Cellular senescence is the results of aging and age-related diseases,and the development of anti-aging methods may improve health and extend longevity.The natural flavonol fisetin has been shown to antagonize senescen...Cellular senescence is the results of aging and age-related diseases,and the development of anti-aging methods may improve health and extend longevity.The natural flavonol fisetin has been shown to antagonize senescence in vitro and increases longevity in vivo,but has poor water solubility and limited bioavailability.In this study,a food-grade and senescent cell-targeted delivery system for fisetin was developed based on whey protein isolate-galactooligosaccharides(WPI-GOS)Maillard conjugate,which could recognize senescence associatedβ-galactosidase in senescent cells.The fisetin nanoparticles possessed a high encapsulation efficiency,excellent dispersibility in water,good storage stability and well biocompatibility.Moreover,they could effectively accumulate and retain in senescent cells with excellent senescent cell-targeting efficacy,and inhibit the oxidative stress-induced cellular senescence in vitro.Thus,this novel nanoparticle system based on WPI-GOS Maillard conjugate showed promise to deliver hydrophobic bioactive ingredients like fisetin to senescent cells to improve their bioavailability and anti-senescence effect.展开更多
RNA interference(RNAi)has become a gold standard for validating gene function in basic life science research and provides a promising therapeutic modality for cancer and other diseases.This minireview focuses on the p...RNA interference(RNAi)has become a gold standard for validating gene function in basic life science research and provides a promising therapeutic modality for cancer and other diseases.This minireview focuses on the potential of small interfering RNAs(siRNAs)in anticancer treatment,including the establishment and screening of cancer-associated siRNA libraries and their applications in anticancer drug target discovery and cancer therapy.This article also describes the current delivery approaches of siRNAs using lipids,polymers,and,in particular,gold nanoparticles to induce significant gene silencing and tumor growth regression.展开更多
Objective: Growing evidence indicates that FAT atypical cadherin 1(FAT1) has aberrant genetic alterations and exhibits potential tumor suppressive function in esophageal squamous cell carcinoma(ESCC). However, the rol...Objective: Growing evidence indicates that FAT atypical cadherin 1(FAT1) has aberrant genetic alterations and exhibits potential tumor suppressive function in esophageal squamous cell carcinoma(ESCC). However, the role of FAT1 in ESCC tumorigenesis remains not well elucidated. The aim of this study was to further investigate genetic alterations and biological functions of FAT1, as well as to explore its transcriptional regulation and downstream targets in ESCC.Methods: The mutations of FAT1 in ESCC were achieved by analyzing a combined study from seven published genomic data, while the copy number variants of FAT1 were obtained from an analysis of our previous data as well as of The Cancer Genome Atlas(TCGA) and Cancer Cell Line Encyclopedia(CCLE) databases using the cBioPortal. The transcriptional regulation of FAT1 expression was investigated by chromatin immunoprecipitation(ChIP) and the luciferase reporter assays. In-cell western, Western blot and reverse transcription-quantitative polymerase chain reaction(RT-qPCR) were used to assess the indicated gene expression. In addition, colony formation and Transwell migration/invasion assays were employed to test cell proliferation, migration and invasion.Finally, RNA sequencing was used to study the transcriptomes.Results: FAT1 was frequently mutated in ESCC and was deleted in multiple cancers. Furthermore, the transcription factor E2 F1 occupied the promoter region of FAT1, and depletion of E2 F1 led to a decrease in transcription activity and mRNA levels of FAT1. Moreover, we found that knockdown of FAT1 promoted KYSE30 and KYSE150 cell proliferation, migration and invasion;while overexpression of FAT1 inhibited KYSE30 and KYSE410 cell proliferation, migration and invasion. In addition, knockdown of FAT1 led to enrichment of the mitogen-activated protein kinase(MAPK) signaling pathway and cell adhesion process.Conclusions: Our data provided evidence for the tumor suppressive function of FAT1 in ESCC cells and elucidated the transcriptional regulation of FAT1 by E2 F1, which may facilitate the understanding of molecular mechanisms of the progression of ESCC.展开更多
Cells usually undergo a long journey of evolution during the progression from normal to precancerous cells and finally to full-fledged cancer cells. Multiple genomic aberrations are acquired during this journey that c...Cells usually undergo a long journey of evolution during the progression from normal to precancerous cells and finally to full-fledged cancer cells. Multiple genomic aberrations are acquired during this journey that could either act as drivers to confer significant growth advantages or act as passengers with little effect on the tumor growth. Recent advances in sequencing technology have made it feasible to decipher the evolutionary course of a cancer cell on a genome-wide level by evaluating the relative number of mutated alleles. Novel terms such as chromothripsis and chromoplexy have been introduced to describe the newly identified patterns of cancer genome evolution. These new insights have greatly expanded our understanding of the initiation and progression of cancers,which should aid in improving the efficiency of cancer management and treatment.展开更多
Cancer cell receives extracellular signal inputs to obtain a stem-like status,yet how tumor microenvironmental(TME)neural signals steer cancer stemness to establish the hierarchical tumor architectures remains elusive...Cancer cell receives extracellular signal inputs to obtain a stem-like status,yet how tumor microenvironmental(TME)neural signals steer cancer stemness to establish the hierarchical tumor architectures remains elusive.Here,a pan-cancer transcriptomic screening for 10852 samples of 33 TCGA cancer types reveals that cAMP-responsive element(CRE)transcription factors are convergent activators for cancer stemness.Deconvolution of transcriptomic profiles,specification of neural markers and illustration of norepinephrine dynamics uncover a bond between TME neural signals and cancer-cell CRE activity.Specifically,neural signal norepinephrine potentiates the stemness of proximal cancer cells by activating cAMP-CRE axis,where ATF1 serves as a conserved hub.Upon activation by norepinephrine,ATF1 potentiates cancer stemness by coordinated trans-activation of both nuclear pluripotency factors MYC/NANOG and mitochondrial biogenesis regulators NRF1/TFAM,thereby orchestrating nuclear reprograming and mitochondrial rejuvenating.Accordingly,single-cell transcriptomes confirm the coordinated activation of nuclear pluripotency with mitochondrial biogenesis in cancer stem-like cells.These findings elucidate that cancer cell acquires stemness via a norepinephrine-ATF1 driven nucleus-mitochondria collaborated program,suggesting a spatialized stemness acquisition by hijacking microenvironmental neural signals.展开更多
Poor differentiation is an important hallnnark of cancer cells,and differentiation therapy holds great promise for cancer treatment.The restoration of IkB kinase a(IKKa)leads to the differentiation of nasopharyngeal c...Poor differentiation is an important hallnnark of cancer cells,and differentiation therapy holds great promise for cancer treatment.The restoration of IkB kinase a(IKKa)leads to the differentiation of nasopharyngeal carcinoma cells with reduced tumorigenicity.The findings by Yan et al.validate the polycomb protein enhancer of zeste homologue2(EZH2)as a target for intervention.展开更多
Targeted therapies include small-molecule inhibitors and monoclonal antibodies, have made treatment more tumor-specific and less toxic, and have opened new possibilities for tailoring cancer treatment. Nevertheless, t...Targeted therapies include small-molecule inhibitors and monoclonal antibodies, have made treatment more tumor-specific and less toxic, and have opened new possibilities for tailoring cancer treatment. Nevertheless, there remain several challenges to targeted therapies, including molecular identification, drug resistance, and exploring reliable biomarkers. Here, we present several selected signaling pathways and molecular targets involved in human cancers including Aurora kinases, PI3K/mTOR signaling, FOXO-FOXM1 axis, and MDM2/MDM4-p53 interaction. Understanding the molecular mechanisms for tumorigenesis and development of drug resistance will provide new insights into drug discovery and design of therapeutic strategies for targeted therapies.展开更多
Background:Breast cancer stem cells(BCSCs)are considered responsible for cancer relapse and drug resistance.Understanding the identity of BCSCs may open new avenues in breast cancer therapy.Although several discoverie...Background:Breast cancer stem cells(BCSCs)are considered responsible for cancer relapse and drug resistance.Understanding the identity of BCSCs may open new avenues in breast cancer therapy.Although several discoveries have been made on BCSC characterization,the factors critical to the origination of BCSCs are largely unclear.This study aimed to determine whether genomic mutations contribute to the acquisition of cancer stem-like phenotype and to investigate the genetic and transcriptional features of BCSCs.Methods:We detected potential BCSC phenotype-associated mutation hotspot regions by using whole-genome sequencing on parental cancer cells and derived serial-generation spheres in increasing order of BCSC frequency,and then performed target deep DNA sequencing at bulk-cell and single-cell levels.To identify the transcriptional program associated with BCSCs,bulk-cell and single-cell RNA sequencing was performed.Results:By using whole-genome sequencing of bulk cells,potential BCSC phenotype-associated mutation hotspot regions were detected.Validation by target deep DNA sequencing,at both bulk-cell and single-cell levels,revealed no genetic changes specifically associated with BCSC phenotype.Moreover,single-cell RNA sequencing showed profound transcriptomic variability in cancer cells at the single-cell level that predicted BCSC features.Notably,this transcriptomic variability was enriched during the transcription of 74 genes,revealed as BCSC markers.Breast cancer patients with a high risk of relapse exhibited higher expression levels of these BCSC markers than those with a low risk of relapse,thereby highlighting the clinical significance of predicting breast cancer prognosis with these BCSC markers.Conclusions:Transcriptomic variability,not genetic mutations,distinguishes BCSCs from non-BCSCs.The identified 74 BCSC markers have the potential of becoming novel targets for breast cancer therapy.展开更多
Introduction Cancer heterogeneity has been characterized with distinct differentiation states,metabolic status,and microenvironmental features,accounting for diverse responses to therapy.Recent view has proposed 14 ha...Introduction Cancer heterogeneity has been characterized with distinct differentiation states,metabolic status,and microenvironmental features,accounting for diverse responses to therapy.Recent view has proposed 14 hallmarks of cancer in order to provide a logical framework for the comprehensive understanding of the characteristics and processes responsible for malignant transformation and progression[1,2].展开更多
The truncated chromosome 22 that results from the reciprocal translocation t(9;22)(q34;q11) is known as the Phila?delphia chromosome(Ph) and is a hallmark of chronic myeloid leukemia(CML).In leukemia cells,Ph not only...The truncated chromosome 22 that results from the reciprocal translocation t(9;22)(q34;q11) is known as the Phila?delphia chromosome(Ph) and is a hallmark of chronic myeloid leukemia(CML).In leukemia cells,Ph not only impairs the physiological signaling pathways but also disrupts genomic stability.This aberrant fusion gene encodes the breakpoint cluster region?proto?oncogene tyrosine?protein kinase(BCR?ABL1) oncogenic protein with persistently enhanced tyrosine kinase activity.The kinase activity is responsible for maintaining proliferation,inhibiting differentia?tion,and conferring resistance to cell death.During the progression of CML from the chronic phase to the accelerated phase and then to the blast phase,the expression patterns of different BCR?ABL1 transcripts vary.Each BCR?ABL1 transcript is present in a distinct leukemia phenotype,which predicts both response to therapy and clinical outcome.Besides CML,the Ph is found in acute lymphoblastic leukemia,acute myeloid leukemia,and mixed?phenotype acute leukemia.Here,we provide an overview of the clinical presentation and cellular biology of different phenotypes of Ph?positive leukemia and highlight key findings regarding leukemogenesis.展开更多
Background:Largely due to incidental detection,asymptomatic pancreatic cystic le-sions(PCLs)have become prevalent in recent years.Among them,intraductal papillary mucinous neoplasm(IPMN)infrequently advances to pancre...Background:Largely due to incidental detection,asymptomatic pancreatic cystic le-sions(PCLs)have become prevalent in recent years.Among them,intraductal papillary mucinous neoplasm(IPMN)infrequently advances to pancreatic ductal adenocarcinoma(PDAC).Conservative surveillance versus surgical intervention is a difficult clinical decision for both caregivers and PCL patients.Because RNF43 loss-of-function mutations and KRAS gain-of-function mutations concur in a subset of IPMN and PDAC,their biological significance and therapeutic potential should be elucidated.Methods:Pancreatic Rnf43 knockout and Kras activated mice(Rnf43^(−/−);Kras^(G12D))were generated to evaluate their clinical significance in pancreatic pre-neoplastic initiation and malignant transformation.Results:Loss of Rnf43 potentiated the occurrence and severity of IPMN and PDAC in oncogenic Kras mice.The Wnt/β-catenin signaling pathway was activated in pan-creatic Kras^(G12D)and Rnf43 knockout mice and the PORCN inhibitor LGK974 blocked pancreatic IPMN initiation and progression to PDAC accordingly.Conclusions:Rnf43 is a tumor suppressor in the prevention of pancreatic malignant transformation.This genetically reconstituted autochthonous pancreatic Rnf43^(−/−);Kras^(G12D)preclinical cancer model recapitulates the pathological process from pancreatic cyst to cancer in humans and can be treated with inhibitors of Wnt/β-catenin signaling.Since the presence of RNF43 and KRAS mutations in IPMNs predicts future development of advanced neoplasia from PCLs,patients with these genetic anomalies warrant surveillance,surgery,and/or targeted therapeutics such as Wnt/β-catenin inhibitors.展开更多
Patients with hepatocellular carcinoma(HCC)have poor long-term survival following curative resection because of the high rate of tumor early recurrence.Little is known about the trajectory of genomic evolution from pr...Patients with hepatocellular carcinoma(HCC)have poor long-term survival following curative resection because of the high rate of tumor early recurrence.Little is known about the trajectory of genomic evolution from primary to early-recurrent HCC.In this study,we performed whole-genome sequencing(WGS)on 40 pairs of primary and early-recurrent hepatitis B virus(HBV)-related HCC tumors from patients who received curative resection,and from four patients whose primary and recurrent tumor were extensively sampled.We identified two recurrence patterns:de novo recurrence(18/40),which developed genetically independently of the primary tumor and carried different HCC drivers,and ancestral recurrence(22/40),which was clonally related to the primary tumor and progressed more rapidly than de novo recurrence.We found that the recurrence location was predictive of the recurrence pattern:distant recurrence tended to display the de novo pattern,whereas local recurrence tended to display the ancestral pattern.We then uncovered the evolutionary trajectories based on the subclonal architecture,driver-gene mutations,and mutational processes observed in the primary and recurrent tumors.Multi-region WGS demonstrated spatiotemporal heterogeneity and polyclonal,monophyletic dissemination in HCC ancestral recurrence.In addition,we identified recurrence-specific mutations and copy-number gains in BCL9,leading to WNT/β-catenin signaling activation and an immuneexcluded tumor microenvironment,which suggests that BCL9 might serve as a new therapeutic target for recurrent HCC.Collectively,our results allow us to view with unprecedented clarity the genomic evolution during HBV-related HCC early recurrence,providing an important molecular foundation for enhanced understanding of HCC with implications for personalized therapy to improve patient survival.展开更多
The homeobox transcription factor Nanog has a vital role in maintaining pluripotency and self-renewal of embryonic stem cells(ESCs).Stabilization of Nanog proteins is essential for ESCs.The ubiquitin–proteasome pathw...The homeobox transcription factor Nanog has a vital role in maintaining pluripotency and self-renewal of embryonic stem cells(ESCs).Stabilization of Nanog proteins is essential for ESCs.The ubiquitin–proteasome pathway mediated by E3 ubiquitin ligases and deubiquitylases is one of the key ways to regulate protein levels and functions.Although ubiquitylation of Nanog catalyzed by the ligase FBXW8 has been demonstrated,the deubiquitylase that maintains the protein levels of Nanog in ESCs yet to be defined.In this study,we identify the ubiquitin-specific peptidase 21(USP21)as a deubiquitylase for Nanog,but not for Oct4 or Sox2.USP21 interacts with Nanog protein in ESCs in vivo and in vitro.The C-terminal USP domain of USP21 and the C-domain of Nanog are responsible for this interaction.USP21 deubiquitylates the K48-type linkage of the ubiquitin chain of Nanog,stabilizing Nanog.USP21-mediated Nanog stabilization is enhanced in mouse ESCs and this stabilization is required to maintain the pluripotential state of the ESCs.Depletion of USP21 in mouse ESCs leads to Nanog degradation and ESC differentiation.Overall,our results demonstrate that USP21 maintains the stemness of mouse ESCs through deubiquitylating and stabilizing Nanog.展开更多
Application of differentiation therapy targeting cellular plasticity for the treatment of solid malignancies has been lagging.Nasopharyngeal carci noma(NPC)is a distinctive cancer with poor differe ntiatio n and high ...Application of differentiation therapy targeting cellular plasticity for the treatment of solid malignancies has been lagging.Nasopharyngeal carci noma(NPC)is a distinctive cancer with poor differe ntiatio n and high prevalenee of Epstein-Barr virus(EBV)infection.Here,we show that the expressi on of EBV latent protein LMP1 in duces dediffere ntiated and stem-like status with high plasticity through the transcriptional inhibition of CEBPA.Mechanistically,LMP1 upregulates STAT5A and recruits HDAC 1/2 to the CEBPA locus to reduce its histone acetylation.HDAC inhibition restored CEBPA expression,reversing cellular dedifferentiation and stem-like status in mouse xeno graft models.These fin dings provide a novel mecha nistic epigenetic-based in sight into virus-induced cellular plasticity and propose a promising concept of differentiation therapy in solid tumor by using HDAC inhibitors to target cellular plasticity.展开更多
Cellular senescence provides a protective barrier against tumorigenesis in precancerous or normal tissues upon distinct stressors.However,the detailed mechanisms by which tumor cells evade premature senescence to mali...Cellular senescence provides a protective barrier against tumorigenesis in precancerous or normal tissues upon distinct stressors.However,the detailed mechanisms by which tumor cells evade premature senescence to malignant progression remain largely elusive.Here we reported that RBM4 adversely impacted cellular senescence to favor glutamine-dependent survival of esophageal squamous cell carcinoma(ESCC)cells by dictating the activity of LKB1,a critical governor of cancer metabolism.The level of RBM4 was specifically elevated in ESCC compared to normal tissues,and RBM4 overexpression promoted the malignant phenotype.RBM4 contributed to overcome H-RAS-or doxorubicin-induced senescence,while its depletion caused P27-dependent senescence and proliferation arrest by activating LKB1-AMPK-mTOR cascade.Mechanistically,RBM4 competitively bound LKB1 to disrupt the LKB1/STRAD/MO25 heterotrimeric complex,subsequently recruiting the E3 ligase TRIM26 to LKB1,promoting LKB1 ubiquitination and degradation in nucleus.Therefore,such molecular process leads to bypassing senescence and sustaining cell proliferation through the activation of glutamine metabolism.Clinically,the ESCC patients with high RBM4 and low LKB1 have significantly worse overall survival than those with low RBM4 and high LKB1.The RBM4 high/LKB1 low expression confers increased sensitivity of ESCC cells to glutaminase inhibitor CB-839,providing a novel insight into mechanisms underlying the glutamine-dependency to improve the efficacy of glutamine inhibitors in ESCC therapeutics.展开更多
Purpose:Breast cancer is now the most common malignant tumor worldwide.About one-fourth of female cancer patients all over the world sufer from breast cancer.And about one in six female cancer deaths worldwide is caus...Purpose:Breast cancer is now the most common malignant tumor worldwide.About one-fourth of female cancer patients all over the world sufer from breast cancer.And about one in six female cancer deaths worldwide is caused by breast cancer.In terms of absolute numbers of cases and deaths,China ranks frst in the world.The CACA Guidelines for Holistic Integrative Management of Breast Cancer were edited to help improve the diagnosis and comprehensive treatment in China.Methods:The Grading of Recommendations Assessment,Development and Evaluation(GRADE)was used to classify evidence and consensus.Results:The CACA Guidelines for Holistic Integrative Management of Breast Cancer include the epidemiology of breast cancer,breast cancer screening,breast cancer diagnosis,early breast cancer treatment,advanced breast cancer treatment,follow-up,rehabilitation,and traditional Chinese medicine treatment of breast cancer patients.Conclusion:We to standardize the diagnosis and treatment of breast cancer in China through the formulation of the CACA Guidelines.展开更多
Golgi membrane protein 1(GOLM1/GP73)is a serum marker of hepatocellular carcinoma(HCC).We have previously shown that mTOR promoted tumorigenesis of HCC through stimulating GOLM1 expression.In this study,we demonstrate...Golgi membrane protein 1(GOLM1/GP73)is a serum marker of hepatocellular carcinoma(HCC).We have previously shown that mTOR promoted tumorigenesis of HCC through stimulating GOLM1 expression.In this study,we demonstrated that the mammalian target of rapamycin(mTOR)was a negative regulator of microRNA-145(miR-145)expression.miR-145 inhibited GOLM1 expression by targeting a coding sequence of GOLM1 gene.GOLM1 and miR-145 were inversely correlated in human HCC tissues.GOLM1-enriched exosomes activated the glycogen synthase kinase-3β/matrix metalloproteinases(GSK-3β/MMPs)signaling axis of recipient cells and accelerated cell proliferation and migration.In contrast,miR-145 suppressed tumorigenesis and metastasis.We suggest that mTOR/miR-145/GOLM1 signaling pathway should be targeted for HCC treatment.展开更多
Alternative splicing is critical for human gene expression regulation,which plays a determined role in expanding the diversity of functional proteins.Importantly,alternative splicing is a hallmark of cancer and a pote...Alternative splicing is critical for human gene expression regulation,which plays a determined role in expanding the diversity of functional proteins.Importantly,alternative splicing is a hallmark of cancer and a potential target for cancer therapeutics.Based on the statistical data,breast cancer is one of the top leading causes of cancer-related deaths in women worldwide.Strikingly,alternative splicing is closely associated with breast cancer development.Here,we seek to provide a general review of the relationship between alternative splicing and breast cancer.We introduce the process of alternative splicing and its regulatory role in cancers.In addition,we highlight the functions of aberrant alternative splicing and mutations of splicing factors in breast cancer progression.Moreover,we discuss the role of alternative splicing in cancer drug resistance and the potential of being targets for cancer therapeutics.展开更多
Liposomes,as one of the most successful nanotherapeutics,have a major impact on many biomedical areas.In this study,we performed laser scanning confocal microscope(LSCM)and immunohistochemistry(IHC)assays to investiga...Liposomes,as one of the most successful nanotherapeutics,have a major impact on many biomedical areas.In this study,we performed laser scanning confocal microscope(LSCM)and immunohistochemistry(IHC)assays to investigate the intra-tumor transport and antitumor mechanism of GE11 peptideconjugated active targeting liposomes(GE11-TLs)in SMMC7721 xenograft model.According to classification of individual cell types in high resolution images,biodistribution of macrophages,tumor cells,cells with high epidermal growth factor receptor(EGFR)expres sion and interstitial matrix in tumor microenvironment,in addition,their impacts on intra-tumor penetration of GE11-TLs were estimated.Type I collagen fibers and macrophage flooded in the whole SMMC7721 tumor xenografts.Tumor angiogenesis was of great heterogeneity from the periphery to the center region.However,the receptor-binding site barriers were supposed to be the leading cause of poor penetration of GE11-TLs.We anticipate these images can give a deep reconsideration for rational design of target nanoparticles for overcoming biological barriers to drag delivery.展开更多
基金supported by Dalian Youth Science and Technology Star Project(2020RQ121)the National Science Fund for Distinguished Young Scholars of China(31925031)+1 种基金Doctoral Scientific Research Foundation of Liaoning Province(2020-BS-211)Liaoning Province Education Administration(J2020101)。
文摘Cellular senescence is the results of aging and age-related diseases,and the development of anti-aging methods may improve health and extend longevity.The natural flavonol fisetin has been shown to antagonize senescence in vitro and increases longevity in vivo,but has poor water solubility and limited bioavailability.In this study,a food-grade and senescent cell-targeted delivery system for fisetin was developed based on whey protein isolate-galactooligosaccharides(WPI-GOS)Maillard conjugate,which could recognize senescence associatedβ-galactosidase in senescent cells.The fisetin nanoparticles possessed a high encapsulation efficiency,excellent dispersibility in water,good storage stability and well biocompatibility.Moreover,they could effectively accumulate and retain in senescent cells with excellent senescent cell-targeting efficacy,and inhibit the oxidative stress-induced cellular senescence in vitro.Thus,this novel nanoparticle system based on WPI-GOS Maillard conjugate showed promise to deliver hydrophobic bioactive ingredients like fisetin to senescent cells to improve their bioavailability and anti-senescence effect.
文摘RNA interference(RNAi)has become a gold standard for validating gene function in basic life science research and provides a promising therapeutic modality for cancer and other diseases.This minireview focuses on the potential of small interfering RNAs(siRNAs)in anticancer treatment,including the establishment and screening of cancer-associated siRNA libraries and their applications in anticancer drug target discovery and cancer therapy.This article also describes the current delivery approaches of siRNAs using lipids,polymers,and,in particular,gold nanoparticles to induce significant gene silencing and tumor growth regression.
基金supported by the National Basic Research Program of China (973 Program) (No. 2015CB553906 and 2015CB553904)the National Natural Science Foundation of China (No. 81490753 and 81830086)the Education Department of Liaoning Province in China (Scientific Research Projects, No. L2016038)
文摘Objective: Growing evidence indicates that FAT atypical cadherin 1(FAT1) has aberrant genetic alterations and exhibits potential tumor suppressive function in esophageal squamous cell carcinoma(ESCC). However, the role of FAT1 in ESCC tumorigenesis remains not well elucidated. The aim of this study was to further investigate genetic alterations and biological functions of FAT1, as well as to explore its transcriptional regulation and downstream targets in ESCC.Methods: The mutations of FAT1 in ESCC were achieved by analyzing a combined study from seven published genomic data, while the copy number variants of FAT1 were obtained from an analysis of our previous data as well as of The Cancer Genome Atlas(TCGA) and Cancer Cell Line Encyclopedia(CCLE) databases using the cBioPortal. The transcriptional regulation of FAT1 expression was investigated by chromatin immunoprecipitation(ChIP) and the luciferase reporter assays. In-cell western, Western blot and reverse transcription-quantitative polymerase chain reaction(RT-qPCR) were used to assess the indicated gene expression. In addition, colony formation and Transwell migration/invasion assays were employed to test cell proliferation, migration and invasion.Finally, RNA sequencing was used to study the transcriptomes.Results: FAT1 was frequently mutated in ESCC and was deleted in multiple cancers. Furthermore, the transcription factor E2 F1 occupied the promoter region of FAT1, and depletion of E2 F1 led to a decrease in transcription activity and mRNA levels of FAT1. Moreover, we found that knockdown of FAT1 promoted KYSE30 and KYSE150 cell proliferation, migration and invasion;while overexpression of FAT1 inhibited KYSE30 and KYSE410 cell proliferation, migration and invasion. In addition, knockdown of FAT1 led to enrichment of the mitogen-activated protein kinase(MAPK) signaling pathway and cell adhesion process.Conclusions: Our data provided evidence for the tumor suppressive function of FAT1 in ESCC cells and elucidated the transcriptional regulation of FAT1 by E2 F1, which may facilitate the understanding of molecular mechanisms of the progression of ESCC.
文摘Cells usually undergo a long journey of evolution during the progression from normal to precancerous cells and finally to full-fledged cancer cells. Multiple genomic aberrations are acquired during this journey that could either act as drivers to confer significant growth advantages or act as passengers with little effect on the tumor growth. Recent advances in sequencing technology have made it feasible to decipher the evolutionary course of a cancer cell on a genome-wide level by evaluating the relative number of mutated alleles. Novel terms such as chromothripsis and chromoplexy have been introduced to describe the newly identified patterns of cancer genome evolution. These new insights have greatly expanded our understanding of the initiation and progression of cancers,which should aid in improving the efficiency of cancer management and treatment.
基金This research work was supported by the National Key R&D Program of China(2019YFA0110300 to Q.L.)the National Natural Science Foundation of China(No.82003096 to R.G.,No.82002943 to B.H.,No.81820108024 to Q.L.and No.81972594 to M.Y.)+1 种基金the Natural Science Foundation of Guangdong(2017A030313608 to Q.L.)the Science and Technology Planning Project of Guangzhou(201804020044 to Q.L.).
文摘Cancer cell receives extracellular signal inputs to obtain a stem-like status,yet how tumor microenvironmental(TME)neural signals steer cancer stemness to establish the hierarchical tumor architectures remains elusive.Here,a pan-cancer transcriptomic screening for 10852 samples of 33 TCGA cancer types reveals that cAMP-responsive element(CRE)transcription factors are convergent activators for cancer stemness.Deconvolution of transcriptomic profiles,specification of neural markers and illustration of norepinephrine dynamics uncover a bond between TME neural signals and cancer-cell CRE activity.Specifically,neural signal norepinephrine potentiates the stemness of proximal cancer cells by activating cAMP-CRE axis,where ATF1 serves as a conserved hub.Upon activation by norepinephrine,ATF1 potentiates cancer stemness by coordinated trans-activation of both nuclear pluripotency factors MYC/NANOG and mitochondrial biogenesis regulators NRF1/TFAM,thereby orchestrating nuclear reprograming and mitochondrial rejuvenating.Accordingly,single-cell transcriptomes confirm the coordinated activation of nuclear pluripotency with mitochondrial biogenesis in cancer stem-like cells.These findings elucidate that cancer cell acquires stemness via a norepinephrine-ATF1 driven nucleus-mitochondria collaborated program,suggesting a spatialized stemness acquisition by hijacking microenvironmental neural signals.
基金the National Basic Research Program of China(973 Program,No.2012CB967000 and 2011CB504300 to QL)Program for Chang Jiang Scholars and Innovative Research Team in University(IRTI 3049 to QL)+1 种基金National Natural Science Foundation of China(No.30888003 to QL and No.81201547 to MY)Guangdong Medical Science Fund(A2011198 to MY)
文摘Poor differentiation is an important hallnnark of cancer cells,and differentiation therapy holds great promise for cancer treatment.The restoration of IkB kinase a(IKKa)leads to the differentiation of nasopharyngeal carcinoma cells with reduced tumorigenicity.The findings by Yan et al.validate the polycomb protein enhancer of zeste homologue2(EZH2)as a target for intervention.
文摘Targeted therapies include small-molecule inhibitors and monoclonal antibodies, have made treatment more tumor-specific and less toxic, and have opened new possibilities for tailoring cancer treatment. Nevertheless, there remain several challenges to targeted therapies, including molecular identification, drug resistance, and exploring reliable biomarkers. Here, we present several selected signaling pathways and molecular targets involved in human cancers including Aurora kinases, PI3K/mTOR signaling, FOXO-FOXM1 axis, and MDM2/MDM4-p53 interaction. Understanding the molecular mechanisms for tumorigenesis and development of drug resistance will provide new insights into drug discovery and design of therapeutic strategies for targeted therapies.
基金supported by Program for Changjiang Scholars and Innovative Research Team in University of Ministry of Education of China(No.IRT_17R15)National Natural Science Foundation of China(Nos.81630005 to QL,81573025 to QL,81472637 to ZL,81672784 to ZL,and 81602200 to DL)+2 种基金Innovative Research Team in University of Liaoning(No.LT2017001 to QL)The program for climbing Scholars of Liaoning,Dalian High-level Talent Innovation Program(2016RD12 to QL)International Scientific and Technological Cooperation of Dalian(2015F11GH095 to QL).
文摘Background:Breast cancer stem cells(BCSCs)are considered responsible for cancer relapse and drug resistance.Understanding the identity of BCSCs may open new avenues in breast cancer therapy.Although several discoveries have been made on BCSC characterization,the factors critical to the origination of BCSCs are largely unclear.This study aimed to determine whether genomic mutations contribute to the acquisition of cancer stem-like phenotype and to investigate the genetic and transcriptional features of BCSCs.Methods:We detected potential BCSC phenotype-associated mutation hotspot regions by using whole-genome sequencing on parental cancer cells and derived serial-generation spheres in increasing order of BCSC frequency,and then performed target deep DNA sequencing at bulk-cell and single-cell levels.To identify the transcriptional program associated with BCSCs,bulk-cell and single-cell RNA sequencing was performed.Results:By using whole-genome sequencing of bulk cells,potential BCSC phenotype-associated mutation hotspot regions were detected.Validation by target deep DNA sequencing,at both bulk-cell and single-cell levels,revealed no genetic changes specifically associated with BCSC phenotype.Moreover,single-cell RNA sequencing showed profound transcriptomic variability in cancer cells at the single-cell level that predicted BCSC features.Notably,this transcriptomic variability was enriched during the transcription of 74 genes,revealed as BCSC markers.Breast cancer patients with a high risk of relapse exhibited higher expression levels of these BCSC markers than those with a low risk of relapse,thereby highlighting the clinical significance of predicting breast cancer prognosis with these BCSC markers.Conclusions:Transcriptomic variability,not genetic mutations,distinguishes BCSCs from non-BCSCs.The identified 74 BCSC markers have the potential of becoming novel targets for breast cancer therapy.
基金supported by the National Key Research and Development Program of China(No.2019YFA0110303 to Quentin Liu)the National Natural Science Foundation of China(No.81972594 to Min Yan)+1 种基金the Innovative Research Team in University of Ministry of Education of China(No.IRT-17R15 to Quentin Liu)the Natural Science Foundation of Guangdong(No.2020A1515010608 to Min Yan).
文摘Introduction Cancer heterogeneity has been characterized with distinct differentiation states,metabolic status,and microenvironmental features,accounting for diverse responses to therapy.Recent view has proposed 14 hallmarks of cancer in order to provide a logical framework for the comprehensive understanding of the characteristics and processes responsible for malignant transformation and progression[1,2].
基金supported by the China Central Budget Recruitment Program of High?Level Overseas Talent (GDW 201221022066 to Q.Liu)the National Basic Research Program of China (973 Program:No.2012CB967000 to Q.Liu)+2 种基金the National Natural Science Foundation of China (NNSF No.81130040 to Q.Liu and No.81201686 to J.Xu)the Program for Changjiang Scholars and Innovative Research Team in Universities (ITR 13049 to Q.Liu)the Liaoning (NSF 2014029102 to Q.Liu)
文摘The truncated chromosome 22 that results from the reciprocal translocation t(9;22)(q34;q11) is known as the Phila?delphia chromosome(Ph) and is a hallmark of chronic myeloid leukemia(CML).In leukemia cells,Ph not only impairs the physiological signaling pathways but also disrupts genomic stability.This aberrant fusion gene encodes the breakpoint cluster region?proto?oncogene tyrosine?protein kinase(BCR?ABL1) oncogenic protein with persistently enhanced tyrosine kinase activity.The kinase activity is responsible for maintaining proliferation,inhibiting differentia?tion,and conferring resistance to cell death.During the progression of CML from the chronic phase to the accelerated phase and then to the blast phase,the expression patterns of different BCR?ABL1 transcripts vary.Each BCR?ABL1 transcript is present in a distinct leukemia phenotype,which predicts both response to therapy and clinical outcome.Besides CML,the Ph is found in acute lymphoblastic leukemia,acute myeloid leukemia,and mixed?phenotype acute leukemia.Here,we provide an overview of the clinical presentation and cellular biology of different phenotypes of Ph?positive leukemia and highlight key findings regarding leukemogenesis.
基金The National Natural Science Foundation of China(81872287,81730078)the Chinese Academy of Medical Sciences Initiative for Innovative Medicine(2021-1-I2M-018).
文摘Background:Largely due to incidental detection,asymptomatic pancreatic cystic le-sions(PCLs)have become prevalent in recent years.Among them,intraductal papillary mucinous neoplasm(IPMN)infrequently advances to pancreatic ductal adenocarcinoma(PDAC).Conservative surveillance versus surgical intervention is a difficult clinical decision for both caregivers and PCL patients.Because RNF43 loss-of-function mutations and KRAS gain-of-function mutations concur in a subset of IPMN and PDAC,their biological significance and therapeutic potential should be elucidated.Methods:Pancreatic Rnf43 knockout and Kras activated mice(Rnf43^(−/−);Kras^(G12D))were generated to evaluate their clinical significance in pancreatic pre-neoplastic initiation and malignant transformation.Results:Loss of Rnf43 potentiated the occurrence and severity of IPMN and PDAC in oncogenic Kras mice.The Wnt/β-catenin signaling pathway was activated in pan-creatic Kras^(G12D)and Rnf43 knockout mice and the PORCN inhibitor LGK974 blocked pancreatic IPMN initiation and progression to PDAC accordingly.Conclusions:Rnf43 is a tumor suppressor in the prevention of pancreatic malignant transformation.This genetically reconstituted autochthonous pancreatic Rnf43^(−/−);Kras^(G12D)preclinical cancer model recapitulates the pathological process from pancreatic cyst to cancer in humans and can be treated with inhibitors of Wnt/β-catenin signaling.Since the presence of RNF43 and KRAS mutations in IPMNs predicts future development of advanced neoplasia from PCLs,patients with these genetic anomalies warrant surveillance,surgery,and/or targeted therapeutics such as Wnt/β-catenin inhibitors.
基金This study was jointly supported by the National Key R&D Program of China(No.2019YFC1315800,2019YFC1315802,2018YFA0109400)the National Natural Science Foundation of China(No.81830102,No.81772578,No.82173260+4 种基金No.81972708,No.82073123,No.81773069,No.82072681,No.82003082)Shanghai Technical Standard Program(21DZ2201100)Shanghai Rising-Star Program(18QA1401200)Municipal Human Resources Development Program for Outstanding Young Talents in Medical and Health Sciences in Shanghai(2018YQ14)Original Scientific Personalized Support Project of Fudan University(IDF152064/015).
文摘Patients with hepatocellular carcinoma(HCC)have poor long-term survival following curative resection because of the high rate of tumor early recurrence.Little is known about the trajectory of genomic evolution from primary to early-recurrent HCC.In this study,we performed whole-genome sequencing(WGS)on 40 pairs of primary and early-recurrent hepatitis B virus(HBV)-related HCC tumors from patients who received curative resection,and from four patients whose primary and recurrent tumor were extensively sampled.We identified two recurrence patterns:de novo recurrence(18/40),which developed genetically independently of the primary tumor and carried different HCC drivers,and ancestral recurrence(22/40),which was clonally related to the primary tumor and progressed more rapidly than de novo recurrence.We found that the recurrence location was predictive of the recurrence pattern:distant recurrence tended to display the de novo pattern,whereas local recurrence tended to display the ancestral pattern.We then uncovered the evolutionary trajectories based on the subclonal architecture,driver-gene mutations,and mutational processes observed in the primary and recurrent tumors.Multi-region WGS demonstrated spatiotemporal heterogeneity and polyclonal,monophyletic dissemination in HCC ancestral recurrence.In addition,we identified recurrence-specific mutations and copy-number gains in BCL9,leading to WNT/β-catenin signaling activation and an immuneexcluded tumor microenvironment,which suggests that BCL9 might serve as a new therapeutic target for recurrent HCC.Collectively,our results allow us to view with unprecedented clarity the genomic evolution during HBV-related HCC early recurrence,providing an important molecular foundation for enhanced understanding of HCC with implications for personalized therapy to improve patient survival.
基金This work was supported by Chinese National Basic Research Programs(2013CB910803)the Program of International S&T Cooperation(2014DFB30020)+1 种基金Chinese National Natural Science Foundation Projects(81521064)the NIH funding GM094777.
文摘The homeobox transcription factor Nanog has a vital role in maintaining pluripotency and self-renewal of embryonic stem cells(ESCs).Stabilization of Nanog proteins is essential for ESCs.The ubiquitin–proteasome pathway mediated by E3 ubiquitin ligases and deubiquitylases is one of the key ways to regulate protein levels and functions.Although ubiquitylation of Nanog catalyzed by the ligase FBXW8 has been demonstrated,the deubiquitylase that maintains the protein levels of Nanog in ESCs yet to be defined.In this study,we identify the ubiquitin-specific peptidase 21(USP21)as a deubiquitylase for Nanog,but not for Oct4 or Sox2.USP21 interacts with Nanog protein in ESCs in vivo and in vitro.The C-terminal USP domain of USP21 and the C-domain of Nanog are responsible for this interaction.USP21 deubiquitylates the K48-type linkage of the ubiquitin chain of Nanog,stabilizing Nanog.USP21-mediated Nanog stabilization is enhanced in mouse ESCs and this stabilization is required to maintain the pluripotential state of the ESCs.Depletion of USP21 in mouse ESCs leads to Nanog degradation and ESC differentiation.Overall,our results demonstrate that USP21 maintains the stemness of mouse ESCs through deubiquitylating and stabilizing Nanog.
基金supported by National Key R&D Program of China(2019YFA0110300,2017YFA0505600-04 to Q.L.)Innovative Research Team in University of Ministry of Education of China(IRT_17R15 to Q.L.)+7 种基金National Natural Science Foundation of China(81630005,81573025 to Q.L.,81773166 to Z.W.,81702683 to J.X.,81972594 to M.Y.,81402445 to C.W.,81502579 to Z.H.)Natural Science Foundation of Guangdong(2017A030313608 to Q.L,2018A0303130299,2020A1515010608 to M.Y.)the Science and Technology Planning Project of Guangzhou(201804020044 to Q.L.)the Key Project of Liaoning Natural Science Funding of China(201702031 to Q.L.)Fundamental Research Funds for the Central Universities(I9ykpy187 to M.Y.).EW-FL's work is supported by MRC(MR/N012097/1)CRUK(Al 2011)Breast Cancer Now(2012MayPR070,2012NovPhD016)the Cancer Research UK Imperial Centre,Imperial ECMC,and NIHR Imperial BRC.
文摘Application of differentiation therapy targeting cellular plasticity for the treatment of solid malignancies has been lagging.Nasopharyngeal carci noma(NPC)is a distinctive cancer with poor differe ntiatio n and high prevalenee of Epstein-Barr virus(EBV)infection.Here,we show that the expressi on of EBV latent protein LMP1 in duces dediffere ntiated and stem-like status with high plasticity through the transcriptional inhibition of CEBPA.Mechanistically,LMP1 upregulates STAT5A and recruits HDAC 1/2 to the CEBPA locus to reduce its histone acetylation.HDAC inhibition restored CEBPA expression,reversing cellular dedifferentiation and stem-like status in mouse xeno graft models.These fin dings provide a novel mecha nistic epigenetic-based in sight into virus-induced cellular plasticity and propose a promising concept of differentiation therapy in solid tumor by using HDAC inhibitors to target cellular plasticity.
基金supported by the National Natural Science Foundation of China (82225034,81830088 to Y.W.,82103148 to Y.Q.81872247 to W.Z.)+4 种基金the Department of Science and Technology of Liaoning Province (2021JH6/10500160 to Y.W.)the Basic Scientific Research Project of Education Department of Liaoning Province (LJKQZ2021104 to Y.Q.)the Science and Technology Innovation Talent Support Program of Dalian (2022RQ056 Y.Q.)the Science and Technology Innovation Foundation of Dalian (2022JJ11CG009 to Y.W.)Dalian High Level Talents Renovation Supporting Program (2019RQ097 to W.Z.).
文摘Cellular senescence provides a protective barrier against tumorigenesis in precancerous or normal tissues upon distinct stressors.However,the detailed mechanisms by which tumor cells evade premature senescence to malignant progression remain largely elusive.Here we reported that RBM4 adversely impacted cellular senescence to favor glutamine-dependent survival of esophageal squamous cell carcinoma(ESCC)cells by dictating the activity of LKB1,a critical governor of cancer metabolism.The level of RBM4 was specifically elevated in ESCC compared to normal tissues,and RBM4 overexpression promoted the malignant phenotype.RBM4 contributed to overcome H-RAS-or doxorubicin-induced senescence,while its depletion caused P27-dependent senescence and proliferation arrest by activating LKB1-AMPK-mTOR cascade.Mechanistically,RBM4 competitively bound LKB1 to disrupt the LKB1/STRAD/MO25 heterotrimeric complex,subsequently recruiting the E3 ligase TRIM26 to LKB1,promoting LKB1 ubiquitination and degradation in nucleus.Therefore,such molecular process leads to bypassing senescence and sustaining cell proliferation through the activation of glutamine metabolism.Clinically,the ESCC patients with high RBM4 and low LKB1 have significantly worse overall survival than those with low RBM4 and high LKB1.The RBM4 high/LKB1 low expression confers increased sensitivity of ESCC cells to glutaminase inhibitor CB-839,providing a novel insight into mechanisms underlying the glutamine-dependency to improve the efficacy of glutamine inhibitors in ESCC therapeutics.
基金Department of Breast Surgery,Harbin Medical University Cancer Hospital,Harbin,China。
文摘Purpose:Breast cancer is now the most common malignant tumor worldwide.About one-fourth of female cancer patients all over the world sufer from breast cancer.And about one in six female cancer deaths worldwide is caused by breast cancer.In terms of absolute numbers of cases and deaths,China ranks frst in the world.The CACA Guidelines for Holistic Integrative Management of Breast Cancer were edited to help improve the diagnosis and comprehensive treatment in China.Methods:The Grading of Recommendations Assessment,Development and Evaluation(GRADE)was used to classify evidence and consensus.Results:The CACA Guidelines for Holistic Integrative Management of Breast Cancer include the epidemiology of breast cancer,breast cancer screening,breast cancer diagnosis,early breast cancer treatment,advanced breast cancer treatment,follow-up,rehabilitation,and traditional Chinese medicine treatment of breast cancer patients.Conclusion:We to standardize the diagnosis and treatment of breast cancer in China through the formulation of the CACA Guidelines.
基金supported by National Basic Research Program of China 973 Program (2015CB553802)the National Natural Science Foundation of China (81730078)Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (CIFMS2016-I2M-1-001)
文摘Golgi membrane protein 1(GOLM1/GP73)is a serum marker of hepatocellular carcinoma(HCC).We have previously shown that mTOR promoted tumorigenesis of HCC through stimulating GOLM1 expression.In this study,we demonstrated that the mammalian target of rapamycin(mTOR)was a negative regulator of microRNA-145(miR-145)expression.miR-145 inhibited GOLM1 expression by targeting a coding sequence of GOLM1 gene.GOLM1 and miR-145 were inversely correlated in human HCC tissues.GOLM1-enriched exosomes activated the glycogen synthase kinase-3β/matrix metalloproteinases(GSK-3β/MMPs)signaling axis of recipient cells and accelerated cell proliferation and migration.In contrast,miR-145 suppressed tumorigenesis and metastasis.We suggest that mTOR/miR-145/GOLM1 signaling pathway should be targeted for HCC treatment.
基金This work was supported by the National Natural Science Foundation of China(81830088,81422038,91540110,and31471235 to Y.W.,81872247 and 31400726 to W.Z.)the Department of Science and Tech no logy of Dalian City(‘Dalia n Supports High Level Talents Innovation and Entrepreneurship Program’2016RJ02 to Y.W.).
文摘Alternative splicing is critical for human gene expression regulation,which plays a determined role in expanding the diversity of functional proteins.Importantly,alternative splicing is a hallmark of cancer and a potential target for cancer therapeutics.Based on the statistical data,breast cancer is one of the top leading causes of cancer-related deaths in women worldwide.Strikingly,alternative splicing is closely associated with breast cancer development.Here,we seek to provide a general review of the relationship between alternative splicing and breast cancer.We introduce the process of alternative splicing and its regulatory role in cancers.In addition,we highlight the functions of aberrant alternative splicing and mutations of splicing factors in breast cancer progression.Moreover,we discuss the role of alternative splicing in cancer drug resistance and the potential of being targets for cancer therapeutics.
基金supported by National Science Foundation of China(Grant Nos.30825045 and 81273465).
文摘Liposomes,as one of the most successful nanotherapeutics,have a major impact on many biomedical areas.In this study,we performed laser scanning confocal microscope(LSCM)and immunohistochemistry(IHC)assays to investigate the intra-tumor transport and antitumor mechanism of GE11 peptideconjugated active targeting liposomes(GE11-TLs)in SMMC7721 xenograft model.According to classification of individual cell types in high resolution images,biodistribution of macrophages,tumor cells,cells with high epidermal growth factor receptor(EGFR)expres sion and interstitial matrix in tumor microenvironment,in addition,their impacts on intra-tumor penetration of GE11-TLs were estimated.Type I collagen fibers and macrophage flooded in the whole SMMC7721 tumor xenografts.Tumor angiogenesis was of great heterogeneity from the periphery to the center region.However,the receptor-binding site barriers were supposed to be the leading cause of poor penetration of GE11-TLs.We anticipate these images can give a deep reconsideration for rational design of target nanoparticles for overcoming biological barriers to drag delivery.