Contrary to the adult central nervous system,the peripheral nervous system has an intrinsic ability to regenerate that relies on the expression of regenerationassociated genes,such as some kinesin family members.Kines...Contrary to the adult central nervous system,the peripheral nervous system has an intrinsic ability to regenerate that relies on the expression of regenerationassociated genes,such as some kinesin family members.Kinesins contribute to nerve regeneration through the transport of specific cargo,such as proteins and membrane components,from the cell body towards the axon periphery.We show here that KIF4A,associated with neurodevelopmental disorders and previously believed to be only expressed during development,is also expressed in the adult vertebrate nervous system and up-regulated in injured peripheral nervous system cells.KIF4A is detected both in the cell bodies and regrowing axons of injured neurons,consistent with its function as an axonal transporter of cargoes such asβ1-integrin and L1CAM.Our study further demonstrates that KIF4A levels are greatly increased in Schwann cells from injured distal nerve stumps,particularly at a time when they are reprogrammed into an essential proliferative repair phenotype.Moreover,Kif4a m RNA levels were approximately~6-fold higher in proliferative cultured Schwann cells compared with non-proliferative ones.A hypothesized function for Kif4a in Schwann cell proliferation was further confirmed by Kif4a knockdown,as this significantly reduced Schwann cell proliferation in vitro.Our findings show that KIF4A is expressed in adult vertebrate nervous systems and is up-regulated following peripheral injury.The timing of KIF4A up-regulation,its location during regeneration,and its proliferative role,all suggest a dual role for this protein in neuroregeneration that is worth exploring in the future.展开更多
目的 探究驱动蛋白家族成员2A(kinesin family member 2A,KIF2A)对肝癌细胞5-FU耐药的作用及其作用机制。方法 采用浓度梯度递增联合大剂量间断冲击的方法诱导肝癌细胞BEL7402对5-FU耐药,以构建耐药株BEL7402/5-FU。采用慢病毒技术构建K...目的 探究驱动蛋白家族成员2A(kinesin family member 2A,KIF2A)对肝癌细胞5-FU耐药的作用及其作用机制。方法 采用浓度梯度递增联合大剂量间断冲击的方法诱导肝癌细胞BEL7402对5-FU耐药,以构建耐药株BEL7402/5-FU。采用慢病毒技术构建KIF2A沉默的BEL7402/5-FU细胞。用Notch1/Hes1信号通路激动剂丙戊酸(valproic acid,VPA)对KIF2A沉默的BEL7402/5-FU细胞进行干预。用CCK-8实验、蛋白印迹法、免疫荧光、流式细胞术检测细胞活性、细胞凋亡率、KIF2A、cleaved-caspase-3、Notch1和Hes1的蛋白表达。结果 BEL7402/5-FU细胞具有强5-FU耐药性,其IC_(50)为344.2μmol/L,是BEL7402细胞的92倍(IC_(50)=3.730μmol/L)。与BEL7402细胞比较,BEL7402/5-FU细胞中KIF2A蛋白表达明显增加(P<0.001);与si-NC组比较,si-KIF2A组BEL7402/5-FU细胞活性明显下降(P<0.001)、凋亡率和cleaved-caspase-3蛋白表达明显增加(P<0.001),另外Notch1和Hes1蛋白表达明显减少(P<0.001);与si-NC+5-FU组比较,si-KIF2A+5-FU组BEL7402/5-FU细胞活性显著下降(P<0.001)、凋亡率显著增加(P<0.001);与si-KIF2A+5-FU组比较,si-KIF2A+5-FU+VPA组BEL7402/5-FU细胞活性明显提高(P<0.001)、凋亡率显著降低(P<0.001)、Notch1和Hes1蛋白表达量显著增加(P<0.001)。结论 KIF2A的沉默通过抑制Notch1/Hes1信号通路活性减弱BEL7402/5-FU细胞对5-FU的化疗耐药性。展开更多
Hepatocellular carcinoma(HCC)is a highly lethal malignancy with limited treatment options,particularly for patients with advanced stages of the disease.Sorafenib,the standard first-line therapy,faces significant chall...Hepatocellular carcinoma(HCC)is a highly lethal malignancy with limited treatment options,particularly for patients with advanced stages of the disease.Sorafenib,the standard first-line therapy,faces significant challenges due to the development of drug resistance.Yu et al explored the mechanisms by which lncRNA KIF9-AS1 regulates the stemness and sorafenib resistance in HCC using a combination of cell culture,transfection,RNA immunoprecipitation,co-immunoprecipitation,and xenograft tumor models.They demonstrate that N6-methyladenosine-modified long non-coding RNA KIF9-AS1 acts as an oncogene in HCC.This modification involves methyltransferase-like 3 and insulin-like growth factor 2 mRNA-binding protein 1,which play critical roles in regulating KIF9-AS1.Furthermore,KIF9-AS1 stabilizes and upregulates short stature homeobox 2 by promoting its deubiquitination through ubiquitin-specific peptidase 1,thereby enhancing stemness and contributing to sorafenib resistance in HCC cells.These findings provide a theoretical basis for KIF9-AS1 as a diagnostic marker and therapeutic target for HCC,highlighting the need for further investigation into its clinical application potential.展开更多
Morphological alterations in dendritic spines have been linked to changes in functional communication between neurons that affect learning and memory.Kinesin-4 KIF21A helps organize the microtubule-actin network at th...Morphological alterations in dendritic spines have been linked to changes in functional communication between neurons that affect learning and memory.Kinesin-4 KIF21A helps organize the microtubule-actin network at the cell cortex by interacting with KANK1;however,whether KIF21A modulates dendritic structure and function in neurons remains unknown.In this study,we found that KIF21A was distributed in a subset of dendritic spines,and that these KIF21A-positive spines were larger and more structurally plastic than KIF21A-negative spines.Furthermore,the interaction between KIF21A and KANK1 was found to be critical for dendritic spine morphogenesis and synaptic plasticity.Knockdown of either KIF21A or KANK1 inhibited dendritic spine morphogenesis and dendritic branching,and these deficits were fully rescued by coexpressing full-length KIF21A or KANK1,but not by proteins with mutations disrupting direct binding between KIF21A and KANK1 or binding between KANK1 and talin1.Knocking down KIF21A in the hippocampus of rats inhibited the amplitudes of long-term potentiation induced by high-frequency stimulation and negatively impacted the animals’cognitive abilities.Taken together,our findings demonstrate the function of KIF21A in modulating spine morphology and provide insight into its role in synaptic function.展开更多
Background:Kinesin family member 13B(KIF13B),a crucial motor protein,exerts multiple cellular biological functions.However,the implication of KIF13B in metabolic dysfunction-associated fatty liver disease(MAFLD)has no...Background:Kinesin family member 13B(KIF13B),a crucial motor protein,exerts multiple cellular biological functions.However,the implication of KIF13B in metabolic dysfunction-associated fatty liver disease(MAFLD)has not been explored yet.This study aimed to investigate KIF13B’s role and underlying mechanism in MAFLD and proposes it as a potential pharmacological target.Methods:We assessed KIF13B expression in MAFLD patients and rodent models.The roles of Kif13b in lipid metabolism and MAFLD were investigated using whole-body Kif13b knockout mice,hepatocyte-specific Kif13b-deficient mice and hamsters exposed to different diets.The underlying mechanisms by which Kif13bgoverned hepatic lipid homeostasis and MAFLD progression were explored in vitro.Finally,the Kif13b’s impact on atherosclerotic development was studied in the context of MAFLD.Results:KIF13B expression was reduced in patients and murine models with MAFLD.Rodents with global or liver-specific knockout of the Kif13b gene exhibit spontaneous hepatic steatosis,which is further exacerbated by different overnutrition diets.Overexpression of human KIF13B by lentivirus effectively prevented metabolic dysfunction-associated steatohepatitis(MASH)in methionine-choline-deficient diet(MCD)-fed mice.Furthermore,Kif13b deficiency accelerates atherosclerosis in the context of MAFLD.Mechanistically,Kif13b depletion increases hepatic lipid synthesis and impairs mitochondrial oxidative phosphorylation.Further screening reveals that Kif13b interacts with AMP-activated catalytic subunit alpha 1(AMPKα1)to regulate the phosphorylation of AMPKα1,governing mitochondrial homeostasis and suppressing sterol regulatory element binding protein 1(Srebp1)-mediated denovo lipogenesis in the liver.Conclusion:This work establishes a causal relationship between KIF13B deficiency and MAFLD,emphasizing KIF13B as a potential therapeutic target for treating MAFLD.展开更多
Objective:To investigate the biological functions and molecular regulatory mechanisms of kinesin family member 11(KIF11)in colorectal cancer(CRC).Methods:The expression of KIF11 in CRC was examined by qRT⁃PCR and publ...Objective:To investigate the biological functions and molecular regulatory mechanisms of kinesin family member 11(KIF11)in colorectal cancer(CRC).Methods:The expression of KIF11 in CRC was examined by qRT⁃PCR and public databases.Functional assays(CCK⁃8,colony formation,EdU,and Transwell)were employed to evaluate KIF11’s roles in CRC progression.Western blot,RIP⁃qPCR,MeRIP⁃qPCR,and RNA stability assays were performed to elucidate the molecular mechanism of N6⁃methyladenosine(m6A)modification for KIF11.RNA sequencing(RNA⁃seq)and correlation analysis were used to examine the downstream mechanism of KIF11 regulation.Results:KIF11 was highly expressed in CRC and promoted CRC proliferation and migration.Mechanistically,methyltransferase⁃like 3(METTL3)/insulin like growth factor 2 mRNA binding protein 2(IGF2BP2)enhanced KIF11 mRNA stability and expression in an m6A⁃dependent way.Furthermore,by means of the PROM1/PI3K/AKT pathway,KIF11 facilitated the progression of CRC.Conclusion:The m6A modification of KIF11 by METTL3/IGF2BP2 contributes to CRC progression via the PI3K/AKT signaling pathway,highlighting its potential as a prognostic biomarker and therapeutic target.展开更多
In the article“LncRNA PCGEM1 facilitates cervical cancer progression via miR-642a-5p/KIF5B axis”(Oncology Research,2024,Vol 32,No.7,pp.1221-1229.doi:10.32604/or.2024.047454),there were some errors in the content.In ...In the article“LncRNA PCGEM1 facilitates cervical cancer progression via miR-642a-5p/KIF5B axis”(Oncology Research,2024,Vol 32,No.7,pp.1221-1229.doi:10.32604/or.2024.047454),there were some errors in the content.In order to ensure the scientific and rigorous nature of our academic publications,we deleted the incorrect content that is not related to this study,supplemented the details of the method.展开更多
Background Tactile and mechanical pain are crucial to our interaction with the environment,yet the underpinning molecular mechanism is still elusive.Endophilin A2(EndoA2)is an evolutionarily conserved protein that is ...Background Tactile and mechanical pain are crucial to our interaction with the environment,yet the underpinning molecular mechanism is still elusive.Endophilin A2(EndoA2)is an evolutionarily conserved protein that is documented in the endocytosis pathway.However,the role of EndoA2 in the regulation of mechanical sensitivity and its underlying mechanisms are currently unclear.Methods Male and female C57BL/6 mice(8–12 weeks)and male cynomolgus monkeys(7–10 years old)were used in our experiments.Nerve injury-,inflammatory-,and chemotherapy-induced pathological pain models were established for this study.Behavioral tests of touch,mechanical pain,heat pain,and cold pain were performed in mice and nonhuman primates.Western blotting,immunostaining,co-immunoprecipitation,proximity ligation and patch-clamp recordings were performed to gain insight into the mechanisms.Results The results showed that EndoA2 was primarily distributed in neurofilament-200-positive(NF200+)medium-to-large diameter dorsal root ganglion(DRG)neurons of mice and humans.Loss of EndoA2 in mouse NF200+DRG neurons selectively impaired the tactile and mechanical allodynia.Furthermore,EndoA2 interacted with the mechanically sensitive ion channel Piezo2 and promoted the membrane trafficking of Piezo2 in DRG neurons.Moreover,as an adaptor protein,EndoA2 also bound to kinesin family member 5B(KIF5B),which was involved in the EndoA2-mediated membrane trafficking process of Piezo2.Loss of EndoA2 in mouse DRG neurons damaged Piezo2-mediated rapidly adapting mechanically activated currents,and re-expression of EndoA2 rescued the MA currents.In addition,interference with EndoA2 also suppressed touch sensitivity and mechanical hypersensitivity in nonhuman primates.Conclusions Our data reveal that the KIF5B/EndoA2/Piezo2 complex is essential for Piezo2 trafficking and for sustaining transmission of touch and mechanical hypersensitivity signals.EndoA2 regulates touch and mechanical allodynia via kinesin-mediated Piezo2 trafficking in sensory neurons.Our findings identify a potential new target for the treatment of mechanical pain.展开更多
近年来,探究KIFs家族成员在肿瘤发生和发展过程中的功能及作用机制已成为研究热点之一。驱动蛋白超家族包含一类保守的微管依赖性分子运动蛋白,具有腺苷三磷酸酶活性和运动特性。驱动蛋白的主动运动支持多种细胞功能,包括有丝分裂、减...近年来,探究KIFs家族成员在肿瘤发生和发展过程中的功能及作用机制已成为研究热点之一。驱动蛋白超家族包含一类保守的微管依赖性分子运动蛋白,具有腺苷三磷酸酶活性和运动特性。驱动蛋白的主动运动支持多种细胞功能,包括有丝分裂、减数分裂和大分子的转运。有丝分裂是真核细胞分裂的过程,涉及将细胞核、细胞质、细胞器和细胞膜分裂成2个子细胞,这些子细胞成分的部分大致相同。这个过程中的任何错误都可能导致细胞死亡、异常(如基因缺失、染色体易位或重复)和癌症。由于有丝分裂复杂且高度调节,驱动蛋白表达或功能的改变可能导致癌变。此外,由于人类癌症是一种涉及异常细胞生长的基因相关疾病,因此靶向驱动蛋白可能会为控制人类癌症创造一种新的策略。KIF18B属于驱动蛋白家族-8,近年来已经发现部分功能并证明其与多种恶性肿瘤有关。In recent years, investigating the functions and underlying mechanisms of KIFs family members in tumorigenesis and tumor development has emerged as a prominent research area. The kinesin superfamily consists of a group of conserved microtubule-dependent molecular motor proteins, which possess adenosine triphosphatase activity and motility properties. The active motility of kinesins is crucial for supporting diverse cellular functions, such as mitosis, meiosis, and macromolecular transport. Mitosis, the process of eukaryotic cell division, involves the partitioning of the nucleus, cytoplasm, organelles, and cell membrane into two daughter cells with approximately identical components. Any aberration during this process can give rise to cell death, genetic anomalies (e.g., gene deletions, chromosomal translocations, or duplications), and cancer. Given the complexity and highly regulated nature of mitosis, changes in kinesin expression or function may trigger carcinogenesis. Moreover, as human cancer is a gene-related disorder characterized by abnormal cell growth, targeting kinesins could potentially offer a novel strategy for cancer control. KIF18B belongs to the kinesin family-8. In recent years, certain functions of KIF18B have been identified, and it has been demonstrated to be associated with various malignant tumors.展开更多
基金supported by the Portuguese Foundation for Science and Technology(FCT),Centro 2020 and Portugol2020 and the EU FEDER program,via the project GoBack to SIV(PTDC/CVT-CVT/32261/2017,CENTRO-01-0145-FEDER-032261)the doctoral grants of PDC(SFRH/BD/139974/2018)and BMS(2020.06525.BD and DOI 10.54499/2020.06525.BD)+5 种基金the post-doctoral grant to JPF(SFRH/BPD/113359/2015-program-contract described in paragraphs 4,5,6 of art.23 of Law no.100157/2016,of August 29,as amended by Law no.57/2017 of July 2019),the project PTDC/MED-NEU/1677/2021 to JBRthe Institute of Biomedicine iBiMED(UIDB/04501/2020 and DOI 10.54499/UIDB/04501/2020,UIDP/04501/2020 and DOI 10.54499/UIDP/04501/2020)its LiM Bioimaging Facility-a PPBI node(POCI-01-0145-FEDER-022122)supported by the Research Commission of the Medical Faculty of the Heinrich-Heine-University(HHU)Düsseldorf,of the Biologisch-Medizinisches Forschungszentrum(BMFZ)of HHUfinanced by the Spanish"Plan Nacional de Investigacion Cientifica,Desarrollo e Innovacion Tecnologica,Ministerio de Economia y Competitividad(Instituto de Salud CarlosⅢ)",co-financed by the European Union(FEDER program),(grant FIS P/20/00318 and FIS P23/00337 to VC)grant CPP2021-009070 to VC by the"Proyectos de colaboracion publico-privada,Plan de Investigacion Cientifica,Tecnica y de inovacion 2021-2023,Ministerio de Ciencia e Innovacion,Union Europea,Agencia Estatal de Investigacion,Espana"。
文摘Contrary to the adult central nervous system,the peripheral nervous system has an intrinsic ability to regenerate that relies on the expression of regenerationassociated genes,such as some kinesin family members.Kinesins contribute to nerve regeneration through the transport of specific cargo,such as proteins and membrane components,from the cell body towards the axon periphery.We show here that KIF4A,associated with neurodevelopmental disorders and previously believed to be only expressed during development,is also expressed in the adult vertebrate nervous system and up-regulated in injured peripheral nervous system cells.KIF4A is detected both in the cell bodies and regrowing axons of injured neurons,consistent with its function as an axonal transporter of cargoes such asβ1-integrin and L1CAM.Our study further demonstrates that KIF4A levels are greatly increased in Schwann cells from injured distal nerve stumps,particularly at a time when they are reprogrammed into an essential proliferative repair phenotype.Moreover,Kif4a m RNA levels were approximately~6-fold higher in proliferative cultured Schwann cells compared with non-proliferative ones.A hypothesized function for Kif4a in Schwann cell proliferation was further confirmed by Kif4a knockdown,as this significantly reduced Schwann cell proliferation in vitro.Our findings show that KIF4A is expressed in adult vertebrate nervous systems and is up-regulated following peripheral injury.The timing of KIF4A up-regulation,its location during regeneration,and its proliferative role,all suggest a dual role for this protein in neuroregeneration that is worth exploring in the future.
文摘目的 探究驱动蛋白家族成员2A(kinesin family member 2A,KIF2A)对肝癌细胞5-FU耐药的作用及其作用机制。方法 采用浓度梯度递增联合大剂量间断冲击的方法诱导肝癌细胞BEL7402对5-FU耐药,以构建耐药株BEL7402/5-FU。采用慢病毒技术构建KIF2A沉默的BEL7402/5-FU细胞。用Notch1/Hes1信号通路激动剂丙戊酸(valproic acid,VPA)对KIF2A沉默的BEL7402/5-FU细胞进行干预。用CCK-8实验、蛋白印迹法、免疫荧光、流式细胞术检测细胞活性、细胞凋亡率、KIF2A、cleaved-caspase-3、Notch1和Hes1的蛋白表达。结果 BEL7402/5-FU细胞具有强5-FU耐药性,其IC_(50)为344.2μmol/L,是BEL7402细胞的92倍(IC_(50)=3.730μmol/L)。与BEL7402细胞比较,BEL7402/5-FU细胞中KIF2A蛋白表达明显增加(P<0.001);与si-NC组比较,si-KIF2A组BEL7402/5-FU细胞活性明显下降(P<0.001)、凋亡率和cleaved-caspase-3蛋白表达明显增加(P<0.001),另外Notch1和Hes1蛋白表达明显减少(P<0.001);与si-NC+5-FU组比较,si-KIF2A+5-FU组BEL7402/5-FU细胞活性显著下降(P<0.001)、凋亡率显著增加(P<0.001);与si-KIF2A+5-FU组比较,si-KIF2A+5-FU+VPA组BEL7402/5-FU细胞活性明显提高(P<0.001)、凋亡率显著降低(P<0.001)、Notch1和Hes1蛋白表达量显著增加(P<0.001)。结论 KIF2A的沉默通过抑制Notch1/Hes1信号通路活性减弱BEL7402/5-FU细胞对5-FU的化疗耐药性。
基金Supported by National Natural Science Foundation of China,No.82405223Yunling Scholars Program,No.XDYC-YLXZ-2022-0027.
文摘Hepatocellular carcinoma(HCC)is a highly lethal malignancy with limited treatment options,particularly for patients with advanced stages of the disease.Sorafenib,the standard first-line therapy,faces significant challenges due to the development of drug resistance.Yu et al explored the mechanisms by which lncRNA KIF9-AS1 regulates the stemness and sorafenib resistance in HCC using a combination of cell culture,transfection,RNA immunoprecipitation,co-immunoprecipitation,and xenograft tumor models.They demonstrate that N6-methyladenosine-modified long non-coding RNA KIF9-AS1 acts as an oncogene in HCC.This modification involves methyltransferase-like 3 and insulin-like growth factor 2 mRNA-binding protein 1,which play critical roles in regulating KIF9-AS1.Furthermore,KIF9-AS1 stabilizes and upregulates short stature homeobox 2 by promoting its deubiquitination through ubiquitin-specific peptidase 1,thereby enhancing stemness and contributing to sorafenib resistance in HCC cells.These findings provide a theoretical basis for KIF9-AS1 as a diagnostic marker and therapeutic target for HCC,highlighting the need for further investigation into its clinical application potential.
基金supported by the National Key Research and Development Program of China,No.2021ZD0202503(to AHT)the National Natural Science Foundation of China,Nos.31872759(to AHT)and 32070707(to CF)+1 种基金Shenzhen Science and Technology Program,No.RCJC20210609104333007(to ZW)Shenzhen-Hong Kong Institute of Brain Science,Shenzhen Fundamental Research Institutions,No.2021SHIBS0002(to ZW).
文摘Morphological alterations in dendritic spines have been linked to changes in functional communication between neurons that affect learning and memory.Kinesin-4 KIF21A helps organize the microtubule-actin network at the cell cortex by interacting with KANK1;however,whether KIF21A modulates dendritic structure and function in neurons remains unknown.In this study,we found that KIF21A was distributed in a subset of dendritic spines,and that these KIF21A-positive spines were larger and more structurally plastic than KIF21A-negative spines.Furthermore,the interaction between KIF21A and KANK1 was found to be critical for dendritic spine morphogenesis and synaptic plasticity.Knockdown of either KIF21A or KANK1 inhibited dendritic spine morphogenesis and dendritic branching,and these deficits were fully rescued by coexpressing full-length KIF21A or KANK1,but not by proteins with mutations disrupting direct binding between KIF21A and KANK1 or binding between KANK1 and talin1.Knocking down KIF21A in the hippocampus of rats inhibited the amplitudes of long-term potentiation induced by high-frequency stimulation and negatively impacted the animals’cognitive abilities.Taken together,our findings demonstrate the function of KIF21A in modulating spine morphology and provide insight into its role in synaptic function.
基金supported by the National Natural Science Foundation of China(82270479,82070460)the Beijing Natural Science Foundation(7242084 to Xun-De Xian)the National Key Research and Development Program of China from the Ministry of Science and Technology(2021YFF0702802 to Yu-Hui Wang).
文摘Background:Kinesin family member 13B(KIF13B),a crucial motor protein,exerts multiple cellular biological functions.However,the implication of KIF13B in metabolic dysfunction-associated fatty liver disease(MAFLD)has not been explored yet.This study aimed to investigate KIF13B’s role and underlying mechanism in MAFLD and proposes it as a potential pharmacological target.Methods:We assessed KIF13B expression in MAFLD patients and rodent models.The roles of Kif13b in lipid metabolism and MAFLD were investigated using whole-body Kif13b knockout mice,hepatocyte-specific Kif13b-deficient mice and hamsters exposed to different diets.The underlying mechanisms by which Kif13bgoverned hepatic lipid homeostasis and MAFLD progression were explored in vitro.Finally,the Kif13b’s impact on atherosclerotic development was studied in the context of MAFLD.Results:KIF13B expression was reduced in patients and murine models with MAFLD.Rodents with global or liver-specific knockout of the Kif13b gene exhibit spontaneous hepatic steatosis,which is further exacerbated by different overnutrition diets.Overexpression of human KIF13B by lentivirus effectively prevented metabolic dysfunction-associated steatohepatitis(MASH)in methionine-choline-deficient diet(MCD)-fed mice.Furthermore,Kif13b deficiency accelerates atherosclerosis in the context of MAFLD.Mechanistically,Kif13b depletion increases hepatic lipid synthesis and impairs mitochondrial oxidative phosphorylation.Further screening reveals that Kif13b interacts with AMP-activated catalytic subunit alpha 1(AMPKα1)to regulate the phosphorylation of AMPKα1,governing mitochondrial homeostasis and suppressing sterol regulatory element binding protein 1(Srebp1)-mediated denovo lipogenesis in the liver.Conclusion:This work establishes a causal relationship between KIF13B deficiency and MAFLD,emphasizing KIF13B as a potential therapeutic target for treating MAFLD.
基金江苏省卫生健康委员会医学科研重点项目(K2023024)789 Outstanding Talent Program of SAHNMU(789ZYRC202090147)。
文摘Objective:To investigate the biological functions and molecular regulatory mechanisms of kinesin family member 11(KIF11)in colorectal cancer(CRC).Methods:The expression of KIF11 in CRC was examined by qRT⁃PCR and public databases.Functional assays(CCK⁃8,colony formation,EdU,and Transwell)were employed to evaluate KIF11’s roles in CRC progression.Western blot,RIP⁃qPCR,MeRIP⁃qPCR,and RNA stability assays were performed to elucidate the molecular mechanism of N6⁃methyladenosine(m6A)modification for KIF11.RNA sequencing(RNA⁃seq)and correlation analysis were used to examine the downstream mechanism of KIF11 regulation.Results:KIF11 was highly expressed in CRC and promoted CRC proliferation and migration.Mechanistically,methyltransferase⁃like 3(METTL3)/insulin like growth factor 2 mRNA binding protein 2(IGF2BP2)enhanced KIF11 mRNA stability and expression in an m6A⁃dependent way.Furthermore,by means of the PROM1/PI3K/AKT pathway,KIF11 facilitated the progression of CRC.Conclusion:The m6A modification of KIF11 by METTL3/IGF2BP2 contributes to CRC progression via the PI3K/AKT signaling pathway,highlighting its potential as a prognostic biomarker and therapeutic target.
文摘In the article“LncRNA PCGEM1 facilitates cervical cancer progression via miR-642a-5p/KIF5B axis”(Oncology Research,2024,Vol 32,No.7,pp.1221-1229.doi:10.32604/or.2024.047454),there were some errors in the content.In order to ensure the scientific and rigorous nature of our academic publications,we deleted the incorrect content that is not related to this study,supplemented the details of the method.
基金National Natural Science Foundation of China(82271241 and 82001172 to XLZ,81801112 to MXX)Guangdong Basic and Applied Basic Research Foundation(2022A1515012389 to MXX,2022A1515012543 to RCL)+2 种基金Young Talent Support Project of Guangzhou Association for Science and Technology(QT20220101169 to XLZ)Excellent Young Talents Project of Guangdong Provincial People’s Hospital,Guangdong Academy of Medical Sciences(KY012021188 to XLZ)Science and Technology Projects in Guangzhou(202201010792 to RCL)。
文摘Background Tactile and mechanical pain are crucial to our interaction with the environment,yet the underpinning molecular mechanism is still elusive.Endophilin A2(EndoA2)is an evolutionarily conserved protein that is documented in the endocytosis pathway.However,the role of EndoA2 in the regulation of mechanical sensitivity and its underlying mechanisms are currently unclear.Methods Male and female C57BL/6 mice(8–12 weeks)and male cynomolgus monkeys(7–10 years old)were used in our experiments.Nerve injury-,inflammatory-,and chemotherapy-induced pathological pain models were established for this study.Behavioral tests of touch,mechanical pain,heat pain,and cold pain were performed in mice and nonhuman primates.Western blotting,immunostaining,co-immunoprecipitation,proximity ligation and patch-clamp recordings were performed to gain insight into the mechanisms.Results The results showed that EndoA2 was primarily distributed in neurofilament-200-positive(NF200+)medium-to-large diameter dorsal root ganglion(DRG)neurons of mice and humans.Loss of EndoA2 in mouse NF200+DRG neurons selectively impaired the tactile and mechanical allodynia.Furthermore,EndoA2 interacted with the mechanically sensitive ion channel Piezo2 and promoted the membrane trafficking of Piezo2 in DRG neurons.Moreover,as an adaptor protein,EndoA2 also bound to kinesin family member 5B(KIF5B),which was involved in the EndoA2-mediated membrane trafficking process of Piezo2.Loss of EndoA2 in mouse DRG neurons damaged Piezo2-mediated rapidly adapting mechanically activated currents,and re-expression of EndoA2 rescued the MA currents.In addition,interference with EndoA2 also suppressed touch sensitivity and mechanical hypersensitivity in nonhuman primates.Conclusions Our data reveal that the KIF5B/EndoA2/Piezo2 complex is essential for Piezo2 trafficking and for sustaining transmission of touch and mechanical hypersensitivity signals.EndoA2 regulates touch and mechanical allodynia via kinesin-mediated Piezo2 trafficking in sensory neurons.Our findings identify a potential new target for the treatment of mechanical pain.
文摘近年来,探究KIFs家族成员在肿瘤发生和发展过程中的功能及作用机制已成为研究热点之一。驱动蛋白超家族包含一类保守的微管依赖性分子运动蛋白,具有腺苷三磷酸酶活性和运动特性。驱动蛋白的主动运动支持多种细胞功能,包括有丝分裂、减数分裂和大分子的转运。有丝分裂是真核细胞分裂的过程,涉及将细胞核、细胞质、细胞器和细胞膜分裂成2个子细胞,这些子细胞成分的部分大致相同。这个过程中的任何错误都可能导致细胞死亡、异常(如基因缺失、染色体易位或重复)和癌症。由于有丝分裂复杂且高度调节,驱动蛋白表达或功能的改变可能导致癌变。此外,由于人类癌症是一种涉及异常细胞生长的基因相关疾病,因此靶向驱动蛋白可能会为控制人类癌症创造一种新的策略。KIF18B属于驱动蛋白家族-8,近年来已经发现部分功能并证明其与多种恶性肿瘤有关。In recent years, investigating the functions and underlying mechanisms of KIFs family members in tumorigenesis and tumor development has emerged as a prominent research area. The kinesin superfamily consists of a group of conserved microtubule-dependent molecular motor proteins, which possess adenosine triphosphatase activity and motility properties. The active motility of kinesins is crucial for supporting diverse cellular functions, such as mitosis, meiosis, and macromolecular transport. Mitosis, the process of eukaryotic cell division, involves the partitioning of the nucleus, cytoplasm, organelles, and cell membrane into two daughter cells with approximately identical components. Any aberration during this process can give rise to cell death, genetic anomalies (e.g., gene deletions, chromosomal translocations, or duplications), and cancer. Given the complexity and highly regulated nature of mitosis, changes in kinesin expression or function may trigger carcinogenesis. Moreover, as human cancer is a gene-related disorder characterized by abnormal cell growth, targeting kinesins could potentially offer a novel strategy for cancer control. KIF18B belongs to the kinesin family-8. In recent years, certain functions of KIF18B have been identified, and it has been demonstrated to be associated with various malignant tumors.
