Background:Osteoporosis is a chronic bone disease characterized by bone loss and decreased bone strength.However,current anti-resorptive drugs carry a risk of various complications.The deep learning-based efficacy pre...Background:Osteoporosis is a chronic bone disease characterized by bone loss and decreased bone strength.However,current anti-resorptive drugs carry a risk of various complications.The deep learning-based efficacy prediction system(DLEPS)is a forecasting tool that can effectively compete in drug screening and prediction based on gene expression changes.This study aimed to explore the protective effect and potential mechanisms of cinobufotalin(CB),a traditional Chinese medicine(TCM),on bone loss.Methods:DLEPS was employed for screening anti-osteoporotic agents according to gene profile changes in primary osteoporosis.Micro-CT,histological and morphological analysis were applied for the bone protective detection of CB,and the osteogenic differentiation/function in human bone marrow mesenchymal stem cells(hBMMSCs)were also investigated.The underlying mechanism was verified using qRT-PCR,Western blot(WB),immunofluorescence(IF),etc.Results:A safe concentration(0.25mg/kg in vivo,0.05μM in vitro)of CB could effectively preserve bone mass in estrogen deficiency-induced bone loss and promote osteogenic differentiation/function of hBMMSCs.Both BMPs/SMAD and Wnt/β-catenin signaling pathways participated in CB-induced osteogenic differentiation,further regulating the expression of osteogenesis-associated factors,and ultimately promoting osteogenesis.Conclusion:Our study demonstrated that CB could significantly reverse estrogen deficiency-induced bone loss,further promoting osteogenic differentiation/function of hBMMSCs,with BMPs/SMAD and Wnt/β-catenin signaling pathways involved.展开更多
Myeloid checkpoints are receptors on the myeloid cell surface which can mediate inhibitory signals to modulate anti-tumor immune activities.They can either inhibit cellular phagocytosis or suppress T cells and are thu...Myeloid checkpoints are receptors on the myeloid cell surface which can mediate inhibitory signals to modulate anti-tumor immune activities.They can either inhibit cellular phagocytosis or suppress T cells and are thus involved in the pathogenesis of various diseases.In the tumor microenvironment,besides killing tumor cells by phagocytosis or activating anti-tumor immunity by tumor antigen presentation,myeloid cells could execute protumor efficacies through myeloid checkpoints by interacting with counter-receptors on other immune cells or cancer cells.In summary,myeloid checkpoints may be promising therapeutic targets for cancer immunotherapy.展开更多
Adult tendon stem/progenitor cells(TSPCs)are essential for tendon maintenance,regeneration,and repair,yet they become susceptible to senescence with age,impairing the self-healing capacity of tendons.In this study,we ...Adult tendon stem/progenitor cells(TSPCs)are essential for tendon maintenance,regeneration,and repair,yet they become susceptible to senescence with age,impairing the self-healing capacity of tendons.In this study,we employ a recently developed deep-learning-based efficacy prediction system to screen potential stemness-promoting and senescence-inhibiting drugs from natural products using the transcriptional signatures of stemness.The top-ranked candidate,prim-O-glucosylcimifugin(POG),a saposhnikovia root extract,could ameliorate TPSC senescent phenotypes caused by long-term passage and natural aging in rats and humans,as well as restore the self-renewal and proliferative capacities and tenogenic potential of aged TSPCs.In vivo,the systematic administration of POG or the local delivery of POG nanoparticles functionally rescued endogenous tendon regeneration and repair in aged rats to levels similar to those of normal animals.Mechanistically,POG protects TSPCs against functional impairment during both passage-induced and natural aging by simultaneously suppressing nuclear factor-κB and decreasing mTOR signaling with the induction of autophagy.Thus,the strategy of pharmacological intervention with the deep learning-predicted compound POG could rejuvenate aged TSPCs and improve the regenerative capacity of aged tendons.展开更多
Abnormal metabolism is regarded as an oncogenic hallmark related to tumor progression and therapeutic resistance.Present study employed multi-omics,including phosphoproteomics,untargeted metabolomics and lipidomics,to...Abnormal metabolism is regarded as an oncogenic hallmark related to tumor progression and therapeutic resistance.Present study employed multi-omics,including phosphoproteomics,untargeted metabolomics and lipidomics,to demonstrate that the pAKT2 Ser128 and pCCTαSer315/319/323-positive cancer-associated fibroblasts(CAFs)substantially release phosphatidylcholines(PCs),contributing to the resistance of focal adhesion kinase(FAK)inhibitors in esophageal squamous cell carcinoma(ESCC)treatment.Additionally,we observed extremely low levels of FAK Tyr397 expression in CAFs,potentially offering no available target for FAK inhibitors playing their anti-growth role in CAFs.Consequently,FAK inhibitor increased the intracellular concentration of Ca2+in CAFs,promoting the formation of AKT2/CCTαcomplex,leading to phosphorylation of CCTαSer315/319/323 sites and eventually enhancing stromal PC production.This activation could stimulate the intratumoral Janus kinase 2(JAK2)/Signal transducer and activator of transcription 3(STAT3)pathway,triggering resistance to FAK inhibition.Analysis of clinical samples demonstrated that stromal pAKT2 Ser128 and pCCTαSer315/319/323 are related to the tumor malignancy and reduced patient survival.Pseudo-targeted lipidomics and further validation cohort quantitatively showed that plasma PCs enable to distinguish the malignant extent of ESCC patients.In conclusion,inhibition of stroma-derived PCs and related pathway could be possible therapeutic strategies for tumor therapy.展开更多
Throughout our life journey,two unstoppable forces shape our existence:the specter of aging and cancer.Seemingly unrelated,these phenomena are more intertwined than we might think[1].The incidence and mortality rates ...Throughout our life journey,two unstoppable forces shape our existence:the specter of aging and cancer.Seemingly unrelated,these phenomena are more intertwined than we might think[1].The incidence and mortality rates of cancer increase exponentially with age,and their underlying causes are both related to cellular dysfunction.Studying these commonalities is not only key to unlocking cancer therapies,but it may also inspire us to find interventions that delay the aging process itself.展开更多
FRMD6,a member of the 4.1 ezrin-radixin-moesin domain-containing protein family,has been reported to inhibit tumor progression in multiple cancers.Here,we demonstrate the involvement of FRMD6 in lung cancer progressio...FRMD6,a member of the 4.1 ezrin-radixin-moesin domain-containing protein family,has been reported to inhibit tumor progression in multiple cancers.Here,we demonstrate the involvement of FRMD6 in lung cancer progression.We find that FRMD6 is overexpressed in lung cancer tissues relative to in normal lung tissues.In addition,the enhanced expression of FRMD6 is associated with poor outcomes in patients with lung squamous cell carcinoma(n=75,P=0.0054)and lung adenocarcinoma(n=94,P=0.0330).Cell migration and proliferation in vitro and tumor formation in vivo are promoted by FRMD6 but are suppressed by the depletion of FRMD6.Mechanistically,FRMD6 interacts and colocalizes with mTOR and S6K,which are the key molecules of the mTOR signaling pathway.FRMD6 markedly enhances the interaction between mTOR and S6K,subsequently increasing the levels of endogenous pS6K and downstream pS6 in lung cancer cells.Furthermore,knocking out FRMD6 inhibits the activation of the mTOR signaling pathway in Frmd6^(−/−)gene KO MEFs and mice.Altogether,our results show that FRMD6 contributes to lung cancer progression by activating the mTOR signaling pathway.展开更多
Cancer immunology has witnessed remarkable development over the past century.In the early 20^(th) century,William Coley embarked on pioneering efforts to activate the immune system against cancer using heat-killed Str...Cancer immunology has witnessed remarkable development over the past century.In the early 20^(th) century,William Coley embarked on pioneering efforts to activate the immune system against cancer using heat-killed Streptococcus pyogenes and Serratia marcescens^([1]).These attempts yielded varying clinical outcomes,some of which were notably successful,providing early evidence of the immune system’s potential in combating cancer.Moving into the mid-20th century,Dr.Lewis Thomas and Dr.Macfarlane Burnet introduced the concept“immune surveillance”^([2]).This theory proposed that the immune systemconstantlymonitors the body,identifying and eliminating emerging cancer cells to prevent them from developing into full-fledged tumors.This concept laid the foundation for future research in cancer immunology.Simultaneously,the concept of immune evasion emerged,emphasizing how cancer cells can elude immune detection and destruction,enabling them to proliferate and spread within the body.Thus,understanding and overcoming these mechanisms of immune escape became a pivotal focus of cancer immunotherapy.展开更多
METTL3 methylates RNA and regulates the fate of mRNA through its methyltransferase activity.METTL3 enhances RNA translation independently of its catalytic activity.However,the underlying mechanism is still elusive.Her...METTL3 methylates RNA and regulates the fate of mRNA through its methyltransferase activity.METTL3 enhances RNA translation independently of its catalytic activity.However,the underlying mechanism is still elusive.Here,we report that METTL3 is both interacted with and acetylated at lysine 177 by the acetyltransferase PCAF and deacetylated by SIRT3.Neither the methyltransferase activity nor the stability of METTL3 is affected by its acetylation at K177.Importantly,acetylation of METTL3 blocks its interaction with EIF3H,a subunit of the translation initiation factor,thereby reducing mRNA translation efficiency.Interestingly,acetylation of METTL3 responds to oxidative stress.Mechanistically,oxidative stress enhances the interaction of PCAF with METTL3,increases METTL3 acetylation,and suppresses the interaction of METTL3 with EIF3H,thereby decreasing the translation efficiency of ribosomes and inhibiting cell proliferation.Altogether,we suggest a mechanism by which oxidative stress regulates RNA translation efficiency by the modulation of METTL3 acetylation mediated by PCAF.展开更多
As a key sensor of double-stranded DNA(dsDNA),cyclic GMP-AMP synthase(cGAS)detects cytosolic dsDNA and initiates the synthesis of 2′3′cyclic GMP-AMP(cGAMP)that activates the stimulator of interferon genes(STING).Thi...As a key sensor of double-stranded DNA(dsDNA),cyclic GMP-AMP synthase(cGAS)detects cytosolic dsDNA and initiates the synthesis of 2′3′cyclic GMP-AMP(cGAMP)that activates the stimulator of interferon genes(STING).This finally promotes the production of type I interferons(IFN-I)that is crucial for bridging innate and adaptive immunity.Recent evidence show that several antitumor therapies,including radiotherapy(RT),chemotherapy,targeted therapies and immunotherapies,activate the cGAS-STING pathway to provoke the antitumor immunity.In the last decade,the development of STING agonists has been a major focus in both basic research and the pharmaceutical industry.However,up to now,none of STING agonists have been approved for clinical use.Considering the broad expression of STING in whole body and the direct lethal effect of STING agonists on immune cells in the draining lymph node(dLN),research on the optimal way to activate STING in tumor microenvironment(TME)appears to be a promising direction.Moreover,besides enhancing IFN-I signaling,the cGAS-STING pathway also plays roles in senescence,autophagy,apoptosis,mitotic arrest,and DNA repair,contributing to tumor development and metastasis.In this review,we summarize the recent advances on cGAS-STING pathway’s response to antitumor therapies and the strategies involving this pathway for tumor treatment.展开更多
Phosphatase and tensin homolog(PTEN)is a multifunctional gene involved in a variety of physiological and pathological processes.Circular RNAs(circRNAs)are generated from back-splicing events during mRNA processing and...Phosphatase and tensin homolog(PTEN)is a multifunctional gene involved in a variety of physiological and pathological processes.Circular RNAs(circRNAs)are generated from back-splicing events during mRNA processing and participate in cell biological processes through binding to RNAs or proteins.However,PTEN-related circRNAs are largely unknown.Here,we report that circPTEN-mitochondria(MT)(hsa_circ_0002934)is a circular RNA encoded by exons 3,4,and 5 of PTEN and is a critical regulator of mitochondrial energy metabolism.CircPTEN-MT is localized to mitochondria and physically associated with leucine-rich pentatricopeptide repeat-containing protein(LRPPRC),which regulates posttranscriptional gene expression in mitochondria.Knocking down circPTEN-MT reduces the interaction of LRPPRC and steroid receptor RNA activator(SRA)stem-loop interacting RNA binding protein(SLIRP)and inhibits the polyadenylation of mitochondrial mRNA,which decreases the mRNA level of the mitochondrial complex I subunit and reduces mitochondrial membrane potential and adenosine triphosphate production.Our data demonstrate that circPTEN-MT is an important regulator of cellular energy metabolism.This study expands our understanding of the role of PTEN,which produces both linear and circular RNAs with different and independent functions.展开更多
Chemoresistance is a significant barrier to effective cancer treatment.Potential mechanisms for chemoresistance include reactive oxygen species(ROS)accumulation and expression of chemoresistance-promoting genes.Here,w...Chemoresistance is a significant barrier to effective cancer treatment.Potential mechanisms for chemoresistance include reactive oxygen species(ROS)accumulation and expression of chemoresistance-promoting genes.Here,we report a novel function of lncRNA16 in the inhibition of ROS generation and the progression of chemoresistance.By analyzing the serum levels of lncRNA16 in a cohort of 35 patients with non-small cell lung cancer(NSCLC)and paired serum samples pre-and post-treatment from 10 NSCLC patients receiving neoadjuvant platinum-based chemotherapy,performing immunohistochemistry(IHC)assays on 188 NSCLC tumor samples,using comprehensive identification of RNA-binding proteins by mass spectrometry(ChIRP-MS)assays,as well as RNA immunoprecipitation(RIP)and RNA pull-down analyses,we discovered that patients with increased serum levels of lncRNA16 exhibited a poor response to platinum-based chemotherapy.The expression of hemoglobin subunit beta(HBB)and NDUFAF5 significantly increases with the development of chemoresistance.LncRNA16 binds to HBB and promotes HBB accumulation by inhibiting autophagy.LncRNA16 can also inhibit ROS generation via the HBB/NDUFAF5 axis and function as a scaffold to facilitate the colocalization of HBB and NDUFAF5 in the mitochondria.Importantly,preclinical studies in mouse models of chemo-resistant NSCLC have suggested that lncRNA16 targeting by trivalent N-acetylgalactosamine(GalNAc)-conjugated siRNA restores chemosensitivity and results in tumor growth inhibition with no detectable toxicity in vivo.Overall,lncRNA16 is a promising therapeutic target for overcoming chemoresistance,and the combination of first-line platinum-based chemotherapy with lncRNA16 intervention can substantially enhance anti-tumor efficacy.展开更多
As the crisp air of a new year washes over us,carrying with it the scent of possibilities and the whispers of unfinished endeavors,it is time for reflection and,of course,renewed dedication.Here at Medical Review,we s...As the crisp air of a new year washes over us,carrying with it the scent of possibilities and the whispers of unfinished endeavors,it is time for reflection and,of course,renewed dedication.Here at Medical Review,we stand tall amidst the constant churn of scientific discovery,witnessing firsthand the tireless efforts of researchers,clinicians,and healthcare professionals who relentlessly push the boundaries of medical knowledge.展开更多
The cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING)pathway is an evolving DNA-sensing mechanism involved in innate immunity and pathogen defense that has been optimized while remaining conserved.As...The cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING)pathway is an evolving DNA-sensing mechanism involved in innate immunity and pathogen defense that has been optimized while remaining conserved.Aside from recognizing pathogens through conserved motifs,these receptors also detect aberrant or misplaced self-molecules as possible signs of perturbed homeostasis.Upon binding external or self-derived DNA,a mobile sec-ondary messenger 2′3′-cyclic GMP-AMP(cGAMP)is produced by cGAS and in turn activates its adapter STING in the endo-plasmic reticulum(ER).Resting-state or activated STING protein isfinely restricted by multiple degradation machin-eries.The post-translational changes of the STING protein,along with the regulatory machinery ofthe secret routes,limit the onset,strength and sustention of STING signal.STING experiences a conformational shift and relocates with TBK1 from the ER to perinuclear vesicles containing transcription factors,provoking the transcription activity of IRF3/IFN-I and NF-κB pathways,as well as to initiate a number of cellular processes that have been shown to alter the immune landscape in cancer,such as autophagy,NLRP3 inflamma-some,ER stress,and cell death.STING signal thus serves as a potent activator for immune mobilization yet also triggers immune-mediated pathology in tissues.Recent advances have established the vital role of STING in immune surveil-lance as well as tumorigenic process.This review provides an overview of the disparate outcomes of cancer attributed to the actions of pleiotropic and coordinated STING downstream signalosomes,along with the underlying mechanisms of STING function in pathologies,providing therapeutic impli-cations for new approaches in hunt for the next generation of cancer immunotherapy base on STING.展开更多
The long battle with cancer began centuries ago and despite many victories,the overall incidence continues to rise and it sometimes feels like that we are losing the war.The high rates and mortality of cancer have bro...The long battle with cancer began centuries ago and despite many victories,the overall incidence continues to rise and it sometimes feels like that we are losing the war.The high rates and mortality of cancer have brought an increasing burden to society and so defeating the disease remains an urgent and unmet clinical need.In recent years,there has been a profound development of new knowledge and technologies that are widely employed in cancer research across multiple disciplines and even moreso,across the world.In modern times,it is hard to keep up with these breakthroughs,especially when they occur in varying regions.To address this,we are delighted to announce the launch of Malignancy Spectrum(MSP)in a bid to bring global advances in these disciplines together in one place.展开更多
Nowadays,according to estimates from the World Health Organization(WHO),cancer still ranks as the top leading cause of death disease worldwide[1].In case of the rapid growing of the cancer incidence and mortality,the ...Nowadays,according to estimates from the World Health Organization(WHO),cancer still ranks as the top leading cause of death disease worldwide[1].In case of the rapid growing of the cancer incidence and mortality,the global cancer burden is expected to increase about 50%in the next twenty years[1].Considering the complexity of main risk fac-tors for cancer,efforts to uncover the underlying mechanism of tumorigenesis and establish the molecular classification models for prevention are critical for global cancer control.展开更多
Stroma surrounding the tumor cells plays crucial roles for tumor progression.However,little is known about the factors that maintain the symbiosis between stroma and tumor cells.In this study,we found that the transcr...Stroma surrounding the tumor cells plays crucial roles for tumor progression.However,little is known about the factors that maintain the symbiosis between stroma and tumor cells.In this study,we found that the transcriptional regulator-signal transducer and activator of transcription 3(Stat3)was frequently activated in cancer-associated fibroblasts(CAFs),which was a potent facilitator of tumor malignancy,and formed forward feedback loop with platelet-activating factor receptor(PAFR)both in CAFs and tumor cells.Importantly,PAFR/Stat3 axis connected intercellular signaling crosstalk between CAFs and cancer cells and drove mutual transcriptional programming of these two types of cells.Two central Stat3-related cytokine signaling molecules-interleukin 6(IL-6)and IL-11 played the critical role in the process of PAFR/Stat3 axis-mediated communication between tumor and CAFs.Pharmacological inhibition of PAFR and Stat3 activities effectively reduced tumor progression using CAFs/tumor co-culture xenograft model.Our study reveals that PAFR/Stat3 axis enhances the interaction between tumor and its associated stroma and suggests that targeting this axis can be an effective therapeutic strategy against tumor malignancy.展开更多
Although Src is one of the oldest and most investigated oncoproteins,its function in tumor malignancy remains to be defined further.In this study,we demonstrated that the inhibition of Src activity by ponatinib effect...Although Src is one of the oldest and most investigated oncoproteins,its function in tumor malignancy remains to be defined further.In this study,we demonstrated that the inhibition of Src activity by ponatinib effectively suppressed several malignant phenotypes of esophageal squamous cell carcinoma(ESCC)both in vitro and in vivo,whereas it did not produce growthinhibitory effects on normal esophageal epithelial cells(NEECs).Importantly,we combined phosphoproteomics and several cellular and molecular biologic strategies to identify that Src interacted with the members of Src-family kinases(SFKs),such as Fyn or Lyn,to form heterodimers.Src interactions with Fyn and Lyn phosphorylated the tyrosine sites in SH2(Fyn Tyr^(185)or Lyn Tyr^(183))and kinase domains(Fyn Tyr^(420) or Lyn Tyr^(397)),which critically contributed to ESCC development.By contrast,Src could not form heterodimers with Fyn or Lyn in NEECs.We used RNA sequencing to comprehensively demonstrate that the inhibition of Src activity effectively blocked several critical tumor-promoting pathways,such as JAK/STAT,mTOR,stemness-related,and metabolism-related pathways.Results of the real-time polymerase chain reaction(RT-PCR)assay confirmed that Lyn and Fyn were critical effectors for the Src-mediated expression of tumor growth or metastasis-related molecules.Furthermore,results of the clinical ESCC samples showed that the hyperactivation of pSrc Tyr^(419),Fyn Tyr^(185) or Tyr^(420),and Lyn Tyr^(183)or Tyr^(397)could be biomarkers of ESCC prognosis.This study illustrates that Src/Fyn and Src/Lyn heterodimers serve as targets for the treatment of ESCC.展开更多
The era of advanced artificial intelligence has arrived with the development of chatbots like ChatGPT(Chat Generative Pre-trained Transformer).As described by Ouyang et al.(2022),ChatGPT demonstrates an impressive abi...The era of advanced artificial intelligence has arrived with the development of chatbots like ChatGPT(Chat Generative Pre-trained Transformer).As described by Ouyang et al.(2022),ChatGPT demonstrates an impressive ability to generate human-like responses and solve practical problems,surpassing original expectations for its capabilities.The rapid release and adoption of ChatGPT signals a new phase in AI development,powered by large language models that can be fine-tuned through human feedback.However,risks remain regarding how such powerful models may be misused.Further research is needed to ensure safe and ethical deployment of these transformative technologies.展开更多
Aging biomarkers are a combination of biological parameters to(i)assess age-related changes,(ii)track the physiological aging process,and(iii)predict the transition into a pathological status.Although a broad spectrum...Aging biomarkers are a combination of biological parameters to(i)assess age-related changes,(ii)track the physiological aging process,and(iii)predict the transition into a pathological status.Although a broad spectrum of aging biomarkers has been developed,their potential uses and limitations remain poorly characterized.An immediate goal of biomarkers is to help us answer the following three fundamental questions in aging research:How old are we?Why do we get old?And how can we age slower?This review aims to address this need.Here,we summarize our current knowledge of biomarkers developed for cellular,organ,and organismal levels of aging,comprising six pillars:physiological characteristics,medical imaging,histological features,cellular alterations,molecular changes,and secretory factors.To fulfill all these requisites,we propose that aging biomarkers should qualify for being specific,systemic,and clinically relevant.展开更多
Tumor cell dependence on activated oncogenes is considered a therapeutic target,but protumorigenic microenvironment-mediated cellular addiction to specific oncogenic signaling molecules remains to be further defined.H...Tumor cell dependence on activated oncogenes is considered a therapeutic target,but protumorigenic microenvironment-mediated cellular addiction to specific oncogenic signaling molecules remains to be further defined.Here,we showed that tumor-associated macrophages(TAMs)produced an abundance of C-C motif chemokine 22(CCL22),whose expression in the tumor stroma was positively associated with the level of intratumoral phospho-focal adhesion kinase(pFAK Tyr^(397)),tumor metastasis and reduced patient survival.Functionally,CCL22-stimulated hyperactivation of FAK was correlated with increased malignant progression of cancer cells.CCL22-induced addiction to FAK was demonstrated by the persistent suppression of tumor progression upon FAK-specific inhibition.Mechanistically,we identified that diacylglycerol kinaseα(DGKα)acted as a signaling adaptor to link the CCL22 receptor C-C motif chemokine receptor 4(CCR4)and FAK and promoted CCL22-induced activation of the FAK/AKT pathway.CCL22/CCR4 signaling activated the intracellular Ca^(2+)/phospholipase C-γ1(PLC-γ1)axis to stimulate the phosphorylation of DGKαat a tyrosine residue(Tyr^(335))and promoted the translocation of DGKαto the plasma membrane to assemble the DGKα/FAK signalosome,which critically contributed to regulating sensitivity to FAK inhibitors in cancer cells.The identification of TAM-driven intratumoral FAK addiction provides opportunities for utilizing the tumor-promoting microenvironment to achieve striking anticancer effects.展开更多
基金Beijing Natural Science Foundation,Grant/Award Number:L222145 and L222030Emerging Engineering Interdisciplinary Project and the Fundamental Research Funds for the Central Universities,Grant/Award Number:PKU2022XGK008Peking University Medicine Fund of Fostering Young Scholars’Scientific&Technological Innovation,Grant/Award Number:BMU2022PY010。
文摘Background:Osteoporosis is a chronic bone disease characterized by bone loss and decreased bone strength.However,current anti-resorptive drugs carry a risk of various complications.The deep learning-based efficacy prediction system(DLEPS)is a forecasting tool that can effectively compete in drug screening and prediction based on gene expression changes.This study aimed to explore the protective effect and potential mechanisms of cinobufotalin(CB),a traditional Chinese medicine(TCM),on bone loss.Methods:DLEPS was employed for screening anti-osteoporotic agents according to gene profile changes in primary osteoporosis.Micro-CT,histological and morphological analysis were applied for the bone protective detection of CB,and the osteogenic differentiation/function in human bone marrow mesenchymal stem cells(hBMMSCs)were also investigated.The underlying mechanism was verified using qRT-PCR,Western blot(WB),immunofluorescence(IF),etc.Results:A safe concentration(0.25mg/kg in vivo,0.05μM in vitro)of CB could effectively preserve bone mass in estrogen deficiency-induced bone loss and promote osteogenic differentiation/function of hBMMSCs.Both BMPs/SMAD and Wnt/β-catenin signaling pathways participated in CB-induced osteogenic differentiation,further regulating the expression of osteogenesis-associated factors,and ultimately promoting osteogenesis.Conclusion:Our study demonstrated that CB could significantly reverse estrogen deficiency-induced bone loss,further promoting osteogenic differentiation/function of hBMMSCs,with BMPs/SMAD and Wnt/β-catenin signaling pathways involved.
基金Imported Scholar Project and Startup from Peking University Health Science Center(BMU2021YJ063 to MD)the Biotechnology Innovation Plan from Beijing Sungen Biomedical Technology Co.,Ltd(2022066 to MD)the Excellent Young Scientists Fund Program(overseas)from National Natural Science Fund(HY2021-7 to MD)。
文摘Myeloid checkpoints are receptors on the myeloid cell surface which can mediate inhibitory signals to modulate anti-tumor immune activities.They can either inhibit cellular phagocytosis or suppress T cells and are thus involved in the pathogenesis of various diseases.In the tumor microenvironment,besides killing tumor cells by phagocytosis or activating anti-tumor immunity by tumor antigen presentation,myeloid cells could execute protumor efficacies through myeloid checkpoints by interacting with counter-receptors on other immune cells or cancer cells.In summary,myeloid checkpoints may be promising therapeutic targets for cancer immunotherapy.
基金supported by the National Natural Science Foundations of China 82230030 and 81871492(Y.L.),82201020(Y.W),and 82100980(S.S.J)the Beijing Natural Science Foundation JL23002(Y.L.)and 7214305(S.S.J)+6 种基金the Beijing International Science and Technology Cooperation Project Z221100002722003(Y.L.)the Innovative Research Team of High-level Local Universities in Shanghai SHSMU-ZLCX20212402(Y.L.)Ten-Thousand Talents Program QNBJ2019-2(Y.L.)the Key R&D Plan of Ningxia Hui Autonomous Region 2020BCG01001(Y.L.)Beijing Nova Program Z211100002121043(Y.W.)China National Postdoctoral Program for Innovative Talents BX2021022(Y.W.),BX20200020(S.S.J)China Postdoctoral Science Foundation 2021M700281(Y.W.)。
文摘Adult tendon stem/progenitor cells(TSPCs)are essential for tendon maintenance,regeneration,and repair,yet they become susceptible to senescence with age,impairing the self-healing capacity of tendons.In this study,we employ a recently developed deep-learning-based efficacy prediction system to screen potential stemness-promoting and senescence-inhibiting drugs from natural products using the transcriptional signatures of stemness.The top-ranked candidate,prim-O-glucosylcimifugin(POG),a saposhnikovia root extract,could ameliorate TPSC senescent phenotypes caused by long-term passage and natural aging in rats and humans,as well as restore the self-renewal and proliferative capacities and tenogenic potential of aged TSPCs.In vivo,the systematic administration of POG or the local delivery of POG nanoparticles functionally rescued endogenous tendon regeneration and repair in aged rats to levels similar to those of normal animals.Mechanistically,POG protects TSPCs against functional impairment during both passage-induced and natural aging by simultaneously suppressing nuclear factor-κB and decreasing mTOR signaling with the induction of autophagy.Thus,the strategy of pharmacological intervention with the deep learning-predicted compound POG could rejuvenate aged TSPCs and improve the regenerative capacity of aged tendons.
基金supported by the National Natural Science Foundation of China(81988101,81830086,and 81972243)CAMS Innovation Fund for Medical Sciences(2019-I2M-5-081)+3 种基金Suzhou Top-Notch Talent Groups(ZXD2022003)Major Program of Shenzhen Bay Laboratory(S201101004)Guangdong Basic and Applied Basic Research Foundation(2019B030302012)the Fund of“San-ming”Project of Medicine in Shenzhen(No.SZSM201812088).
文摘Abnormal metabolism is regarded as an oncogenic hallmark related to tumor progression and therapeutic resistance.Present study employed multi-omics,including phosphoproteomics,untargeted metabolomics and lipidomics,to demonstrate that the pAKT2 Ser128 and pCCTαSer315/319/323-positive cancer-associated fibroblasts(CAFs)substantially release phosphatidylcholines(PCs),contributing to the resistance of focal adhesion kinase(FAK)inhibitors in esophageal squamous cell carcinoma(ESCC)treatment.Additionally,we observed extremely low levels of FAK Tyr397 expression in CAFs,potentially offering no available target for FAK inhibitors playing their anti-growth role in CAFs.Consequently,FAK inhibitor increased the intracellular concentration of Ca2+in CAFs,promoting the formation of AKT2/CCTαcomplex,leading to phosphorylation of CCTαSer315/319/323 sites and eventually enhancing stromal PC production.This activation could stimulate the intratumoral Janus kinase 2(JAK2)/Signal transducer and activator of transcription 3(STAT3)pathway,triggering resistance to FAK inhibition.Analysis of clinical samples demonstrated that stromal pAKT2 Ser128 and pCCTαSer315/319/323 are related to the tumor malignancy and reduced patient survival.Pseudo-targeted lipidomics and further validation cohort quantitatively showed that plasma PCs enable to distinguish the malignant extent of ESCC patients.In conclusion,inhibition of stroma-derived PCs and related pathway could be possible therapeutic strategies for tumor therapy.
基金supported by NSFC(32170756)National Key R&D Program of China(2023YFF1205103)。
文摘Throughout our life journey,two unstoppable forces shape our existence:the specter of aging and cancer.Seemingly unrelated,these phenomena are more intertwined than we might think[1].The incidence and mortality rates of cancer increase exponentially with age,and their underlying causes are both related to cellular dysfunction.Studying these commonalities is not only key to unlocking cancer therapies,but it may also inspire us to find interventions that delay the aging process itself.
基金supported by grants from the National Natural Science Foundation of China(Nos.82172972,81972609,81472734,31170711,81773199,81730071,81972616,81230051,and 81670626)the Beijing Natural Science Foundation(Nos.202084,7171005,7120002,and 7202080).
文摘FRMD6,a member of the 4.1 ezrin-radixin-moesin domain-containing protein family,has been reported to inhibit tumor progression in multiple cancers.Here,we demonstrate the involvement of FRMD6 in lung cancer progression.We find that FRMD6 is overexpressed in lung cancer tissues relative to in normal lung tissues.In addition,the enhanced expression of FRMD6 is associated with poor outcomes in patients with lung squamous cell carcinoma(n=75,P=0.0054)and lung adenocarcinoma(n=94,P=0.0330).Cell migration and proliferation in vitro and tumor formation in vivo are promoted by FRMD6 but are suppressed by the depletion of FRMD6.Mechanistically,FRMD6 interacts and colocalizes with mTOR and S6K,which are the key molecules of the mTOR signaling pathway.FRMD6 markedly enhances the interaction between mTOR and S6K,subsequently increasing the levels of endogenous pS6K and downstream pS6 in lung cancer cells.Furthermore,knocking out FRMD6 inhibits the activation of the mTOR signaling pathway in Frmd6^(−/−)gene KO MEFs and mice.Altogether,our results show that FRMD6 contributes to lung cancer progression by activating the mTOR signaling pathway.
基金supported by the National Natural Science Foundation of China(91942307).
文摘Cancer immunology has witnessed remarkable development over the past century.In the early 20^(th) century,William Coley embarked on pioneering efforts to activate the immune system against cancer using heat-killed Streptococcus pyogenes and Serratia marcescens^([1]).These attempts yielded varying clinical outcomes,some of which were notably successful,providing early evidence of the immune system’s potential in combating cancer.Moving into the mid-20th century,Dr.Lewis Thomas and Dr.Macfarlane Burnet introduced the concept“immune surveillance”^([2]).This theory proposed that the immune systemconstantlymonitors the body,identifying and eliminating emerging cancer cells to prevent them from developing into full-fledged tumors.This concept laid the foundation for future research in cancer immunology.Simultaneously,the concept of immune evasion emerged,emphasizing how cancer cells can elude immune detection and destruction,enabling them to proliferate and spread within the body.Thus,understanding and overcoming these mechanisms of immune escape became a pivotal focus of cancer immunotherapy.
基金supported by the National Key Research and Development Program of China(2022YFA1104003,2021YFC2501003)the National Natural Science Foundation of China(82230094,81972616,81730071)+1 种基金Peking University Medicine Sailing Program for Young Scholars'Scientific&Technological Innovation(BMU2024YFJHPY004)the Fundamental Research Funds for the Central Universities。
文摘METTL3 methylates RNA and regulates the fate of mRNA through its methyltransferase activity.METTL3 enhances RNA translation independently of its catalytic activity.However,the underlying mechanism is still elusive.Here,we report that METTL3 is both interacted with and acetylated at lysine 177 by the acetyltransferase PCAF and deacetylated by SIRT3.Neither the methyltransferase activity nor the stability of METTL3 is affected by its acetylation at K177.Importantly,acetylation of METTL3 blocks its interaction with EIF3H,a subunit of the translation initiation factor,thereby reducing mRNA translation efficiency.Interestingly,acetylation of METTL3 responds to oxidative stress.Mechanistically,oxidative stress enhances the interaction of PCAF with METTL3,increases METTL3 acetylation,and suppresses the interaction of METTL3 with EIF3H,thereby decreasing the translation efficiency of ribosomes and inhibiting cell proliferation.Altogether,we suggest a mechanism by which oxidative stress regulates RNA translation efficiency by the modulation of METTL3 acetylation mediated by PCAF.
基金supported by National Key Research and Development Program of China 2023YFC3404600National Natural Science Foundation of China grant(82371848)。
文摘As a key sensor of double-stranded DNA(dsDNA),cyclic GMP-AMP synthase(cGAS)detects cytosolic dsDNA and initiates the synthesis of 2′3′cyclic GMP-AMP(cGAMP)that activates the stimulator of interferon genes(STING).This finally promotes the production of type I interferons(IFN-I)that is crucial for bridging innate and adaptive immunity.Recent evidence show that several antitumor therapies,including radiotherapy(RT),chemotherapy,targeted therapies and immunotherapies,activate the cGAS-STING pathway to provoke the antitumor immunity.In the last decade,the development of STING agonists has been a major focus in both basic research and the pharmaceutical industry.However,up to now,none of STING agonists have been approved for clinical use.Considering the broad expression of STING in whole body and the direct lethal effect of STING agonists on immune cells in the draining lymph node(dLN),research on the optimal way to activate STING in tumor microenvironment(TME)appears to be a promising direction.Moreover,besides enhancing IFN-I signaling,the cGAS-STING pathway also plays roles in senescence,autophagy,apoptosis,mitotic arrest,and DNA repair,contributing to tumor development and metastasis.In this review,we summarize the recent advances on cGAS-STING pathway’s response to antitumor therapies and the strategies involving this pathway for tumor treatment.
基金Y.Yin including the National Natural Science Foundation of China(82030081 and 81874235)the National Key Research and Development Program of China(2021YFA1300601)the Shenzhen High-level Hospital Construction Fund and Shenzhen Basic Research Key Project(JCYJ20220818102811024).
文摘Phosphatase and tensin homolog(PTEN)is a multifunctional gene involved in a variety of physiological and pathological processes.Circular RNAs(circRNAs)are generated from back-splicing events during mRNA processing and participate in cell biological processes through binding to RNAs or proteins.However,PTEN-related circRNAs are largely unknown.Here,we report that circPTEN-mitochondria(MT)(hsa_circ_0002934)is a circular RNA encoded by exons 3,4,and 5 of PTEN and is a critical regulator of mitochondrial energy metabolism.CircPTEN-MT is localized to mitochondria and physically associated with leucine-rich pentatricopeptide repeat-containing protein(LRPPRC),which regulates posttranscriptional gene expression in mitochondria.Knocking down circPTEN-MT reduces the interaction of LRPPRC and steroid receptor RNA activator(SRA)stem-loop interacting RNA binding protein(SLIRP)and inhibits the polyadenylation of mitochondrial mRNA,which decreases the mRNA level of the mitochondrial complex I subunit and reduces mitochondrial membrane potential and adenosine triphosphate production.Our data demonstrate that circPTEN-MT is an important regulator of cellular energy metabolism.This study expands our understanding of the role of PTEN,which produces both linear and circular RNAs with different and independent functions.
基金supported by the National Natural Science Foundation of China (81972842, 82373082, 81988101, 82173152)
文摘Chemoresistance is a significant barrier to effective cancer treatment.Potential mechanisms for chemoresistance include reactive oxygen species(ROS)accumulation and expression of chemoresistance-promoting genes.Here,we report a novel function of lncRNA16 in the inhibition of ROS generation and the progression of chemoresistance.By analyzing the serum levels of lncRNA16 in a cohort of 35 patients with non-small cell lung cancer(NSCLC)and paired serum samples pre-and post-treatment from 10 NSCLC patients receiving neoadjuvant platinum-based chemotherapy,performing immunohistochemistry(IHC)assays on 188 NSCLC tumor samples,using comprehensive identification of RNA-binding proteins by mass spectrometry(ChIRP-MS)assays,as well as RNA immunoprecipitation(RIP)and RNA pull-down analyses,we discovered that patients with increased serum levels of lncRNA16 exhibited a poor response to platinum-based chemotherapy.The expression of hemoglobin subunit beta(HBB)and NDUFAF5 significantly increases with the development of chemoresistance.LncRNA16 binds to HBB and promotes HBB accumulation by inhibiting autophagy.LncRNA16 can also inhibit ROS generation via the HBB/NDUFAF5 axis and function as a scaffold to facilitate the colocalization of HBB and NDUFAF5 in the mitochondria.Importantly,preclinical studies in mouse models of chemo-resistant NSCLC have suggested that lncRNA16 targeting by trivalent N-acetylgalactosamine(GalNAc)-conjugated siRNA restores chemosensitivity and results in tumor growth inhibition with no detectable toxicity in vivo.Overall,lncRNA16 is a promising therapeutic target for overcoming chemoresistance,and the combination of first-line platinum-based chemotherapy with lncRNA16 intervention can substantially enhance anti-tumor efficacy.
文摘As the crisp air of a new year washes over us,carrying with it the scent of possibilities and the whispers of unfinished endeavors,it is time for reflection and,of course,renewed dedication.Here at Medical Review,we stand tall amidst the constant churn of scientific discovery,witnessing firsthand the tireless efforts of researchers,clinicians,and healthcare professionals who relentlessly push the boundaries of medical knowledge.
基金National Natural Science Foundation of China (82000003)China Postdoctoral Science Foundation (2023M743039)National Key Research and Development Program of China (2022YFC3401400).
文摘The cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING)pathway is an evolving DNA-sensing mechanism involved in innate immunity and pathogen defense that has been optimized while remaining conserved.Aside from recognizing pathogens through conserved motifs,these receptors also detect aberrant or misplaced self-molecules as possible signs of perturbed homeostasis.Upon binding external or self-derived DNA,a mobile sec-ondary messenger 2′3′-cyclic GMP-AMP(cGAMP)is produced by cGAS and in turn activates its adapter STING in the endo-plasmic reticulum(ER).Resting-state or activated STING protein isfinely restricted by multiple degradation machin-eries.The post-translational changes of the STING protein,along with the regulatory machinery ofthe secret routes,limit the onset,strength and sustention of STING signal.STING experiences a conformational shift and relocates with TBK1 from the ER to perinuclear vesicles containing transcription factors,provoking the transcription activity of IRF3/IFN-I and NF-κB pathways,as well as to initiate a number of cellular processes that have been shown to alter the immune landscape in cancer,such as autophagy,NLRP3 inflamma-some,ER stress,and cell death.STING signal thus serves as a potent activator for immune mobilization yet also triggers immune-mediated pathology in tissues.Recent advances have established the vital role of STING in immune surveil-lance as well as tumorigenic process.This review provides an overview of the disparate outcomes of cancer attributed to the actions of pleiotropic and coordinated STING downstream signalosomes,along with the underlying mechanisms of STING function in pathologies,providing therapeutic impli-cations for new approaches in hunt for the next generation of cancer immunotherapy base on STING.
文摘The long battle with cancer began centuries ago and despite many victories,the overall incidence continues to rise and it sometimes feels like that we are losing the war.The high rates and mortality of cancer have brought an increasing burden to society and so defeating the disease remains an urgent and unmet clinical need.In recent years,there has been a profound development of new knowledge and technologies that are widely employed in cancer research across multiple disciplines and even moreso,across the world.In modern times,it is hard to keep up with these breakthroughs,especially when they occur in varying regions.To address this,we are delighted to announce the launch of Malignancy Spectrum(MSP)in a bid to bring global advances in these disciplines together in one place.
文摘Nowadays,according to estimates from the World Health Organization(WHO),cancer still ranks as the top leading cause of death disease worldwide[1].In case of the rapid growing of the cancer incidence and mortality,the global cancer burden is expected to increase about 50%in the next twenty years[1].Considering the complexity of main risk fac-tors for cancer,efforts to uncover the underlying mechanism of tumorigenesis and establish the molecular classification models for prevention are critical for global cancer control.
基金supported by National Natural Science Foundation of China(Nos.81988101,81830086,and 81972243,China)CAMS Innovation Fund for Medical Sciences(No.2019-I2M-5081,China)Guangdong Basic and Applied Basic Research Foundation(No.2019B030302012,China)。
文摘Stroma surrounding the tumor cells plays crucial roles for tumor progression.However,little is known about the factors that maintain the symbiosis between stroma and tumor cells.In this study,we found that the transcriptional regulator-signal transducer and activator of transcription 3(Stat3)was frequently activated in cancer-associated fibroblasts(CAFs),which was a potent facilitator of tumor malignancy,and formed forward feedback loop with platelet-activating factor receptor(PAFR)both in CAFs and tumor cells.Importantly,PAFR/Stat3 axis connected intercellular signaling crosstalk between CAFs and cancer cells and drove mutual transcriptional programming of these two types of cells.Two central Stat3-related cytokine signaling molecules-interleukin 6(IL-6)and IL-11 played the critical role in the process of PAFR/Stat3 axis-mediated communication between tumor and CAFs.Pharmacological inhibition of PAFR and Stat3 activities effectively reduced tumor progression using CAFs/tumor co-culture xenograft model.Our study reveals that PAFR/Stat3 axis enhances the interaction between tumor and its associated stroma and suggests that targeting this axis can be an effective therapeutic strategy against tumor malignancy.
基金supported by the National Natural Science Foundation of China (81988101,81830086 and 81972243)CAMS Innovation Fund for Medical Sciences (2019-I2M-5-081)+2 种基金Major Program of Shenzhen Bay Laboratory (S201101004)Guangdong Basic and Applied Basic Research Foundation (2019B030302012)the Fund of“San-ming”Project of Medicine in Shenzhen (SZSM201812088)。
文摘Although Src is one of the oldest and most investigated oncoproteins,its function in tumor malignancy remains to be defined further.In this study,we demonstrated that the inhibition of Src activity by ponatinib effectively suppressed several malignant phenotypes of esophageal squamous cell carcinoma(ESCC)both in vitro and in vivo,whereas it did not produce growthinhibitory effects on normal esophageal epithelial cells(NEECs).Importantly,we combined phosphoproteomics and several cellular and molecular biologic strategies to identify that Src interacted with the members of Src-family kinases(SFKs),such as Fyn or Lyn,to form heterodimers.Src interactions with Fyn and Lyn phosphorylated the tyrosine sites in SH2(Fyn Tyr^(185)or Lyn Tyr^(183))and kinase domains(Fyn Tyr^(420) or Lyn Tyr^(397)),which critically contributed to ESCC development.By contrast,Src could not form heterodimers with Fyn or Lyn in NEECs.We used RNA sequencing to comprehensively demonstrate that the inhibition of Src activity effectively blocked several critical tumor-promoting pathways,such as JAK/STAT,mTOR,stemness-related,and metabolism-related pathways.Results of the real-time polymerase chain reaction(RT-PCR)assay confirmed that Lyn and Fyn were critical effectors for the Src-mediated expression of tumor growth or metastasis-related molecules.Furthermore,results of the clinical ESCC samples showed that the hyperactivation of pSrc Tyr^(419),Fyn Tyr^(185) or Tyr^(420),and Lyn Tyr^(183)or Tyr^(397)could be biomarkers of ESCC prognosis.This study illustrates that Src/Fyn and Src/Lyn heterodimers serve as targets for the treatment of ESCC.
基金the National key R&D program of China(2018YFA0900200)and NSFC(31771519)。
文摘The era of advanced artificial intelligence has arrived with the development of chatbots like ChatGPT(Chat Generative Pre-trained Transformer).As described by Ouyang et al.(2022),ChatGPT demonstrates an impressive ability to generate human-like responses and solve practical problems,surpassing original expectations for its capabilities.The rapid release and adoption of ChatGPT signals a new phase in AI development,powered by large language models that can be fine-tuned through human feedback.However,risks remain regarding how such powerful models may be misused.Further research is needed to ensure safe and ethical deployment of these transformative technologies.
基金supported by the National Natural Science Foundation of China(31730036,31871380,31871382,31930055,31930058,32000500,32022034,32030033,32070730,32130046,3217050247,32150005,32200595,32222024,81730019,81730022,81830014,81921006,81925005,81970426,81971301,81971312,82030041,82061160495,82070805,82071595,82090020,82100841,82120108009,82122024,82125002,82125011,82125012,82130045,82171284,82173061,82173398,82225007,82225015,82225017,82225018,82230047,82230088,82271600,91949106,91949201,92049116,92049302,92049304,92149303,92149306,92157202,92168201,92169102,92249301,92268201)the National Key Research and Development Program of China(2018YFA0800700,2018YFC2000100,2018YFC2000102,2018YFC2002003,2019YFA0110900,2019YFA0801703,2019YFA0801903,2019YFA0802202,2019YFA0904800,2020YFA0113400,2020YFA0803401,2020YFA0804000,2020YFC2002900,2020YFC2008000,2020YFE0202200,2021YFA0804900,2021YFA1100103,2021YFA1100900,2021YFE0114200,2021ZD0202400,2022YFA0806001,2022YFA0806002,2022YFA0806600,2022YFA1103200,2022YFA1103601,2022YFA1103701,2022YFA1103800,2022YFA1103801,2022YFA1104100,2022YFA1104904,2022YFA1303000,2022YFC2009900,2022YFC2502401,2022YFC3602400,2022YFE0118000,2022ZD0213200)+14 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16030302,XDB39000000,XDB39030600)the Youth Innovation Promotion Association of Chinese Academy of Sciences(2020085,2021080)CAS Project for Young Scientists in Basic Research(YSBR-076)the Program of the Beijing Natural Science Foundation(JQ20031)Clinical Research Operating Fund of Central High level hospitals(2022-PUMCHE-001)CAMS Innovation Fund for Medical Sciences(CIFMS)(2022-I2M1-004)Talent Program of the Chinese Academy of Medical Science(2022RC310-10)Research Funds from Health@Inno HK Program launched by Innovation Technology Commission of the Hong Kong Special Administrative Region,Guangdong Basic and Applied Basic Research Foundation(2020B1515020044)Guangzhou Planned Project of Science and Technology(202002020039)the Major Technology Innovation of Hubei Province(2019ACA141)the Science and Technology Major Project of Hunan Provincial Science and Technology Department(2021SK1010)Shanghai Municipal Science and Technology Major Project(2017SHZDZX01)the Natural Science Foundation of Sichuan Province(2023NSFSC0003)Yunnan Fundamental Research Project(202201AS070080)the State Key Laboratory of Membrane Biology。
文摘Aging biomarkers are a combination of biological parameters to(i)assess age-related changes,(ii)track the physiological aging process,and(iii)predict the transition into a pathological status.Although a broad spectrum of aging biomarkers has been developed,their potential uses and limitations remain poorly characterized.An immediate goal of biomarkers is to help us answer the following three fundamental questions in aging research:How old are we?Why do we get old?And how can we age slower?This review aims to address this need.Here,we summarize our current knowledge of biomarkers developed for cellular,organ,and organismal levels of aging,comprising six pillars:physiological characteristics,medical imaging,histological features,cellular alterations,molecular changes,and secretory factors.To fulfill all these requisites,we propose that aging biomarkers should qualify for being specific,systemic,and clinically relevant.
基金This work was supported by the National Natural Science Foundation of China(81988101,81830086 and 81972243)the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-081)+2 种基金Funding by the Major Program of Shenzhen Bay Laboratory(S201101004)the Guangdong Basic and Applied Basic Research Foundation(2019B030302012)the Fund of“San-ming”Project of Medicine in Shenzhen(No.SZSM201812088).
文摘Tumor cell dependence on activated oncogenes is considered a therapeutic target,but protumorigenic microenvironment-mediated cellular addiction to specific oncogenic signaling molecules remains to be further defined.Here,we showed that tumor-associated macrophages(TAMs)produced an abundance of C-C motif chemokine 22(CCL22),whose expression in the tumor stroma was positively associated with the level of intratumoral phospho-focal adhesion kinase(pFAK Tyr^(397)),tumor metastasis and reduced patient survival.Functionally,CCL22-stimulated hyperactivation of FAK was correlated with increased malignant progression of cancer cells.CCL22-induced addiction to FAK was demonstrated by the persistent suppression of tumor progression upon FAK-specific inhibition.Mechanistically,we identified that diacylglycerol kinaseα(DGKα)acted as a signaling adaptor to link the CCL22 receptor C-C motif chemokine receptor 4(CCR4)and FAK and promoted CCL22-induced activation of the FAK/AKT pathway.CCL22/CCR4 signaling activated the intracellular Ca^(2+)/phospholipase C-γ1(PLC-γ1)axis to stimulate the phosphorylation of DGKαat a tyrosine residue(Tyr^(335))and promoted the translocation of DGKαto the plasma membrane to assemble the DGKα/FAK signalosome,which critically contributed to regulating sensitivity to FAK inhibitors in cancer cells.The identification of TAM-driven intratumoral FAK addiction provides opportunities for utilizing the tumor-promoting microenvironment to achieve striking anticancer effects.
