upstream transcriptional regulators of TMEM106C.In LIHC,we examined mRNA profiles,performed in-house quantitative polymerase chain reaction,immunohistochemistry,and constructed a co-expression gene network.Functional assays,including cell counting kit-8,cell cycle,apoptosis,migration,and invasion,were conducted.The effect of nitidine chloride(NC)on LIHC xenograft was evaluated through RNA sequencing and molecular docking.Finally,potential therapeutic agents targeting TMEM106C were predicted.RESULTS TMEM106C was significantly overexpressed in 27 different cancer types and presaged poor prognosis in four of these types,including LIHC.Across pan-cancers,TMEM106C was inversely correlated to the abundances of immune and stromal cells.Furthermore,TMEM106C was significantly linked to cell cycle and DNA replication pathways in pan-cancers.ChIP-seq analysis predicted CCCTC-binding factor as a pivotal transcriptional factor targeting the TMEM106C gene in pan-cancers.Integrated analysis showed that TMEM106C was upregulated in 4657 LIHC compared with 3652 normal liver tissue[combined standardized mean difference=1.31(1.09,1.52)].Inhouse LIHC samples verified the expression status of TMEM106C.Higher TMEM106C expression signified worse survival conditions in LIHC patients treated with sorafenib,a tyrosine kinase inhibitor(TKI).Co-expressed analysis revealed that TMEM106C were significantly enriched in the cell cycle pathway.Knockout experiments demonstrated that TMEM106C plays a crucial role in LIHC cell proliferation,migration,and invasion,with cell cycle arrest occurring at the DNA synthesis phase,and increased apoptosis.Notably,TMEM106C upregulation was attenuated by NC treatment.Finally,TMEM106C expression levels were significantly correlated with the drug sensitivity of anti-hepatocellular carcinoma agents,including JNJ-42756493,a TKI agent.CONCLUSION Overexpressed TMEM106C was predicted as an oncogene in pan-cancers,which may serve as a promising therapeutic target for various cancers,including LIHC.Targeting TMEM106C could potentially offer a novel direction in overcoming TKI resistance specifically in LIHC.Future research directions include in-depth experimental validation and exploration of TMEM106C’s role in other cancer types.展开更多
BACKGROUND Activation of the epithelial-mesenchymal transition(EMT),a pivotal process in tumor metastasis and evasion,as well as the NLRP3 inflammasome,both promote colorectal cancer(CRC)progression.Recent studies hav...BACKGROUND Activation of the epithelial-mesenchymal transition(EMT),a pivotal process in tumor metastasis and evasion,as well as the NLRP3 inflammasome,both promote colorectal cancer(CRC)progression.Recent studies have shown that Transmembrane protein 176B(TMEM176B)regulates NLRP3 and promotes CRC malignant phenotypes.AIM To investigate the role of TMEM176B in modulating NLRP3 inflammasome and its implications on EMT and tumor progression in CRC.METHODS CRC in situ mouse and co-cultured cell models were established using CT26 cells,BALB/c mice,and primary cultured mouse natural killer(NK)cells.Short hairpin RNA knocked down TMEM176B and NLRP3 expression in CT26 cells.Fluorescence imaging,Terminal deoxynucleotidyl transferase dUTP nick end labeling assays,immunohistochemistry staining,flow cytometry,and molecular assays were used to investigate the effects of TMEM176B knockdown on the NLRP3 inflammasome in NK cells to assess tumor metastasis,apoptosis,and EMT indicators.RESULTS Silencing TMEM176B in CRC mice significantly reduced tumor metastasis,proliferation,and EMT,while activating apoptosis,NLRP3 inflammasome,and NK cell activity.Furthermore,silencing TMEM176B in co-cultured cell models inhibited cell migration and invasion,and promoted apoptosis.The interference of NLRP3 reversed these effects by modulating key proteins such as phosphorylated nuclear factor kappa B subunit 1 p65,matrix metallopeptidase 9,and transforming growth factor-β.CONCLUSION This study highlights the critical role of TMEM176B/NLRP3 in CRC progression and provides a basis for targeting this axis as a novel therapeutic approach to manage CRC progression and metastasis.展开更多
Crimean-Congo hemorrhagic fever(CCHF)is a hemorrhagic fever caused by infection with the CCHF virus(CCHFV)and has a mortality rate of up to 30%.Thrombocytopenia is a hallmark of CCHF;however,the mechanisms underlying ...Crimean-Congo hemorrhagic fever(CCHF)is a hemorrhagic fever caused by infection with the CCHF virus(CCHFV)and has a mortality rate of up to 30%.Thrombocytopenia is a hallmark of CCHF;however,the mechanisms underlying this manifestation remain poorly understood.In addition to hemostasis,platelets play a crucial role in recognizing pathogens and mediating immune responses.We investigated the mechanisms underlying thrombocytopenia associated with CCHFV infection by analyzing the platelet transcriptome in mice.Interferon-induced transmembrane protein 3(IFITM3),a known antiviral factor,was significantly upregulated.The role of IFITM3 in response to CCHFV infection was characterized using the human megakaryoblast cell line MEG-01,considered a parental cell line of platelets.Although the CCHFV infection rate was limited,MEG-01 cells maintained the infection and replication of CCHFV,leading to increased IFITM3 protein expression.We demonstrated that IFITM3 overexpression efficiently inhibited CCHFV infection,whereas IFITM3 knockout promoted viral infection.An interaction between IFITM3 and the CCHFV glycoprotein Gc was identified,which suppressed CCHFV entry into cells.The IFITM3 CIL-TMD domain is critical for this interaction.These results suggest that IFITM3 is a restriction factor and plays an antiviral role during CCHFV infection.Elevated expression of IFITM3 in platelets indicates that this could be a common mechanism by which platelets protect against viruses,including CCHFV,which may reduce platelet consumption and destruction caused by CCHFV infection.These findings provide valuable insights into the pathogenesis of CCHF-associated thrombocytopenia and offer foundational theoretical support for future therapeutic strategies.展开更多
Tmnsmembrane（TM） protein plays an important role in the life activity of the cells, and the prediction of transmembrane helical segments （TMHs） is an important subject in the bioinformatics research. Thus far, sev...Tmnsmembrane（TM） protein plays an important role in the life activity of the cells, and the prediction of transmembrane helical segments （TMHs） is an important subject in the bioinformatics research. Thus far, several prediction methods have been reported, but there are some deficiencies in prediction accuracy and adaptability in these methods. In this paper, a method based on discrete wavelet transform （DWT） was developed to predict the TMHs. Two sets of test data sets containing total 60 protein sequences were utilized to access the effect of the method. Compared with the prediction results of TMHMM2.0 and MEMSAT, the obtained results indicate that the presented method has high prediction accuracy.展开更多
Remifentanil is widely used to control intraoperative pain. However, its analgesic effect is limited by the generation of postoperative hyperalgesia. In this study, we investigated whether the impairment of transmembr...Remifentanil is widely used to control intraoperative pain. However, its analgesic effect is limited by the generation of postoperative hyperalgesia. In this study, we investigated whether the impairment of transmembrane protein 16C(TMEM16C)/Slack is required for a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor(AMPAR) activation in remifentanil-induced postoperative hyperalgesia. Remifentanil anesthesia reduced the paw withdrawal threshold from 2 h to 48 h postoperatively,with a decrease in the expression of TMEM16C and Slack in the dorsal root ganglia(DRG) and spinal cord.Knockdown of TMEM16C in the DRG reduced the expression of Slack and elevated the basal peripheral sensitivity and AMPAR expression and function. Overexpression of TMEM16C in the DRG impaired remifentanilinduced ERK1/2 phosphorylation and behavioral hyperalgesia. AMPAR-mediated current and neuronal excitability were downregulated by TMEM16C overexpression in the spinal cord. Taken together, these findings suggest that TMEM16C/Slack regulation of excitatory synaptic plasticity via GluA1-containing AMPARs is critical in the pathogenesis of remifentanil-induced postoperative hyperalgesia in rats.展开更多
BACKGROUND The molecular mechanisms of colorectal cancer development and progression are far from being elucidated.AIM To investigate the role of microRNA-363-3p(miR-363-3p)in the progression of colorectal cancer.METH...BACKGROUND The molecular mechanisms of colorectal cancer development and progression are far from being elucidated.AIM To investigate the role of microRNA-363-3p(miR-363-3p)in the progression of colorectal cancer.METHODS Real-time polymerase chain reaction was performed to detect miRNA expression in human colorectal cancer tissues and paired normal colorectal tissues.PITA 6 was utilized to predict the targets of miR-363-3p.Dual-luciferase reporter system was used to validate the target of miR-363-3p.Plate colony formation assay and wound-healing assay were performed to evaluate cancer cells’clonogenic survival ability and migration ability,respectively.Cell proliferation was examined by cell counting kit-8 assay.Immunohistochemical staining was used to determine the expression level of interferon-induced transmembrane protein 1(IFITM1)in colorectal cancer tissues and adjacent tissues.The TCGA and GTEx databases were used to compare the expression levels of IFITM1 mRNA in colorectal cancer tissues and normal colorectal tissues and analyze the correlation between the expression levels of IFITM1 mRNA and overall survival and disease-free survival of patients.A colorectal cancer cell line with a deficiency of IFITM1 was constructed,and the regulation effect of IFITM1 on the clonogenic growth of colorectal cancer cells was clarified.RESULTS MiR-363-3p was decreased in colorectal cancer tissues compared to normal colorectal tissues.IFITM1 was characterized as a direct target of miR-363-3p.Overexpression of miR-363-3p led to decreased clonogenic survival,proliferation,and migration of colorectal cancer cells,which could be reversed by forced IFITM1 expression.CONCLUSION MiR-363-3p can constrain clonogenic survival,proliferation,and migration of colorectal cancer cells via targeting IFITM1.展开更多
Topology of the transmembrane protein is closely related to its functions.So,it is desiderated to depict the topology of transmembrane proteins.In this work,an effective approach of Increment of Diversity with Quadrat...Topology of the transmembrane protein is closely related to its functions.So,it is desiderated to depict the topology of transmembrane proteins.In this work,an effective approach of Increment of Diversity with Quadratic Discriminant(IDQD)was presented to predict the topology of transmembrane proteins.展开更多
Objective: To clone and analyze the structure of a novel gene, named EST 1 (endoplasmic reticulum localized seven span transmembrane protein 1) and to analyze the expression pattern and intracellular location of EST 1...Objective: To clone and analyze the structure of a novel gene, named EST 1 (endoplasmic reticulum localized seven span transmembrane protein 1) and to analyze the expression pattern and intracellular location of EST 1. Methods: The cDNA library was screened to isolate novel cDNA fragment. The structure of novel gene was analysed by computer software. Expression of EST 1 was analyzed by dot blot and Northern blotting. Intracellular localization was observed after EST 1 enhanced green fluorescence protein (EGFP) fusion gene was transfected into mammalian cells. Results: The full length cDNA of mouse EST 1 was 1 802 bp, with a 1 293 bp open reading frame encoding 431 amino acids. It was predicated that protein encoded by EST 1 contained a signal peptide sequence at the N terminus, seven putative transmembrane domains, and an ER retaining signal at the C terminus. EST 1 EGFP fusion protein showed an ER like intracellular distribution in mammalian cells. Expression pattern analysis showed that EST 1 is expressed in all tissues examined. Conclusion: EST 1 is encoding a putative seven span transmembrane protein localized in endoplasmic reticulum. EST 1 was expressed in all tissues examined, suggesting an essential function of EST 1 in cells.展开更多
Background： Antibody drug conjugated （ADC） is one kind of very important method of therapy to cancer diseases. In this research, the authors introduce BLAST and some other important algorithms to create transmembra...Background： Antibody drug conjugated （ADC） is one kind of very important method of therapy to cancer diseases. In this research, the authors introduce BLAST and some other important algorithms to create transmembrane protein databases. These databases are acquired from well-known databases such as NCBI or Swiss-Prot as template, and then collect all possible transmembrane protein by using BLAST or physical character. After collect these databases, the authors will aim at each nucleotide sequences to design the probes of oligonucleotide microarray, which can detect the high express transmembrane proteins very efficiently. Finally, the authors can accelerate the anti-cancer drug discovery by using these databases. Result： This study constructed a web service, the Transmembrane Protein Database, to researchers that are interested in or need to oligonucleotide microarray probe design for detecting potential targets of antibody drug. With user friendly web based windows containing each necessary selections, users can easily choose the parameters and get the suitable probe design suggestions. Conclusion： Transmembrane protein database is very important and powerful in detecting cancers or other human disease. By using this database, the authors offer a good strategy in transmembrane protein research as well.展开更多
To the Editor:Chimeric antigen receptor(CAR)-T cells targeting CD19 have transformed the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia(R/R B-ALL)therapy.[1]However,cytokine release syndrome(C...To the Editor:Chimeric antigen receptor(CAR)-T cells targeting CD19 have transformed the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia(R/R B-ALL)therapy.[1]However,cytokine release syndrome(CRS)represents a serious and potentially life-threatening complication,marked by excessive proinflammatory cytokine release,poses a severe,potentially fatal complication,manifesting as fever,nausea,fatigue,and,in severe cases,multi-organ failure.展开更多
Background Interferon-induced transmembrane protein 1 （IFITM1） has been identified as a molecular marker of the colorectal tumors; however its influences on the biological behaviors of the colorectal cancer cells ar...Background Interferon-induced transmembrane protein 1 （IFITM1） has been identified as a molecular marker of the colorectal tumors; however its influences on the biological behaviors of the colorectal cancer cells are currently unknown.We aimed to study the influences of IFITM1 on the proliferation,invasion,and metastasis of the colorectal cancer SW480 cell lines.Methods We constructed IFITM1/pEGFP-C3 recombinant plasmids and transfected them into the colorectal cancer SW480 cell lines.IFITM1/pEGFP-C3 recombinant plasmids were identified by means of immunofluorescence,laser confocal scanning microscopy,and reverse transcription polymerase chain reaction.IFITM1/SW480 cells with stable over-expression of IFITM1 were confirmed by G418 screening.The influences of IFITM1 on the proliferation of the SW480 cell lines were investigated by MTT assay and tumor transplantation experiments in nude mice.Cell invasion experiments were performed to determine the invasion capacity of the IFITM1/SW480 cells.Matrix metalloproteinase 2 （MMP-2） and MMP-9 activities were detected by the gelatin zymographic analysis,and MMP-9 expression by the Western blotting analysis.Results IFITM1/pEGFP-C3 recombinant plasmids were successfully constructed in this study,and the IFITM1/SW480 cells with stable IFITM1 gene over-expression were confirmed by G418 screening.MTT results showed that the proliferation of the IFITM1/SW480 cells was significantly enhanced （P 〈0.01）.Tumors were harvested from four weeks old mice.Tumor volumes were （1347.00±60.94） mm3,（1032.40±111.38） mm3 and （1018.78±28.83） mm3; and tumor weights were （1522.34±62.76） mg,（1137.78±97.22） mg and （1155.76±133.31） mg for mice inoculated with the IFITM1/SW480 cells,pEGFP-C3/SW480 cells and SW480 cells,respectively.Tumor volumes and weights from mice inoculated with the IFITM1/SW480 cells were significantly increased （P 〈0.01）.In addition,the numbers of the SW480 cells and IFITM1/SW480 cells that migrated through Matrigel were 448.64±38.09 and 540.45±44.61,respectively; so the invasive ability of the SW480 cells transfected with IFITM1 gene was significantly greater than that of the SW480 cells （P 〈0.01）.Gelatin zymographic analysis showed that MMP-9 and MMP-2 protein activities in the IFITM1/SW480 cells were significantly enhanced,and Western blotting analysis showed that MMP-9 expression in the IFITM1/SW480 cells was also increased.Conclusion IFITMl can enhance the proliferation,invasion,and metastasis of the colorectal cancer SW480 cell lineS.展开更多
Objective： Lysosome associated protein transmembrane 4 beta （LAPTM4B） was originally identified as a gene in human hepatocellular carcinoma （HCC）. It was successfully cloned by fluorescence differential display, ...Objective： Lysosome associated protein transmembrane 4 beta （LAPTM4B） was originally identified as a gene in human hepatocellular carcinoma （HCC）. It was successfully cloned by fluorescence differential display, rapid amplification of cDNA ends （RACE） and reverse transcription polymerase chain reaction （RT-PCR）. Previous study showed that the novel gene played an important role in the occurrence, development, migration and prognosis of tumors. Pancreatic cancer is an aggressive malignancy with the majority of patients dying within one year after diagnosis. This study tries to find out the relationship between lysosome associated protein transmembrane 4 beta gene polymorphism and the susceptibility of pancreatic cancer. Methods： A case-control study was conducted in China, including 58 pancreatic cancer cases and 156 healthy controls. Human genomic DNA was used as the template, polymerase chain reaction （PCR） was used to detect the distribution of LAPTM4B genotype. Analyses Odds ratio （OR） and corresponding 95% confidence interval （95%CI） with logistic regression were performed. Results： Two alleles of LAPTM4B generated three kinds of genotypes in population, ＊1/1, ＊1/2, and ＊2/2. The genotype frequency of ＊1/1, ＊1/2 and ＊2/2 in the pancreatic cancer group were 41.4%, 44.8% and 13.8% respectively, which were not significantly different from those of healthy group （47.4%, 42.9%, 9.6%） （P=0.773, P=0.291）. Also the ＊2 allele frequency of LAPTM4B among pancreatic cancer had no significantly difference with the controls （P=0.354）. When compared to the ＊1 allele, the people with ＊2 allele had no increased risk of pancreatic cancer. Conclusion： The gene polymorphism of LAPTM4B may not influence the susceptibility of pancreatic cancer.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)is a difficult cancer to manage due to its highly invasive and metastatic nature.AIM To investigate the molecular function of transmembrane channel-like 5(TMC5)in vitro and in v...BACKGROUND Hepatocellular carcinoma(HCC)is a difficult cancer to manage due to its highly invasive and metastatic nature.AIM To investigate the molecular function of transmembrane channel-like 5(TMC5)in vitro and in vivo,with the objective of identifying novel diagnosis and treatment targets for HCC.METHODS The expression of TMC in cancer and normal tissues,along with its correlation with HCC prognosis,was analyzed using the GENT2,GEPIA database,and Human Protein Atlas.COX analysis was conducted to assess the relationship between TMC5 expression and overall survival in TCGA-LIHC patients.Further experiments were conducted to investigate the effect of TMC5 in cancer progression through loss-and gain-of-function assays in vitro and in vivo.RESULTS Bioinformatics revealed that TMC5 expression was generally higher in tumors than in normal tissues,and its expression was associated with poorer patient survival outcomes.TMC5 expression in HCC tissues and cells was consistent with the results of the bioinformatics analysis.Suppression of TMC5 expression reduced migration,invasion,and proliferation,while also decreasing the expression of epithelial-mesenchymal transition(EMT)-associated molecules in MHCC97-LM3 cells.Conversely,higher TMC5 expression significantly increased cell migration,invasion,proliferation,and EMT in MHCC97 L cells.TMC5 knockdown significantly decreased both the formation and spread of nodules in liver tissue,whereas TMC5 overexpression promoted them.CONCLUSION Our study provides compelling evidence that TMC5 is highly expressed in HCC and drives cancer progression through the activation of EMT-mediated invasion.TMC5 could represent a valuable molecular target for the diagnosis and treatment of HCC.展开更多
A variety of glycosylphosphatidylinositol （GPI）-linked proteins are acquired on spermatozoa from epididymal luminal fluids （ELF） during sperm maturation. These proteins serve roles in immunoprotection and in key s...A variety of glycosylphosphatidylinositol （GPI）-linked proteins are acquired on spermatozoa from epididymal luminal fluids （ELF） during sperm maturation. These proteins serve roles in immunoprotection and in key steps of fertilization such as capacitation, acrosomal exocytosis and sperm-egg interactions. Their acquisition on sperm cells is mediated both by membrane vesicles （epididymosomes, EP） which were first reported to dock on the sperm surface, and by lipid carriers which facilitate the transfer of proteins associated with the membrane-free fraction of ELF. While the nonvesicular fraction is more efficient, both pathways are dependent on hydrophobic interactions between the GPI-anchor and the external lipid layer of the sperm surface. More recently proteomic and hypothesis-driven studies have shown that EP from several mammals carry transmembrane （TM） proteins, including plasma membrane Ca^2＋-ATPase 4 （PMCA4）. Synthesized in the testis, PMCA4 is an essential protein and the major Ca^2＋ efflux pump in murine spermatozoa. Delivery of PMCA4 to spermatozoa from bovine and mouse EP during epididymal maturation and in vitro suggests that the docking of EP on the sperm surface precedes fusion, and experimental evidence supports a fusogenic mechanism for TM proteins. Fusion is facilitated by CD9, which generates fusion-competent sites on membranes. On the basis of knowledge of PMCA4＇s interacting partners a number of TM and membrane-associated proteins have been identified or are predicted to be present, in the epididymosomal cargo deliverable to spermatozoa. These Ca^2＋-dependent proteins, undetected in proteomic studies, play essential roles in sperm motility and fertility, and their detection highlights the usefulness of the hypothesis-driven approach.展开更多
Interferon-inducible transmembrane protein 3(IFITM3)inhibits influenza virus infection by blocking viral membrane fusion,but the exact mechanism remains elusive.Here,we investigated the function and key region of IFIT...Interferon-inducible transmembrane protein 3(IFITM3)inhibits influenza virus infection by blocking viral membrane fusion,but the exact mechanism remains elusive.Here,we investigated the function and key region of IFITM3 in blocking influenza virus entry mediated by hemagglutinin(HA).The restriction of IFITM3 on HAmediated viral entry was confirmed by pseudovirus harboring HA protein from H5 and H7 influenza viruses.Subcellular co-localization and immunocoprecipitation analyses revealed that IFITM3 partially co-located with the full-length HA protein and could directly interact with HA_(2) subunit but not HA_(1) subunit of H5 and H7 virus.Truncated analyses showed that the transmembrane domain of the IFITM3 and HA_(2) subunit might play an important role in their interaction.Finally,this interaction of IFITM3 was also verified with HA_(2) subunits from other subtypes of influenza A virus and influenza B virus.Overall,our data demonstrate for the first time a direct interaction between IFITM3 and influenza HA protein via the transmembrane domain,providing a new perspective for further exploring the biological significance of IFITM3 restriction on influenza virus infection or HA-mediated antagonism or escape.展开更多
Objective Although immune dysregulation is implicated in the pathogenesis of endometriosis(EMs),the specific role of prostate transmembrane protein androgen induced 1(PMEPA1)in modulating the function of regulatory T ...Objective Although immune dysregulation is implicated in the pathogenesis of endometriosis(EMs),the specific role of prostate transmembrane protein androgen induced 1(PMEPA1)in modulating the function of regulatory T cells(Tregs)remains inadequately understood.This study aimed to elucidate the regulatory mechanisms by which PMEPA1 influences the activity of Tregs,thereby facilitating the invasion of endometrial stromal cells(ESCs).Methods Single-cell RNA sequencing(scRNA-seq)was performed on matched ectopic ovarian lesions and eutopic endometria from 3 patients.Clinical specimens from patients with EMs and control subjects were examined for PMEPA1 expression.Primary human Tregs isolated from peripheral blood mononuclear cells were subjected to PMEPA1 overexpression(via plasmid)or knockdown(via siRNA).Modulation of the PI3K pathway was conducted via the activator 740Y-P or the inhibitor LY294002.The secretion of IL-10 and TGF-βby Tregs was quantified using an enzyme-linked immunosorbent assay.Ectopic ESCs cocultured with modified Tregs were assessed for their proliferation,migration,and invasion capabilities.Results scRNA-seq data revealed significant upregulation of PMEPA1 in Tregs from ectopic ovarian lesions compared with paired eutopic endometria.PMEPA1 expression was increased in the ectopic lesions and peritoneal fluid mononuclear cells of patients with EMs.Tregs overexpressing PMEPA1 demonstrated reduced secretion of IL-10 and TGF-βbut exhibited hyperactivation of the PI3K/AKT signaling pathway.Treatment with LY294002 ameliorated the impairment in cytokine secretion.Coculture experiments with Tregs expressing high levels of PMEPA1 resulted in increased invasion,migration,and proliferation of ESCs.Conclusion PMEPA1 impairs Treg-mediated immunosuppression by hyperactivating the PI3K/AKT pathway,thereby facilitating the invasiveness of ESCs in EMs.展开更多
Background:Lung cancer remains a major factor causing cancer-associated mortality globally.While there have been advancements in treatment options,advanced lung cancer patients still have poor outcomes.This study aims...Background:Lung cancer remains a major factor causing cancer-associated mortality globally.While there have been advancements in treatment options,advanced lung cancer patients still have poor outcomes.This study aims to investigate the potential role of Transmembrane protein 33(TMEM33)in the development of lung adenocarcinoma.Methods:We leveraged The Cancer Genome Atlas(TCGA)database to analyze the connection between TMEM33 expression to the prognosis of lung adenocarcinoma(LUAD).Cell proliferation,invasiveness,and sphere formation were analyzed by various experiments.The association of miR-214-3p with TMEM33 was explored using luciferase reporter assay,immunoblotting,and real-time quantitative PCR(RT-qPCR).Additionally,TMEM33’s biological role was confirmed in the mouse xenograft model through lung cancer transplantation and metastasis studies.Results:TMEM33 showed high expression within both LUAD tissues and cells,with its expression correlating with poor patient survival outcomes.Silencing TMEM33 resulted in significant reductions in cell proliferation,invasiveness,and stem-like properties.Further investigation suggested that miR-214-3p negatively regulated TMEM33.In both cellular and animal models,we further demonstrated that TMEM33 knockdown could effectively suppress the aggressiveness of lung cancer cells,impeding tumor growth and inhibiting metastasis in the mouse model.Moreover,reducing TMEM33 expression reduced key signaling molecules within the Wnt/β-catenin pathway,providing insights into TMEM33’s mechanistic role in LUAD.Conclusion:TMEM33 functions as an oncogene,which is under the negative regulation of miR-214-3p,to promote the LUAD malignant characteristics by engaging the Wnt/β-catenin cascade.展开更多
The structural and molecular organization of the cell surface plays a pivotal role in governing cell-extracellular environment interactions.While glycosylated transmembrane proteins have long been considered the prima...The structural and molecular organization of the cell surface plays a pivotal role in governing cell-extracellular environment interactions.While glycosylated transmembrane proteins have long been considered the primary components of plasma membranes,emerging evidence highlights the critical contributions of RNA-binding proteins(RBPs)and glycosylated RNAs(glycoRNAs)to cell surface functions.展开更多
Background:Transmembrane emp24 trafficking protein 3(TMED3)is associated with the development of several tumors;however,whether TMED3 regulates the progression of prostate cancer remains unclear.Materials and Methods:...Background:Transmembrane emp24 trafficking protein 3(TMED3)is associated with the development of several tumors;however,whether TMED3 regulates the progression of prostate cancer remains unclear.Materials and Methods:Short hairpin RNA was performed to repress TMED3 in prostate cancer cells(DU145 cells)and in a prostate cancer mice model to determine its function in prostate cancer in vitro and in vivo.Results:In the present study,we found that TMED3 was highly expressed in prostate cancer cells.In vitro,shTMED3 treatment suppressed the proliferation,invasion,and migration and promoted the apoptosis of DU145 cells.Additionally,the Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed a strong correlation between TMED3 and forkhead box O transcription factor(FOXO)pathway.Furthermore,TMED3 inhibition efficiently decreased FOXO1a and FOXO3a phosphorylation.In vivo,TMED3 downregulation suppressed the apoptosis,growth,and metastasis of prostate cancer cells via FOXO1a and FOXO3a.Conclusion:The present findings show that TMED3 participates in the regulation of prostate cancer progression via FOXO1a and FOXO3a phosphorylation,thereby revealing a novel mechanism underlying prostate cancer development and suggesting that TMED3 inhibition may serve as a novel strategy for prostate cancer treatment.展开更多
Objective Paroxysmal kinesigenic dyskinesia(PKD)is a rare movement disorder PRRT2 gene mutations have been reported to cause PKD.However,the pathophysiological mechanism of PKD remains unclear,and it is unknown whethe...Objective Paroxysmal kinesigenic dyskinesia(PKD)is a rare movement disorder PRRT2 gene mutations have been reported to cause PKD.However,the pathophysiological mechanism of PKD remains unclear,and it is unknown whether an inflammatory response is involved in the occurrence of this disease.We aimed to investigate the symptomatology,genotype,and serum cytokines of patients with PKD.Methods We recruited 21 patients with PKD,including 7 with familial PKD and 14 with sporadic PKD.Their clinical features were investigated,and blood samples were collected,and PRRT2 mutations and cytokine levels were detected.Results The mean age at PKD onset was 12.3±2.2 years old.Dystonia was the most common manifestation of dyskinesia,and the limbs were the most commonly affected parts.All attacks were induced by identifiable kinesigenic triggers,and the attack durations were brief(<1 min).Four different mutations from 9 probands were identified in 7 familial cases(71.4%)and 14 sporadic cases(28.6%).Two of these mutations(c.649dupC,c.620_621delAA)had already been reported,while other 2(c.1018_1019delAA,c.1012+1G>A)were previously undocumented.The tumor necrosis factor(TNF)-αlevel in the PKD group was significantly higher than that in the age-and sex-matched control group(P=0.025).There were no significant differences in the interleukin(IL)-1β,IL-2R,IL-6,IL-8,or IL-10 levels between the two groups.Conclusion In this study,we summarized the clinical and genetic characteristics of PKD.We found that the serum TNF-αlevels were elevated in patients clinically diagnosed with PKD,suggesting that an inflammatory response is involved in the pathogenesis of PKD.展开更多
基金Supported by the National Natural Science Foundation of China,No.NSFC82160762,No.NSFC82460783Natural Science Foundation of Guangxi,No.2022GXNSFBA035657Innovation Project of Guangxi Graduate Education,No.JGY2023068,No.YCSW2023220.
文摘BACKGROUND Although transmembrane protein 106C(TMEM106C)has been elucidated to be overexpressed in cancers,its underlying mechanisms have not yet been fully understood.AIM To investigate the expression levels and molecular mechanisms of TMEM106C across 34 different cancer types,including liver hepatocellular carcinoma(LIHC).METHODS We analyzed TMEM106C expression patterns in pan-cancers using microenvironment cell populations counter to evaluate its association with the tumor microenvironment.Gene set enrichment analysis was conducted to identify molecular pathways related to TMEM106C.Chromatin immunoprecipitation followed by sequencing(ChIP-seq)analysis was conducted to identify upstream transcriptional regulators of TMEM106C.In LIHC,we examined mRNA profiles,performed in-house quantitative polymerase chain reaction,immunohistochemistry,and constructed a co-expression gene network.Functional assays,including cell counting kit-8,cell cycle,apoptosis,migration,and invasion,were conducted.The effect of nitidine chloride(NC)on LIHC xenograft was evaluated through RNA sequencing and molecular docking.Finally,potential therapeutic agents targeting TMEM106C were predicted.RESULTS TMEM106C was significantly overexpressed in 27 different cancer types and presaged poor prognosis in four of these types,including LIHC.Across pan-cancers,TMEM106C was inversely correlated to the abundances of immune and stromal cells.Furthermore,TMEM106C was significantly linked to cell cycle and DNA replication pathways in pan-cancers.ChIP-seq analysis predicted CCCTC-binding factor as a pivotal transcriptional factor targeting the TMEM106C gene in pan-cancers.Integrated analysis showed that TMEM106C was upregulated in 4657 LIHC compared with 3652 normal liver tissue[combined standardized mean difference=1.31(1.09,1.52)].Inhouse LIHC samples verified the expression status of TMEM106C.Higher TMEM106C expression signified worse survival conditions in LIHC patients treated with sorafenib,a tyrosine kinase inhibitor(TKI).Co-expressed analysis revealed that TMEM106C were significantly enriched in the cell cycle pathway.Knockout experiments demonstrated that TMEM106C plays a crucial role in LIHC cell proliferation,migration,and invasion,with cell cycle arrest occurring at the DNA synthesis phase,and increased apoptosis.Notably,TMEM106C upregulation was attenuated by NC treatment.Finally,TMEM106C expression levels were significantly correlated with the drug sensitivity of anti-hepatocellular carcinoma agents,including JNJ-42756493,a TKI agent.CONCLUSION Overexpressed TMEM106C was predicted as an oncogene in pan-cancers,which may serve as a promising therapeutic target for various cancers,including LIHC.Targeting TMEM106C could potentially offer a novel direction in overcoming TKI resistance specifically in LIHC.Future research directions include in-depth experimental validation and exploration of TMEM106C’s role in other cancer types.
基金Ministry of Education Industry-University Co-operation Collaborative Education Project,No.202102242020.
文摘BACKGROUND Activation of the epithelial-mesenchymal transition(EMT),a pivotal process in tumor metastasis and evasion,as well as the NLRP3 inflammasome,both promote colorectal cancer(CRC)progression.Recent studies have shown that Transmembrane protein 176B(TMEM176B)regulates NLRP3 and promotes CRC malignant phenotypes.AIM To investigate the role of TMEM176B in modulating NLRP3 inflammasome and its implications on EMT and tumor progression in CRC.METHODS CRC in situ mouse and co-cultured cell models were established using CT26 cells,BALB/c mice,and primary cultured mouse natural killer(NK)cells.Short hairpin RNA knocked down TMEM176B and NLRP3 expression in CT26 cells.Fluorescence imaging,Terminal deoxynucleotidyl transferase dUTP nick end labeling assays,immunohistochemistry staining,flow cytometry,and molecular assays were used to investigate the effects of TMEM176B knockdown on the NLRP3 inflammasome in NK cells to assess tumor metastasis,apoptosis,and EMT indicators.RESULTS Silencing TMEM176B in CRC mice significantly reduced tumor metastasis,proliferation,and EMT,while activating apoptosis,NLRP3 inflammasome,and NK cell activity.Furthermore,silencing TMEM176B in co-cultured cell models inhibited cell migration and invasion,and promoted apoptosis.The interference of NLRP3 reversed these effects by modulating key proteins such as phosphorylated nuclear factor kappa B subunit 1 p65,matrix metallopeptidase 9,and transforming growth factor-β.CONCLUSION This study highlights the critical role of TMEM176B/NLRP3 in CRC progression and provides a basis for targeting this axis as a novel therapeutic approach to manage CRC progression and metastasis.
基金supported by the the National Key R&D Program of China(2024YFC2310000)the Key Project of Key Laboratory of VirologyBiosafety in the Wuhan Institute of Virology,Chinese Academy of Sciences(2024JZZD-02),the Youth Project of the Wuhan Institute of Virology,Chinese Academy of Sciences(2023QNTJ-03)+2 种基金the"Open Competition for Selecting the Best Candidates"Project of the Wuhan East Lake New Technology Development Zone(2022KJB117)the Natural Science Foundation of Hubei Province(2024AFB986)the Medical Science Research Project of Wuhan Health Commission(WX23B09).
文摘Crimean-Congo hemorrhagic fever(CCHF)is a hemorrhagic fever caused by infection with the CCHF virus(CCHFV)and has a mortality rate of up to 30%.Thrombocytopenia is a hallmark of CCHF;however,the mechanisms underlying this manifestation remain poorly understood.In addition to hemostasis,platelets play a crucial role in recognizing pathogens and mediating immune responses.We investigated the mechanisms underlying thrombocytopenia associated with CCHFV infection by analyzing the platelet transcriptome in mice.Interferon-induced transmembrane protein 3(IFITM3),a known antiviral factor,was significantly upregulated.The role of IFITM3 in response to CCHFV infection was characterized using the human megakaryoblast cell line MEG-01,considered a parental cell line of platelets.Although the CCHFV infection rate was limited,MEG-01 cells maintained the infection and replication of CCHFV,leading to increased IFITM3 protein expression.We demonstrated that IFITM3 overexpression efficiently inhibited CCHFV infection,whereas IFITM3 knockout promoted viral infection.An interaction between IFITM3 and the CCHFV glycoprotein Gc was identified,which suppressed CCHFV entry into cells.The IFITM3 CIL-TMD domain is critical for this interaction.These results suggest that IFITM3 is a restriction factor and plays an antiviral role during CCHFV infection.Elevated expression of IFITM3 in platelets indicates that this could be a common mechanism by which platelets protect against viruses,including CCHFV,which may reduce platelet consumption and destruction caused by CCHFV infection.These findings provide valuable insights into the pathogenesis of CCHF-associated thrombocytopenia and offer foundational theoretical support for future therapeutic strategies.
基金Project supported by National High-Technology Research andDevelopment Program of China (Grant No .2002AA234021)
文摘Tmnsmembrane（TM） protein plays an important role in the life activity of the cells, and the prediction of transmembrane helical segments （TMHs） is an important subject in the bioinformatics research. Thus far, several prediction methods have been reported, but there are some deficiencies in prediction accuracy and adaptability in these methods. In this paper, a method based on discrete wavelet transform （DWT） was developed to predict the TMHs. Two sets of test data sets containing total 60 protein sequences were utilized to access the effect of the method. Compared with the prediction results of TMHMM2.0 and MEMSAT, the obtained results indicate that the presented method has high prediction accuracy.
基金supported by the National Natural Science Foundation of China (82071243, 81801107, 81772043, and 81400908)Tianjin Natural Science Foundation (20JCYBJC00460)Young Elite Scientists Sponsorship Program by Tianjin Municipality, China (TJSQNTJ-2020-10)。
文摘Remifentanil is widely used to control intraoperative pain. However, its analgesic effect is limited by the generation of postoperative hyperalgesia. In this study, we investigated whether the impairment of transmembrane protein 16C(TMEM16C)/Slack is required for a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor(AMPAR) activation in remifentanil-induced postoperative hyperalgesia. Remifentanil anesthesia reduced the paw withdrawal threshold from 2 h to 48 h postoperatively,with a decrease in the expression of TMEM16C and Slack in the dorsal root ganglia(DRG) and spinal cord.Knockdown of TMEM16C in the DRG reduced the expression of Slack and elevated the basal peripheral sensitivity and AMPAR expression and function. Overexpression of TMEM16C in the DRG impaired remifentanilinduced ERK1/2 phosphorylation and behavioral hyperalgesia. AMPAR-mediated current and neuronal excitability were downregulated by TMEM16C overexpression in the spinal cord. Taken together, these findings suggest that TMEM16C/Slack regulation of excitatory synaptic plasticity via GluA1-containing AMPARs is critical in the pathogenesis of remifentanil-induced postoperative hyperalgesia in rats.
文摘BACKGROUND The molecular mechanisms of colorectal cancer development and progression are far from being elucidated.AIM To investigate the role of microRNA-363-3p(miR-363-3p)in the progression of colorectal cancer.METHODS Real-time polymerase chain reaction was performed to detect miRNA expression in human colorectal cancer tissues and paired normal colorectal tissues.PITA 6 was utilized to predict the targets of miR-363-3p.Dual-luciferase reporter system was used to validate the target of miR-363-3p.Plate colony formation assay and wound-healing assay were performed to evaluate cancer cells’clonogenic survival ability and migration ability,respectively.Cell proliferation was examined by cell counting kit-8 assay.Immunohistochemical staining was used to determine the expression level of interferon-induced transmembrane protein 1(IFITM1)in colorectal cancer tissues and adjacent tissues.The TCGA and GTEx databases were used to compare the expression levels of IFITM1 mRNA in colorectal cancer tissues and normal colorectal tissues and analyze the correlation between the expression levels of IFITM1 mRNA and overall survival and disease-free survival of patients.A colorectal cancer cell line with a deficiency of IFITM1 was constructed,and the regulation effect of IFITM1 on the clonogenic growth of colorectal cancer cells was clarified.RESULTS MiR-363-3p was decreased in colorectal cancer tissues compared to normal colorectal tissues.IFITM1 was characterized as a direct target of miR-363-3p.Overexpression of miR-363-3p led to decreased clonogenic survival,proliferation,and migration of colorectal cancer cells,which could be reversed by forced IFITM1 expression.CONCLUSION MiR-363-3p can constrain clonogenic survival,proliferation,and migration of colorectal cancer cells via targeting IFITM1.
基金supported by National Natural Science Foundation(No.90403010)
文摘Topology of the transmembrane protein is closely related to its functions.So,it is desiderated to depict the topology of transmembrane proteins.In this work,an effective approach of Increment of Diversity with Quadratic Discriminant(IDQD)was presented to predict the topology of transmembrane proteins.
基金SupportedbytheNationalNaturalScienceFoundation (No .39970 376) andtheMinistryofScienceandTechnologyofChina (No .2 0 0 1CB50 990 6)
文摘Objective: To clone and analyze the structure of a novel gene, named EST 1 (endoplasmic reticulum localized seven span transmembrane protein 1) and to analyze the expression pattern and intracellular location of EST 1. Methods: The cDNA library was screened to isolate novel cDNA fragment. The structure of novel gene was analysed by computer software. Expression of EST 1 was analyzed by dot blot and Northern blotting. Intracellular localization was observed after EST 1 enhanced green fluorescence protein (EGFP) fusion gene was transfected into mammalian cells. Results: The full length cDNA of mouse EST 1 was 1 802 bp, with a 1 293 bp open reading frame encoding 431 amino acids. It was predicated that protein encoded by EST 1 contained a signal peptide sequence at the N terminus, seven putative transmembrane domains, and an ER retaining signal at the C terminus. EST 1 EGFP fusion protein showed an ER like intracellular distribution in mammalian cells. Expression pattern analysis showed that EST 1 is expressed in all tissues examined. Conclusion: EST 1 is encoding a putative seven span transmembrane protein localized in endoplasmic reticulum. EST 1 was expressed in all tissues examined, suggesting an essential function of EST 1 in cells.
文摘Background： Antibody drug conjugated （ADC） is one kind of very important method of therapy to cancer diseases. In this research, the authors introduce BLAST and some other important algorithms to create transmembrane protein databases. These databases are acquired from well-known databases such as NCBI or Swiss-Prot as template, and then collect all possible transmembrane protein by using BLAST or physical character. After collect these databases, the authors will aim at each nucleotide sequences to design the probes of oligonucleotide microarray, which can detect the high express transmembrane proteins very efficiently. Finally, the authors can accelerate the anti-cancer drug discovery by using these databases. Result： This study constructed a web service, the Transmembrane Protein Database, to researchers that are interested in or need to oligonucleotide microarray probe design for detecting potential targets of antibody drug. With user friendly web based windows containing each necessary selections, users can easily choose the parameters and get the suitable probe design suggestions. Conclusion： Transmembrane protein database is very important and powerful in detecting cancers or other human disease. By using this database, the authors offer a good strategy in transmembrane protein research as well.
基金This work was supported by grants from the National Natural Science Foundation of China(Nos.82330005,82400212,and 82200144)the open fund of Hubei Key Laboratory of Biological Targeted Therapy Research(No.202302).
文摘To the Editor:Chimeric antigen receptor(CAR)-T cells targeting CD19 have transformed the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia(R/R B-ALL)therapy.[1]However,cytokine release syndrome(CRS)represents a serious and potentially life-threatening complication,marked by excessive proinflammatory cytokine release,poses a severe,potentially fatal complication,manifesting as fever,nausea,fatigue,and,in severe cases,multi-organ failure.
文摘Background Interferon-induced transmembrane protein 1 （IFITM1） has been identified as a molecular marker of the colorectal tumors; however its influences on the biological behaviors of the colorectal cancer cells are currently unknown.We aimed to study the influences of IFITM1 on the proliferation,invasion,and metastasis of the colorectal cancer SW480 cell lines.Methods We constructed IFITM1/pEGFP-C3 recombinant plasmids and transfected them into the colorectal cancer SW480 cell lines.IFITM1/pEGFP-C3 recombinant plasmids were identified by means of immunofluorescence,laser confocal scanning microscopy,and reverse transcription polymerase chain reaction.IFITM1/SW480 cells with stable over-expression of IFITM1 were confirmed by G418 screening.The influences of IFITM1 on the proliferation of the SW480 cell lines were investigated by MTT assay and tumor transplantation experiments in nude mice.Cell invasion experiments were performed to determine the invasion capacity of the IFITM1/SW480 cells.Matrix metalloproteinase 2 （MMP-2） and MMP-9 activities were detected by the gelatin zymographic analysis,and MMP-9 expression by the Western blotting analysis.Results IFITM1/pEGFP-C3 recombinant plasmids were successfully constructed in this study,and the IFITM1/SW480 cells with stable IFITM1 gene over-expression were confirmed by G418 screening.MTT results showed that the proliferation of the IFITM1/SW480 cells was significantly enhanced （P 〈0.01）.Tumors were harvested from four weeks old mice.Tumor volumes were （1347.00±60.94） mm3,（1032.40±111.38） mm3 and （1018.78±28.83） mm3; and tumor weights were （1522.34±62.76） mg,（1137.78±97.22） mg and （1155.76±133.31） mg for mice inoculated with the IFITM1/SW480 cells,pEGFP-C3/SW480 cells and SW480 cells,respectively.Tumor volumes and weights from mice inoculated with the IFITM1/SW480 cells were significantly increased （P 〈0.01）.In addition,the numbers of the SW480 cells and IFITM1/SW480 cells that migrated through Matrigel were 448.64±38.09 and 540.45±44.61,respectively; so the invasive ability of the SW480 cells transfected with IFITM1 gene was significantly greater than that of the SW480 cells （P 〈0.01）.Gelatin zymographic analysis showed that MMP-9 and MMP-2 protein activities in the IFITM1/SW480 cells were significantly enhanced,and Western blotting analysis showed that MMP-9 expression in the IFITM1/SW480 cells was also increased.Conclusion IFITMl can enhance the proliferation,invasion,and metastasis of the colorectal cancer SW480 cell lineS.
基金supported by the National Natural Science Foundation of China(No. 81071422)
文摘Objective： Lysosome associated protein transmembrane 4 beta （LAPTM4B） was originally identified as a gene in human hepatocellular carcinoma （HCC）. It was successfully cloned by fluorescence differential display, rapid amplification of cDNA ends （RACE） and reverse transcription polymerase chain reaction （RT-PCR）. Previous study showed that the novel gene played an important role in the occurrence, development, migration and prognosis of tumors. Pancreatic cancer is an aggressive malignancy with the majority of patients dying within one year after diagnosis. This study tries to find out the relationship between lysosome associated protein transmembrane 4 beta gene polymorphism and the susceptibility of pancreatic cancer. Methods： A case-control study was conducted in China, including 58 pancreatic cancer cases and 156 healthy controls. Human genomic DNA was used as the template, polymerase chain reaction （PCR） was used to detect the distribution of LAPTM4B genotype. Analyses Odds ratio （OR） and corresponding 95% confidence interval （95%CI） with logistic regression were performed. Results： Two alleles of LAPTM4B generated three kinds of genotypes in population, ＊1/1, ＊1/2, and ＊2/2. The genotype frequency of ＊1/1, ＊1/2 and ＊2/2 in the pancreatic cancer group were 41.4%, 44.8% and 13.8% respectively, which were not significantly different from those of healthy group （47.4%, 42.9%, 9.6%） （P=0.773, P=0.291）. Also the ＊2 allele frequency of LAPTM4B among pancreatic cancer had no significantly difference with the controls （P=0.354）. When compared to the ＊1 allele, the people with ＊2 allele had no increased risk of pancreatic cancer. Conclusion： The gene polymorphism of LAPTM4B may not influence the susceptibility of pancreatic cancer.
基金Supported by the Yunnan Provincial Department of Science and Technology-Kunming Medical University Joint Special Project on Applied Basic Research,No.202401AY070001-132the Yunnan Provincial Science Foundation,No.2018FE001(-287)+1 种基金National Natural Science Foundation of China,No.81460443the Ten Thousand People Plan of Yunnan Province,No.KH-SWR-MY-2020-002.
文摘BACKGROUND Hepatocellular carcinoma(HCC)is a difficult cancer to manage due to its highly invasive and metastatic nature.AIM To investigate the molecular function of transmembrane channel-like 5(TMC5)in vitro and in vivo,with the objective of identifying novel diagnosis and treatment targets for HCC.METHODS The expression of TMC in cancer and normal tissues,along with its correlation with HCC prognosis,was analyzed using the GENT2,GEPIA database,and Human Protein Atlas.COX analysis was conducted to assess the relationship between TMC5 expression and overall survival in TCGA-LIHC patients.Further experiments were conducted to investigate the effect of TMC5 in cancer progression through loss-and gain-of-function assays in vitro and in vivo.RESULTS Bioinformatics revealed that TMC5 expression was generally higher in tumors than in normal tissues,and its expression was associated with poorer patient survival outcomes.TMC5 expression in HCC tissues and cells was consistent with the results of the bioinformatics analysis.Suppression of TMC5 expression reduced migration,invasion,and proliferation,while also decreasing the expression of epithelial-mesenchymal transition(EMT)-associated molecules in MHCC97-LM3 cells.Conversely,higher TMC5 expression significantly increased cell migration,invasion,proliferation,and EMT in MHCC97 L cells.TMC5 knockdown significantly decreased both the formation and spread of nodules in liver tissue,whereas TMC5 overexpression promoted them.CONCLUSION Our study provides compelling evidence that TMC5 is highly expressed in HCC and drives cancer progression through the activation of EMT-mediated invasion.TMC5 could represent a valuable molecular target for the diagnosis and treatment of HCC.
文摘A variety of glycosylphosphatidylinositol （GPI）-linked proteins are acquired on spermatozoa from epididymal luminal fluids （ELF） during sperm maturation. These proteins serve roles in immunoprotection and in key steps of fertilization such as capacitation, acrosomal exocytosis and sperm-egg interactions. Their acquisition on sperm cells is mediated both by membrane vesicles （epididymosomes, EP） which were first reported to dock on the sperm surface, and by lipid carriers which facilitate the transfer of proteins associated with the membrane-free fraction of ELF. While the nonvesicular fraction is more efficient, both pathways are dependent on hydrophobic interactions between the GPI-anchor and the external lipid layer of the sperm surface. More recently proteomic and hypothesis-driven studies have shown that EP from several mammals carry transmembrane （TM） proteins, including plasma membrane Ca^2＋-ATPase 4 （PMCA4）. Synthesized in the testis, PMCA4 is an essential protein and the major Ca^2＋ efflux pump in murine spermatozoa. Delivery of PMCA4 to spermatozoa from bovine and mouse EP during epididymal maturation and in vitro suggests that the docking of EP on the sperm surface precedes fusion, and experimental evidence supports a fusogenic mechanism for TM proteins. Fusion is facilitated by CD9, which generates fusion-competent sites on membranes. On the basis of knowledge of PMCA4＇s interacting partners a number of TM and membrane-associated proteins have been identified or are predicted to be present, in the epididymosomal cargo deliverable to spermatozoa. These Ca^2＋-dependent proteins, undetected in proteomic studies, play essential roles in sperm motility and fertility, and their detection highlights the usefulness of the hypothesis-driven approach.
基金supported by the National Natural Science Foundation of China (31702210, 31972719)the CAMS Innovation Fund for Medical Sciences (2020–12M-5-001)
文摘Interferon-inducible transmembrane protein 3(IFITM3)inhibits influenza virus infection by blocking viral membrane fusion,but the exact mechanism remains elusive.Here,we investigated the function and key region of IFITM3 in blocking influenza virus entry mediated by hemagglutinin(HA).The restriction of IFITM3 on HAmediated viral entry was confirmed by pseudovirus harboring HA protein from H5 and H7 influenza viruses.Subcellular co-localization and immunocoprecipitation analyses revealed that IFITM3 partially co-located with the full-length HA protein and could directly interact with HA_(2) subunit but not HA_(1) subunit of H5 and H7 virus.Truncated analyses showed that the transmembrane domain of the IFITM3 and HA_(2) subunit might play an important role in their interaction.Finally,this interaction of IFITM3 was also verified with HA_(2) subunits from other subtypes of influenza A virus and influenza B virus.Overall,our data demonstrate for the first time a direct interaction between IFITM3 and influenza HA protein via the transmembrane domain,providing a new perspective for further exploring the biological significance of IFITM3 restriction on influenza virus infection or HA-mediated antagonism or escape.
文摘Objective Although immune dysregulation is implicated in the pathogenesis of endometriosis(EMs),the specific role of prostate transmembrane protein androgen induced 1(PMEPA1)in modulating the function of regulatory T cells(Tregs)remains inadequately understood.This study aimed to elucidate the regulatory mechanisms by which PMEPA1 influences the activity of Tregs,thereby facilitating the invasion of endometrial stromal cells(ESCs).Methods Single-cell RNA sequencing(scRNA-seq)was performed on matched ectopic ovarian lesions and eutopic endometria from 3 patients.Clinical specimens from patients with EMs and control subjects were examined for PMEPA1 expression.Primary human Tregs isolated from peripheral blood mononuclear cells were subjected to PMEPA1 overexpression(via plasmid)or knockdown(via siRNA).Modulation of the PI3K pathway was conducted via the activator 740Y-P or the inhibitor LY294002.The secretion of IL-10 and TGF-βby Tregs was quantified using an enzyme-linked immunosorbent assay.Ectopic ESCs cocultured with modified Tregs were assessed for their proliferation,migration,and invasion capabilities.Results scRNA-seq data revealed significant upregulation of PMEPA1 in Tregs from ectopic ovarian lesions compared with paired eutopic endometria.PMEPA1 expression was increased in the ectopic lesions and peritoneal fluid mononuclear cells of patients with EMs.Tregs overexpressing PMEPA1 demonstrated reduced secretion of IL-10 and TGF-βbut exhibited hyperactivation of the PI3K/AKT signaling pathway.Treatment with LY294002 ameliorated the impairment in cytokine secretion.Coculture experiments with Tregs expressing high levels of PMEPA1 resulted in increased invasion,migration,and proliferation of ESCs.Conclusion PMEPA1 impairs Treg-mediated immunosuppression by hyperactivating the PI3K/AKT pathway,thereby facilitating the invasiveness of ESCs in EMs.
文摘Background:Lung cancer remains a major factor causing cancer-associated mortality globally.While there have been advancements in treatment options,advanced lung cancer patients still have poor outcomes.This study aims to investigate the potential role of Transmembrane protein 33(TMEM33)in the development of lung adenocarcinoma.Methods:We leveraged The Cancer Genome Atlas(TCGA)database to analyze the connection between TMEM33 expression to the prognosis of lung adenocarcinoma(LUAD).Cell proliferation,invasiveness,and sphere formation were analyzed by various experiments.The association of miR-214-3p with TMEM33 was explored using luciferase reporter assay,immunoblotting,and real-time quantitative PCR(RT-qPCR).Additionally,TMEM33’s biological role was confirmed in the mouse xenograft model through lung cancer transplantation and metastasis studies.Results:TMEM33 showed high expression within both LUAD tissues and cells,with its expression correlating with poor patient survival outcomes.Silencing TMEM33 resulted in significant reductions in cell proliferation,invasiveness,and stem-like properties.Further investigation suggested that miR-214-3p negatively regulated TMEM33.In both cellular and animal models,we further demonstrated that TMEM33 knockdown could effectively suppress the aggressiveness of lung cancer cells,impeding tumor growth and inhibiting metastasis in the mouse model.Moreover,reducing TMEM33 expression reduced key signaling molecules within the Wnt/β-catenin pathway,providing insights into TMEM33’s mechanistic role in LUAD.Conclusion:TMEM33 functions as an oncogene,which is under the negative regulation of miR-214-3p,to promote the LUAD malignant characteristics by engaging the Wnt/β-catenin cascade.
基金supported by the National Natural Science Foundation of China(82203474)the Natural Science Foundation of Sichuan,China(2023NSFSC0719)the 1·3·5 Project for Disciplines of Excellence,West China Hospital(ZYGD23017)。
文摘The structural and molecular organization of the cell surface plays a pivotal role in governing cell-extracellular environment interactions.While glycosylated transmembrane proteins have long been considered the primary components of plasma membranes,emerging evidence highlights the critical contributions of RNA-binding proteins(RBPs)and glycosylated RNAs(glycoRNAs)to cell surface functions.
基金supported by Guangxi Medical and Health Appropriate Technology Development and Promotion Application Project(S2022022).
文摘Background:Transmembrane emp24 trafficking protein 3(TMED3)is associated with the development of several tumors;however,whether TMED3 regulates the progression of prostate cancer remains unclear.Materials and Methods:Short hairpin RNA was performed to repress TMED3 in prostate cancer cells(DU145 cells)and in a prostate cancer mice model to determine its function in prostate cancer in vitro and in vivo.Results:In the present study,we found that TMED3 was highly expressed in prostate cancer cells.In vitro,shTMED3 treatment suppressed the proliferation,invasion,and migration and promoted the apoptosis of DU145 cells.Additionally,the Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed a strong correlation between TMED3 and forkhead box O transcription factor(FOXO)pathway.Furthermore,TMED3 inhibition efficiently decreased FOXO1a and FOXO3a phosphorylation.In vivo,TMED3 downregulation suppressed the apoptosis,growth,and metastasis of prostate cancer cells via FOXO1a and FOXO3a.Conclusion:The present findings show that TMED3 participates in the regulation of prostate cancer progression via FOXO1a and FOXO3a phosphorylation,thereby revealing a novel mechanism underlying prostate cancer development and suggesting that TMED3 inhibition may serve as a novel strategy for prostate cancer treatment.
基金This work was supported by the Natural Science Foundation of Hubei Province(No.2019CFB753)the Hubei Technological Innovation Special Fund(No.2019ACA132)the Hubei Natural Science Foundation(No.2020CFB805).
文摘Objective Paroxysmal kinesigenic dyskinesia(PKD)is a rare movement disorder PRRT2 gene mutations have been reported to cause PKD.However,the pathophysiological mechanism of PKD remains unclear,and it is unknown whether an inflammatory response is involved in the occurrence of this disease.We aimed to investigate the symptomatology,genotype,and serum cytokines of patients with PKD.Methods We recruited 21 patients with PKD,including 7 with familial PKD and 14 with sporadic PKD.Their clinical features were investigated,and blood samples were collected,and PRRT2 mutations and cytokine levels were detected.Results The mean age at PKD onset was 12.3±2.2 years old.Dystonia was the most common manifestation of dyskinesia,and the limbs were the most commonly affected parts.All attacks were induced by identifiable kinesigenic triggers,and the attack durations were brief(<1 min).Four different mutations from 9 probands were identified in 7 familial cases(71.4%)and 14 sporadic cases(28.6%).Two of these mutations(c.649dupC,c.620_621delAA)had already been reported,while other 2(c.1018_1019delAA,c.1012+1G>A)were previously undocumented.The tumor necrosis factor(TNF)-αlevel in the PKD group was significantly higher than that in the age-and sex-matched control group(P=0.025).There were no significant differences in the interleukin(IL)-1β,IL-2R,IL-6,IL-8,or IL-10 levels between the two groups.Conclusion In this study,we summarized the clinical and genetic characteristics of PKD.We found that the serum TNF-αlevels were elevated in patients clinically diagnosed with PKD,suggesting that an inflammatory response is involved in the pathogenesis of PKD.
