CIRBP

该研究首先证实了热疗可以显著降低鼻咽癌（NPC）细胞的干性，而热疗和冬凌草甲素（中药冬凌草的主要活性成分）联合治疗极大增强了对NPC细胞和癌症干细胞（CSC）样细胞的杀伤作用。 以我国南方好发的鼻咽癌（NPC）作为癌症研究对象，南方医科大学肿瘤研究所和附属广东省人民医院、南方医院以及南方科技大学第二附属医院（深圳市第三人民医院）等机构的研究人员在 Journal of Experimental & Clinical Cancer Research 期刊发表了题为：ThermomiR-377-3p-induced suppression of Cirbp expression is required for effective elimination of cancer cells and cancer stem-like cells by hyperthermia 的研究论文。 该研究首次报道了冷诱导RNA结合蛋白（Cirbp）可促进癌细胞DNA损伤修复致使热疗抵抗。ThermomiR-377-3p（热敏miRNA-377-3p）及其靶基因Cirbp是热敏的重要调节因子，有望成为癌症治疗有价值的新靶点。 该研究首先证实了热疗可以显著降低鼻咽癌（NPC）细胞的干性，而热疗和冬凌草甲素（中药冬凌草的主要活性成分）联合治疗极大增强了对NPC细胞和癌症干细胞（CSC）样细胞的杀伤作用。此外，热疗显著提高了放疗抵抗的NPC细胞和CSC样细胞对放疗的敏感性。 研究团队进而发现，热疗显著抑制鼻咽癌（NPC）细胞和裸鼠移植瘤中冷诱导RNA结合蛋白（Cirbp）的表达。Cirbp沉默可大为增强热疗对NPC细胞和CSC样细胞的杀伤作用，而Cirbp过表达作用则相反，提示Cirbp可诱导热疗抵抗。在体外实验中，ThermomiR-377-3p通过直接抑制Cirbp的表达来提高NPC细胞和CSC样细胞对热疗的敏感性。更重要的是，Cirbp沉默明显增强了体内移植瘤对热疗的敏感性，其过表达作用则完全相反。 最后，研究团队从机制上进行了深入分析，结果发现，Cirbp沉默通过使ATM-Chk2和ATR-Chk1通路失活而抑制DNA损伤修复，导致癌细胞干性减少和死亡增加；相反，Cirbp过表达促进癌细胞DNA损伤修复、干性增加以及减少细胞凋亡，从而导致热疗抵抗。 Cirbp介导的对热疗抵抗和敏感信号调控机制 林桃燕、贾俊双、罗伟仁和林晓琳等为该论文的共同第一作者，孙妍、肖东、黄文华和赵冰夏为论文共同通讯作者。该研究工作得到了国家自然科学基金委面上项目、广东省自然科学基金面上项目以及深圳市自然科学基金重点/面上项目等支持。

Researchers have identified the protein that enables mammals to sense cold, filling a long-standing knowledge gap in the field of sensory biology. University of Michigan researchers have identified the protein that enables mammals to sense cold, filling a long-standing knowledge gap in the field of sensory biology. The findings, published in Nature Neuroscience, could help unravel how we sense and suffer from cold temperature in the winter, and why some patients experience cold differently under particular disease conditions. "The field started uncovering these temperature sensors over 20 years ago, with the discovery of a heat-sensing protein called TRPV1," said neuroscientist Shawn Xu, a professor at the U-M Life Sciences Institute and a senior author of the new research. "Various studies have found the proteins that sense hot, warm, even cool temperatures -- but we've been unable to confirm what senses temperatures below about 60 degrees Fahrenheit." In a 2019 study, researchers in Xu's lab discovered the first cold-sensing receptor protein in Caenorhabditis elegans, a species of millimeter-long worms that the lab studies as a model system for understanding sensory responses. Because the gene that encodes the C. elegans protein is evolutionarily conserved across many species, including mice and humans, that finding provided a starting point for verifying the cold sensor in mammals: a protein called GluK2 (short for Glutamate ionotropic receptor kainate type subunit 2). For this latest study, a team of researchers from the Life Sciences Institute and the U-M College of Literature, Science, and the Arts tested their hypothesis in mice that were missing the GluK2 gene, and thus could not produce any GluK2 proteins. Through a series of experiments to test the animals' behavioral reactions to temperature and other mechanical stimuli, the team found that the mice responded normally to hot, warm and cool temperatures, but showed no response to noxious cold. GluK2 is primarily found on neurons in the brain, where it receives chemical signals to facilitate communication between neurons. But it is also expressed in sensory neurons in the peripheral nervous system (outside the brain and spinal cord). "We now know that this protein serves a totally different function in the peripheral nervous system, processing temperature cues instead of chemical signals to sense cold," said Bo Duan, U-M associate professor of molecular, cellular, and developmental biology and co-senior author of the study. While GluK2 is best known for its role in the brain, Xu speculates that this temperature-sensing role may have been one of the protein's original purposes. The GluK2 gene has relatives across the evolutionary tree, going all the way back to single-cell bacteria. "A bacterium has no brain, so why would it evolve a way to receive chemical signals from other neurons? But it would have great need to sense its environment, and perhaps both temperature and chemicals," said Xu, who is also a professor of molecular and integrative physiology at the U-M Medical School. "So I think temperature sensing may be an ancient function, at least for some of these glutamate receptors, that was eventually co-opted as organisms evolved more complex nervous systems." In addition to filling a gap in the temperature-sensing puzzle, Xu believes the new finding could have implications for human health and well-being. Cancer patients receiving chemotherapy, for example, often experience painful reactions to cold. "This discovery of GluK2 as a cold sensor in mammals opens new paths to better understand why humans experience painful reactions to cold, and even perhaps offers a potential therapeutic target for treating that pain in patients whose cold sensation is overstimulated," Xu said. The research was supported by the National Institutes of Health. All procedures performed in mice were approved by the Institutional Animal Care and Use Committee and performed in accordance with the institutional guidelines. Study authors are: Wei Cai, Wenwen Zhang, Chia Chun Hor, Tong Pan, Mahar Fatima, Bo Duan and X.Z. Shawn Xu of the University of Michigan; and Qin Zheng and Xinzhong Dong of the Johns Hopkins University School of Medicine

本文为转化医学网原创，转载请注明出处 作者：Sophia 导读： 近年来，用于癌症治疗的辅助治疗性高热疗法的发展受到了相当大的关注。然而，对高热抵抗的潜在机制仍然知之甚少。在这项研究中，我们研究了冷诱导 RNA 结合蛋白 （Cirbp） 在调节鼻咽癌 （NPC） 热疗抵抗中的作用及其潜在机制。 2024年2月29日，南方医科大学肖东、孙妍、汪佳宏和赵冰夏共同在《Journal of Experimental & Clinical Cancer Research》上发表题为“ThermomiR-377-3p-induced suppression of Cirbp expression is required for effective elimination of cancer cells and cancer stem-like cells by hyperthermia”的研究论文， 充分研究了单独或联合化疗或放疗对鼻咽癌癌细胞和干细胞样癌细胞的直接细胞杀伤活性。另一方面，我们阐明了Cirbp在体外和体内鼻咽癌治疗热疗中的潜在功能，以及热耐性和热敏化的分子机制。 https://jeccr-biomedcentral-com.libproxy1.nus.edu.sg/articles/10.1186/s13046-024-02983-3 研究背景 01 近年来，用于癌症治疗的治疗性热疗的发展受到了相当大的关注。治疗性热疗是一种将肿瘤负载组织的温度升高至 40-43°C的治疗程序，而热疗的生物学原理是基于在高于41-42 °C的热休克温度下对细胞的直接杀伤作用。 由于其无毒副作用、不损伤人体正常组织、不损害自身免疫力等优点，温热疗法已成为继手术、放疗、化疗和免疫疗法之后的第五种癌症治疗途径，在各种癌症的多学科治疗中发挥着越来越重要的作用。然而， 肿瘤细胞对热疗反应的潜在分子机制在很大程度上仍然未知。 在鼻咽癌领域，少量临床试验初步证明，热疗联合放疗可改善鼻咽癌患者的无进展生存期和局部无进展生存期，但未观察到总生存期的增加。然而，与其他实体癌相比 ，鼻咽癌的有效热疗治疗的发展并没有得到相当大的关注。 因此，仍需要深入的研究工作来开发有效的鼻咽癌热疗方法。 研究结果 02 我们的研究结果首先表明，热疗显著减弱了鼻咽癌细胞的干性，而热疗和冬凌草甲素的联合治疗显著提高了对鼻咽癌细胞和癌干细胞（CSC）样群体的杀伤作用。此外，热疗显著提高了抗辐射鼻咽癌细胞和CSC样细胞对放疗的敏感性，显著抑制了鼻咽癌细胞和异种移植肿瘤组织中的Cirbp表达。此外，抑制Cirbp显著增强了热疗对NPC细胞和CSC样细胞的抗肿瘤杀伤活性，而Cirbp的异位表达损害了热疗对这些细胞的肿瘤杀伤作用，表明Cirbp过表达诱导了热疗耐药性。ThermomiR-377-3p 通过直接抑制 Cirbp 表达，提高了 NPC 细胞和 CSC 样细胞在体外对热疗的敏感性。更重要的是，我们的研究结果显示，通过体内 Cirbp 沉默，肿瘤异种移植物对热疗的敏化显著增强，但 Cirbp 的异位表达几乎完全抵消了热疗介导的肿瘤细胞对体内肿瘤异种移植物的杀伤作用。从机制上讲， Cirbp 沉默通过灭活 ATM-Chk2 和 ATR-Chk1 通路抑制 DNA 损伤修复、干性降低和细胞死亡增加有助于热敏化;相反，Cirbp 过表达诱导的 DNA 损伤修复促进、干性增加和细胞凋亡减少有助于热耐药性。 ThermomiR-377-3p 诱导的 Cirbp 表达抑制是通过热疗有效消除癌细胞和癌症干细胞样细胞所必需的。 综上，研究结果揭示了 Cirbp 在正向调节热疗耐药性方面以前未被认识到的作用，并表明 thermomiR-377-3p 及其靶基因 Cirbp 代表了治疗性高热的有前途的靶点。 研究结论 03 总之， 这项工作首次确定了以前未被识别的热疗抵抗机制，即 Cirbp 通过增强癌症中的 DNA 损伤修复来引起热疗抵抗。ThermomiR-377-3p 及其靶基因 Cirbp 是热敏性的重要调节因子，可能代表热疗进一步开发的重要靶点。 参考资料： https://jeccr-biomedcentral-com.libproxy1.nus.edu.sg/articles/10.1186/s13046-024-02983-3 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。 热门·直播/活动 🕓 上海｜3月01日-02日 ▶第三届长三角单细胞组学技术应用论坛暨空间组学前沿论坛将在上海召开，诚邀您的参与！ 点击对应文字 查看详情