目的探讨压电型机械敏感离子通道元件2(piezoelectric type mechanosensitive ion channel component 2,PIEZO2)对胰腺癌细胞发生发展的影响。方法采用免疫组织化学技术检测胰腺癌与癌旁组织的PIEZO2阳性率;将PIEZO2干扰片段转染到胰腺...目的探讨压电型机械敏感离子通道元件2(piezoelectric type mechanosensitive ion channel component 2,PIEZO2)对胰腺癌细胞发生发展的影响。方法采用免疫组织化学技术检测胰腺癌与癌旁组织的PIEZO2阳性率;将PIEZO2干扰片段转染到胰腺癌细胞Panc-1中,通过实时荧光定量PCR(qPCR)和蛋白免疫印迹(WB)检测PIEZO2的转录水平及蛋白水平。以细胞计数试剂盒-8(Cell Counting Kit-8,CCK8)检测细胞增殖情况,transwell法检测细胞的迁移侵袭能力。通过Illumina HiSeq^(TM)X Ten进行cDNA文库构建并测序,分析干扰PIEZO2后Panc-1细胞内差异基因并通过GO富集分析参与基因富集的相关通路。结果胰腺癌组织中PIEZO2表达水平高于癌旁组织,且高PIEZO2表达的胰腺癌患者总生存率较低。敲减PIEZO2基因后,qPCR和WB结果显示PIEZO2的表达量较对照组减低,差异具有统计学意义。敲减组的增殖、迁移、侵袭能力均低于对照组,且差异具有统计学意义。对两组进行转录组分析发现,两组分别获得15521,15325个基因,与敲减组相比,对照组有3411个差异表达基因(differentially expressed genes,DEGs)上调,2830个DEGs下调,GO富集分析发现DEGs基因主要富集于细胞内解剖结构、细胞连接和细胞外基质。结论敲除PIEZO2可抑制细胞的增殖、迁移和侵袭,PIEZO2通过调控细胞解剖结构、细胞连接和细胞外基质参与胰腺癌的发生发展,靶向PIEZO2将是胰腺癌新的治疗策略。展开更多
Almost every life form,from the tiniest bacterium to humans,is mechanosensitive,implying it can use mechani-cal stresses to trigger certain physiological responses in the form of electric signals.Mechanotransduction l...Almost every life form,from the tiniest bacterium to humans,is mechanosensitive,implying it can use mechani-cal stresses to trigger certain physiological responses in the form of electric signals.Mechanotransduction largely relies on ion channels that respond to mechanical forces,such as the epithelial sodium channels/degenerins,tran-sient receptor potential channel,and the two-pore domain potassium channel.Piezo1 and Piezo2 proteins were discovered to be the biggest non-selective mechanosensitive cation channels in the cell membrane.A substantial amount of research has previously been published on the Piezo channel’s function in touch sensation,balance,and cardiovascular regression.However,the mechanistic perspective must be refined to fully understand the role of Piezo proteins in tissue engineering.This review centers on the latest insights into the structure of Piezo chan-nels,activation mechanisms,and its interactions with cytoskeletal components,by emphasizing the physiological activities of Piezo channels in different tissues.The study also places focus on the possibilities of targeting this cation channel family as a tissue regeneration aid.展开更多
Vincristine,a widely used chemotherapeutic agent for treating different cancer,often induces severe peripheral neuropathic pain.A common symptom of vincristine-induced peripheral neuropathic pain is mechanical allodyn...Vincristine,a widely used chemotherapeutic agent for treating different cancer,often induces severe peripheral neuropathic pain.A common symptom of vincristine-induced peripheral neuropathic pain is mechanical allodynia and hyperalgesia.However,mechanisms underlying vincristine-induced mechanical allodynia and hyperalgesia are not well understood.In the present study,we show with behavioral assessment in rats that vincristine induces mechanical allodynia and hyperalgesia in a PIEZO2 channel-dependent manner since gene knockdown or pharmacological inhibition of PIEZO2 channels alleviates vincristine-induced mechanical hypersensitivity.Electrophysiological results show that vincristine potentiates PIEZO2 rapidly adapting(RA)mechanically-activated(MA)currents in rat dorsal root ganglion(DRG)neurons.We have found that vincristine-induced potentiation of PIEZO2 MA currents is due to the enhancement of static plasma membrane tension(SPMT)of these cells following vincristine treatment.Reducing SPMT of DRG neurons by cytochalasin D(CD),a disruptor of the actin filament,abolishes vincristine-induced potentiation of PIEZO2 MA currents,and suppresses vincristine-induced mechanical hypersensitivity in rats.Collectively,enhancing SPMT and subsequently potentiating PIEZO2 MA currents in primary afferent neurons may be an underlying mechanism responsible for vincristineinduced mechanical allodynia and hyperalgesia in rats.Targeting to inhibit PIEZO2 channels may be an effective analgesic method to attenuate vincristine-induced mechanical hypersensitivity.展开更多
文摘Almost every life form,from the tiniest bacterium to humans,is mechanosensitive,implying it can use mechani-cal stresses to trigger certain physiological responses in the form of electric signals.Mechanotransduction largely relies on ion channels that respond to mechanical forces,such as the epithelial sodium channels/degenerins,tran-sient receptor potential channel,and the two-pore domain potassium channel.Piezo1 and Piezo2 proteins were discovered to be the biggest non-selective mechanosensitive cation channels in the cell membrane.A substantial amount of research has previously been published on the Piezo channel’s function in touch sensation,balance,and cardiovascular regression.However,the mechanistic perspective must be refined to fully understand the role of Piezo proteins in tissue engineering.This review centers on the latest insights into the structure of Piezo chan-nels,activation mechanisms,and its interactions with cytoskeletal components,by emphasizing the physiological activities of Piezo channels in different tissues.The study also places focus on the possibilities of targeting this cation channel family as a tissue regeneration aid.
基金supported by NSFC grant 81571080(Zhanfeng Jia,China),81872848(Wei Zhang,China)the Central Government Guiding Local Funding Project for Scientific and Technological Development 206Z7703G(Zhanfeng Jia,China)+2 种基金Key Project and Cultivation Project of Precision Medicine Joint Fund of Natural Science Foundation of Hebei Province H2021206406(Zhanfeng Jia,China),H2022206211(Wei Zhang,China)and H2020206165(Zhanfeng Jia,China)Science and Technology Project of Hebei Education Department ZD2020107(Zhanfeng Jia,China)Science Fund for Creative Research Groups of Natural Science Foundation of Hebei Province H2020206474,China.
文摘Vincristine,a widely used chemotherapeutic agent for treating different cancer,often induces severe peripheral neuropathic pain.A common symptom of vincristine-induced peripheral neuropathic pain is mechanical allodynia and hyperalgesia.However,mechanisms underlying vincristine-induced mechanical allodynia and hyperalgesia are not well understood.In the present study,we show with behavioral assessment in rats that vincristine induces mechanical allodynia and hyperalgesia in a PIEZO2 channel-dependent manner since gene knockdown or pharmacological inhibition of PIEZO2 channels alleviates vincristine-induced mechanical hypersensitivity.Electrophysiological results show that vincristine potentiates PIEZO2 rapidly adapting(RA)mechanically-activated(MA)currents in rat dorsal root ganglion(DRG)neurons.We have found that vincristine-induced potentiation of PIEZO2 MA currents is due to the enhancement of static plasma membrane tension(SPMT)of these cells following vincristine treatment.Reducing SPMT of DRG neurons by cytochalasin D(CD),a disruptor of the actin filament,abolishes vincristine-induced potentiation of PIEZO2 MA currents,and suppresses vincristine-induced mechanical hypersensitivity in rats.Collectively,enhancing SPMT and subsequently potentiating PIEZO2 MA currents in primary afferent neurons may be an underlying mechanism responsible for vincristineinduced mechanical allodynia and hyperalgesia in rats.Targeting to inhibit PIEZO2 channels may be an effective analgesic method to attenuate vincristine-induced mechanical hypersensitivity.
