Colorectal cancer(CRC)is the third most frequently diagnosed cancer worldwide,responsible for over 880000 deaths each year.Growth/differentiation factor 15(GDF-15)is reported to be a promising diagnostic and prognosti...Colorectal cancer(CRC)is the third most frequently diagnosed cancer worldwide,responsible for over 880000 deaths each year.Growth/differentiation factor 15(GDF-15)is reported to be a promising diagnostic and prognostic factor in CRC.It induces pleiotropic effects in tumor cells:proliferation,sternness,invasion and metastasis.Some studies indicate that GDF-15 may stimulate angiogenesis in malignant neoplasms.However,it has not been investigated in CRC yet.The aim of our study was to determine the level of GDF-15 and the concentrations of hypoxia-inducible factor-la(HIF-1α),VEGF-A and chemokine-like receptor 1(CMKLR1)in tumor and margin specimens of CRC in relation to histological grade and TNM staging.The study comprised 33 samples of tumor and margin tissues obtained from CRC patients.To assess the concentration of GDF-15,HIF-1α,VEGF-A and CMKLR1,commercially available enzyme-linked immunosorbent assay(ELISA)kits were used.We found significantly increased levels of GDF-15 and CMKLR1 in tumor tissue compared to margin tissue and higher concentrations of HIF-1α and VEGF-A in margin tissue than in tumor tissue.The levels of GDF-15 and HIF-1α were significantly correlated with VEGF-A and CMKLR1 in margin tissue.In CRC,the increased level of GDF-15 might stimulate angiogenesis through upregulation of HIF-1α,VEGF A and CMKLR1 expression.Our study is the first one to reveal the correlation between the levels of GDF-15 and CMKLR1 in CRC.The elevated levels of HIF-1α and VEGF-A in tumor-free margin tissues suggest that noncancer cells in the tumor microenvironment are an important source of proangiogenic factors.展开更多
Dear Editor,Chemerin functions as both an adipocytokine and a chemotactic factor and plays key roles in adipogenesis and inflammation(Bozaoglu et al.,2007;Bondue et al.,2011).The chemerin receptors chemokine-like rece...Dear Editor,Chemerin functions as both an adipocytokine and a chemotactic factor and plays key roles in adipogenesis and inflammation(Bozaoglu et al.,2007;Bondue et al.,2011).The chemerin receptors chemokine-like receptor 1(CMKLR1)and G protein-coupled receptor 1(GPR1),play crucial roles in regulating obesity,inflammation,and cancer,highlighting their potential as therapeutic targets(Bozaoglu et al.,2007;Ernst and Sinal,2010;Su et al.,2021).Although both receptors recognize the same ligand,chemerin,and share high sequence identity,they exhibit distinct signaling properties and biological functions(Bozaoglu et al.,2007;De Henau et al.,2016;Fischer et al.,2021).CMKLR1 is the canonical chemerin receptor that mediates both G protein and arrestin signaling,while GPR1 exhibits weak G protein signaling but strong arrestin-dependent and-independent internalization(De Henau et al.,2016;Fig.1A and 1B).The chemerin-CMKLR1 axis regulates lipid and glucose metabolism(Kennedy and Davenport,2018),and is associated with chronic inflammation,obesity,and obesity-related disorders such as insulin resistance and metabolic syndrome,with several compounds and antibodies under preclinical or early clinical investigation(Goralski et al.,2007;Kennedy et al.,2016;Trilleaud et al.,2021).In contrast,the mechanisms of atypical signaling and biological function of GPR1 remain unclear.展开更多
Induction of beige fat for thermogenesis is a potential therapy to improve homeostasis against obesity.β3-adrenoceptor(β3-AR),a type of G protein-coupled receptor(GPCR),is believed to mediate the thermogenesis of br...Induction of beige fat for thermogenesis is a potential therapy to improve homeostasis against obesity.β3-adrenoceptor(β3-AR),a type of G protein-coupled receptor(GPCR),is believed to mediate the thermogenesis of brown fat in mice.However,β3-AR has low expression in human adipose tissue,precluding its activation as a standalone clinical modality.This study aimed at identifying a potential GPCR target to induce beige fat.We found that chemerin chemokine-like receptor 1(CMKLR1),one of the novel GPCRs,mediated the development of beige fat via its two ligands,chemerin and resolvin E1(RvE1).The RvE1 levels were decreased in the obese mice,and RvE1 treatment led to a substantial improvement in obese features and augmented beige fat markers.Inversely,despite sharing the same receptor as RvE1,the chemerin levels were increased in obesogenic conditions,and chemerin treatment led to an augmented obese phenotype and a decline of beige fat markers.Moreover,RvE1 and chemerin induced or restrained the development of beige fat,respectively,via the mechanistic target of rapamycin complex 1(mTORC1)signaling pathway.We further showed that RvE1 and chemerin regulated mTORC1 signaling differentially by forming hydrogen bonds with different binding sites of CMKLR1.In conclusion,our study showed that RvE1 and chemerin affected metabolic homeostasis differentially,suggesting that selectively modulating CMKLR1 may be a potential therapeutic target for restoring metabolic homeostasis.展开更多
文摘Colorectal cancer(CRC)is the third most frequently diagnosed cancer worldwide,responsible for over 880000 deaths each year.Growth/differentiation factor 15(GDF-15)is reported to be a promising diagnostic and prognostic factor in CRC.It induces pleiotropic effects in tumor cells:proliferation,sternness,invasion and metastasis.Some studies indicate that GDF-15 may stimulate angiogenesis in malignant neoplasms.However,it has not been investigated in CRC yet.The aim of our study was to determine the level of GDF-15 and the concentrations of hypoxia-inducible factor-la(HIF-1α),VEGF-A and chemokine-like receptor 1(CMKLR1)in tumor and margin specimens of CRC in relation to histological grade and TNM staging.The study comprised 33 samples of tumor and margin tissues obtained from CRC patients.To assess the concentration of GDF-15,HIF-1α,VEGF-A and CMKLR1,commercially available enzyme-linked immunosorbent assay(ELISA)kits were used.We found significantly increased levels of GDF-15 and CMKLR1 in tumor tissue compared to margin tissue and higher concentrations of HIF-1α and VEGF-A in margin tissue than in tumor tissue.The levels of GDF-15 and HIF-1α were significantly correlated with VEGF-A and CMKLR1 in margin tissue.In CRC,the increased level of GDF-15 might stimulate angiogenesis through upregulation of HIF-1α,VEGF A and CMKLR1 expression.Our study is the first one to reveal the correlation between the levels of GDF-15 and CMKLR1 in CRC.The elevated levels of HIF-1α and VEGF-A in tumor-free margin tissues suggest that noncancer cells in the tumor microenvironment are an important source of proangiogenic factors.
基金supported by the National Key R&D Program of China 2022YFA1302900(B.W.and S.H.)National Natural Science Foundation of China grants 82121005(B.W.)and 32401012(M.H.)+4 种基金CAS Strategic Priority Research Program XDB37030100(B.W.and Q.Z.)Shanghai Pilot Program for Basic Research-Chinese Academy of Sciences,Shanghai Branch JCYJSHFY-2021-008(B.W.)Shanghai Science and Technology Development Foundation grant 22QA1412000(Y.Z.)Zhejiang Provincial Natural Science Foundation of China LQ24C050004(M.H.)Research Funds from Hangzhou Institute for Advanced Study,University of Chinese Academy of Sciences 2024HIAS-Y011(M.H.).
文摘Dear Editor,Chemerin functions as both an adipocytokine and a chemotactic factor and plays key roles in adipogenesis and inflammation(Bozaoglu et al.,2007;Bondue et al.,2011).The chemerin receptors chemokine-like receptor 1(CMKLR1)and G protein-coupled receptor 1(GPR1),play crucial roles in regulating obesity,inflammation,and cancer,highlighting their potential as therapeutic targets(Bozaoglu et al.,2007;Ernst and Sinal,2010;Su et al.,2021).Although both receptors recognize the same ligand,chemerin,and share high sequence identity,they exhibit distinct signaling properties and biological functions(Bozaoglu et al.,2007;De Henau et al.,2016;Fischer et al.,2021).CMKLR1 is the canonical chemerin receptor that mediates both G protein and arrestin signaling,while GPR1 exhibits weak G protein signaling but strong arrestin-dependent and-independent internalization(De Henau et al.,2016;Fig.1A and 1B).The chemerin-CMKLR1 axis regulates lipid and glucose metabolism(Kennedy and Davenport,2018),and is associated with chronic inflammation,obesity,and obesity-related disorders such as insulin resistance and metabolic syndrome,with several compounds and antibodies under preclinical or early clinical investigation(Goralski et al.,2007;Kennedy et al.,2016;Trilleaud et al.,2021).In contrast,the mechanisms of atypical signaling and biological function of GPR1 remain unclear.
基金funded by the National Natural Science Foundation of China(81570764)Guangzhou Science and Technology Project(201807010069)+2 种基金Shenzhen Science and Technology Project(JCYJ20190807154205627)Guangdong Natural Science Fund(2020A1515010365)Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translation Research of Hakka Population(2018B030322003KF01)received by Zhonghan Yang。
文摘Induction of beige fat for thermogenesis is a potential therapy to improve homeostasis against obesity.β3-adrenoceptor(β3-AR),a type of G protein-coupled receptor(GPCR),is believed to mediate the thermogenesis of brown fat in mice.However,β3-AR has low expression in human adipose tissue,precluding its activation as a standalone clinical modality.This study aimed at identifying a potential GPCR target to induce beige fat.We found that chemerin chemokine-like receptor 1(CMKLR1),one of the novel GPCRs,mediated the development of beige fat via its two ligands,chemerin and resolvin E1(RvE1).The RvE1 levels were decreased in the obese mice,and RvE1 treatment led to a substantial improvement in obese features and augmented beige fat markers.Inversely,despite sharing the same receptor as RvE1,the chemerin levels were increased in obesogenic conditions,and chemerin treatment led to an augmented obese phenotype and a decline of beige fat markers.Moreover,RvE1 and chemerin induced or restrained the development of beige fat,respectively,via the mechanistic target of rapamycin complex 1(mTORC1)signaling pathway.We further showed that RvE1 and chemerin regulated mTORC1 signaling differentially by forming hydrogen bonds with different binding sites of CMKLR1.In conclusion,our study showed that RvE1 and chemerin affected metabolic homeostasis differentially,suggesting that selectively modulating CMKLR1 may be a potential therapeutic target for restoring metabolic homeostasis.
