The interaction between the lactate receptor GPR81(also known as hydroxycarboxylic acid receptor 1,or HCAR1)and Splicing Factor Proline-and Glutamine-Rich protein promotes the tumor cell malignancy.GPR81 nuclear trans...The interaction between the lactate receptor GPR81(also known as hydroxycarboxylic acid receptor 1,or HCAR1)and Splicing Factor Proline-and Glutamine-Rich protein promotes the tumor cell malignancy.GPR81 nuclear translocation plays an important role in driving cancer progression and could serve as a potential therapeutic target.Yang et al concluded in their study that lactate and its receptor,GPR81,play crucial roles in cancer progression,and are key players in linking the lactate-rich tumor microenvironment to cancer cell behavior.The ability of nuclear GPR81 to directly regulate gene expression,combined with extracellular matrix-mediated mechanical signaling,creates a potentially robust system for the coordinated adaptation and survival of cancer cells.Understanding these interactions could lead to the discovery of new therapeutic targets and improved treatment strategies for cancer.展开更多
BACKGROUND The Warburg effect is common in cancers.Lactate and its receptor GPR81 play an important role in cancer progression.It is widely accepted that membrane receptor nuclear translocation plays some novel role i...BACKGROUND The Warburg effect is common in cancers.Lactate and its receptor GPR81 play an important role in cancer progression.It is widely accepted that membrane receptor nuclear translocation plays some novel role in cancer pathology.The mechanism by which the lactate/GPR81 axis regulates cancer malignancy remains unclear.AIM To elucidate the mechanism of GPR81 nuclear transportation promoted by exogenous lactate.METHODS Lung cancer cells were stimulated with exogenous lactate and GPR81 levels were measured by immunofluoresence and western blot analysis in membrane,cytoplasmic,and nuclear fractions.Lung cancer cells were transduced with a mutant GPR81 nuclear localization signal(NLS)construct,wild type GPR81 or empty vector and used to examine how GPR81 nuclear transportation affects lung cancer cells malignancy in vitro and in vivo.Immunoprecipitation Proteomics analysis and Chromatin immunoprecipitation(ChIP)sequencing were used to determine GPR81 interacting proteins and genes.RESULTS In response to hypoxia/Lactate stimulation,GPR81 translocates and accumulates in the nucleus of lung cancer cells.Functionally,GPR81 nuclear translocation promotes cancer cell proliferation and motility.Depletion of the GPR81 NLS depletes GPR81 nuclear levels and decreases cancer cell growth and invasion in vitro,as well as cancer cell malignancy in vivo.Proteomics analysis revealed a set of proteins including SFPQ,that interact with GPR81 in the cancer cell nucleus.Notably,the interaction of GPR81 with SFPQ promotes cancer cell growth and motility.ChIP sequencing analysis discovered that there is a set of genes targeted by GPR81.CONCLUSION The interaction of GPR81 with SFPQ promotes cancer cell malignancy.GPR81 nuclear translocation is critical in conferring cancer progression and may be a potential therapeutic target for limiting cancer progression.展开更多
In polycrystalline Mg-RE magnesium alloys,the lattice parameter,dislocation dynamics and critical resolved shear stress(CRSS)for various deformation modes are altered with the addition of RE atom,finally affecting def...In polycrystalline Mg-RE magnesium alloys,the lattice parameter,dislocation dynamics and critical resolved shear stress(CRSS)for various deformation modes are altered with the addition of RE atom,finally affecting deformation mode and strain accommodation mechanism among neighboring grains.Uniaxial compression tests were performed on as-extruded AZ81-La Mg alloy samples with the c-axis of the majority of crystals vertical to the compression direction.Twin variants and dominant slip systems were examined by electron backscattered diffraction(EBSD)technique.It is found by in-grain misoriention axis(IGMA)analysis that the plastic deformation is mainly accommodated by a combination of the pyramidal slip and the basal slip.The dominant twin variant is{0112}<0111>and{1102}<1101>.Here,we applied a modified displacement gradient accommodation(m-DGA)method to evaluate the selection mechanism of twin/slip in neighbour grain stimulated by{1012}extension twin.It is found that the activated slip system and/or twin variant in the neighbouring grain is determined by the accommodation of the major shear strain induced by{1012}extension twin in such a way that strain concentration along grain boundaries can be relaxed.展开更多
文摘The interaction between the lactate receptor GPR81(also known as hydroxycarboxylic acid receptor 1,or HCAR1)and Splicing Factor Proline-and Glutamine-Rich protein promotes the tumor cell malignancy.GPR81 nuclear translocation plays an important role in driving cancer progression and could serve as a potential therapeutic target.Yang et al concluded in their study that lactate and its receptor,GPR81,play crucial roles in cancer progression,and are key players in linking the lactate-rich tumor microenvironment to cancer cell behavior.The ability of nuclear GPR81 to directly regulate gene expression,combined with extracellular matrix-mediated mechanical signaling,creates a potentially robust system for the coordinated adaptation and survival of cancer cells.Understanding these interactions could lead to the discovery of new therapeutic targets and improved treatment strategies for cancer.
文摘BACKGROUND The Warburg effect is common in cancers.Lactate and its receptor GPR81 play an important role in cancer progression.It is widely accepted that membrane receptor nuclear translocation plays some novel role in cancer pathology.The mechanism by which the lactate/GPR81 axis regulates cancer malignancy remains unclear.AIM To elucidate the mechanism of GPR81 nuclear transportation promoted by exogenous lactate.METHODS Lung cancer cells were stimulated with exogenous lactate and GPR81 levels were measured by immunofluoresence and western blot analysis in membrane,cytoplasmic,and nuclear fractions.Lung cancer cells were transduced with a mutant GPR81 nuclear localization signal(NLS)construct,wild type GPR81 or empty vector and used to examine how GPR81 nuclear transportation affects lung cancer cells malignancy in vitro and in vivo.Immunoprecipitation Proteomics analysis and Chromatin immunoprecipitation(ChIP)sequencing were used to determine GPR81 interacting proteins and genes.RESULTS In response to hypoxia/Lactate stimulation,GPR81 translocates and accumulates in the nucleus of lung cancer cells.Functionally,GPR81 nuclear translocation promotes cancer cell proliferation and motility.Depletion of the GPR81 NLS depletes GPR81 nuclear levels and decreases cancer cell growth and invasion in vitro,as well as cancer cell malignancy in vivo.Proteomics analysis revealed a set of proteins including SFPQ,that interact with GPR81 in the cancer cell nucleus.Notably,the interaction of GPR81 with SFPQ promotes cancer cell growth and motility.ChIP sequencing analysis discovered that there is a set of genes targeted by GPR81.CONCLUSION The interaction of GPR81 with SFPQ promotes cancer cell malignancy.GPR81 nuclear translocation is critical in conferring cancer progression and may be a potential therapeutic target for limiting cancer progression.
基金Project supported by the National Natural Science Foundation of China(52071139,52075167,U21A20130,U20A20275)the Natural Science Foundation of Hunan(2023JJ30262,2023JJ30252)Natural Science Foundation of Chongqing(CSTB2023NSCQ-MSX0886)。
文摘In polycrystalline Mg-RE magnesium alloys,the lattice parameter,dislocation dynamics and critical resolved shear stress(CRSS)for various deformation modes are altered with the addition of RE atom,finally affecting deformation mode and strain accommodation mechanism among neighboring grains.Uniaxial compression tests were performed on as-extruded AZ81-La Mg alloy samples with the c-axis of the majority of crystals vertical to the compression direction.Twin variants and dominant slip systems were examined by electron backscattered diffraction(EBSD)technique.It is found by in-grain misoriention axis(IGMA)analysis that the plastic deformation is mainly accommodated by a combination of the pyramidal slip and the basal slip.The dominant twin variant is{0112}<0111>and{1102}<1101>.Here,we applied a modified displacement gradient accommodation(m-DGA)method to evaluate the selection mechanism of twin/slip in neighbour grain stimulated by{1012}extension twin.It is found that the activated slip system and/or twin variant in the neighbouring grain is determined by the accommodation of the major shear strain induced by{1012}extension twin in such a way that strain concentration along grain boundaries can be relaxed.
