TCF7L2

本文为转化医学网原创，转载请注明出处 作者：Sophia 导读： 化疗耐药性是胃癌（GC）治疗失败的主要原因。异质核糖核蛋白 A2B1 （hnRNPA2B1） 是一种 N6-甲基腺苷 （m6A） 结合蛋白，参与多种癌症。然而，m6A 修饰和 hnRNPA2B1 是否在 GC 化疗耐药中发挥作用在很大程度上是未知的。 2024年3月21日，空军军医大学（第四军医大学）樊代明院士、赵晓迪副教授、卢瑗瑗副教授共同通讯在《Cancer Communications》上发表题为“N6-methyladenosine reader hnRNPA2B1 recognizes and stabilizes NEAT1 to confer chemoresistance in gastric cancer”的研究论文，我们的研究结果表明， hnRNPA2B1 与 lncRNA NEAT1 相互作用并稳定 lncRNA NEAT1，这有助于通过 Wnt/β-catenin 途径维持干性并加剧 GC 的化疗耐药性。 https://onlinelibrary-wiley-com.libproxy1.nus.edu.sg/doi/full/10.1002/cac2.12534 研究背景 01 胃癌（GC）是全球第五大常见恶性肿瘤，也是癌症相关死亡的第四大原因。化疗是GC临床治疗的基本手段和支柱，可显著缩小肿瘤大小，改善转移性GC患者的无进展生存期（PFS）和总生存期（OS）。然而，内在和获得性耐药会阻碍化疗的疗效，并在疾病进展中起至关重要的作用，导致 5 年操作系统低于 10%。因此， 了解癌细胞如何抵抗化疗诱导的细胞死亡非常重要。 N6-甲基腺苷（m6A）是真核RNA中最普遍的修饰，与多种生理过程有关，包括耐药性。m6A RNA修饰过程受写入器、橡皮擦和读取器的动态相互作用调节。异质核糖核蛋白 A2B1 （hnRNPA2B1）是一种m6A读取器，是多种恶性行为的关键参与者，包括肿瘤发生、血管生成、转移和化疗耐药。我们之前已经发现长链非编码RNA（lncRNA）MIR100HG与hnRNPA2B1相互作用，促进转录因子7样2（TCF7L2）的mRNA稳定性，这有助于结直肠癌（CRC）的西妥昔单抗耐药性和转移。然而， hnRNPA2B1在GC中的研究还很差，其详细的生物学功能和相应的分子机制，特别是在GC的耐药性方面，仍有待研究。 核富集丰本 1（NEAT1）是一种广泛表达的 lncRNA，参与多种生理和病理过程，例如免疫反应、病毒感染、肿瘤发生和神经退行性疾病。NEAT1 通过与 RNA 结合蛋白（RBP）、募集转录因子或作为竞争性内源性 RNA 来改变靶基因表达，从而调节基因表达，从而驱动肿瘤的发生和进展。消化系统癌中 NEAT1 的上调与肿瘤大小、TNM 分期、远处转移和不良预后显著相关。然而， hnRNPA2B1 和 NEAT1 之间的关系仍有待进一步研究。 Wnt/β-catenin通路是参与胚胎发育、组织稳态和细胞增殖的关键信号级联反应。研究表明，Wnt/β-catenin 通路的异常激活有助于 GC 的肿瘤发生、进展和转移。这种失调导致癌细胞内的干性特性增加，其特征是自我更新能力和分化潜力。然而， hnRNPA2B1是否与Wnt/β-catenin通路和干性特性有关，需要进一步探索。 研究结果 02 本研究，我们在GC细胞和组织中发现hnRNPA2B1的表达升高，特别是在多重耐药（MDR）GC细胞系中。hnRNPA2B1 的表达与 GC 患者的不良结局相关，尤其是在接受 5-氟尿嘧啶治疗的患者中。沉默 hnRNPA2B1 通过抑制细胞增殖和诱导体外和体内凋亡，有效地使 GC 细胞对化疗敏感。在机制上， hnRNPA2B1 以 m6A 依赖性方式与长链非编码 RNA NEAT1 相互作用并稳定。 此外， hnRNPA2B1 和 NEAT1 共同通过 Wnt/β-catenin 信号通路增强 GC 细胞的干性特性。在接受化疗的GC患者的临床标本中，与应答者相比，无反应者hnRNPA2B1、NEAT1、CD133和CD44的表达水平显著升高。 总之，本研究已将 hnRNPA2B1/NEAT1/Wnt 通路确定为癌症干性的新型上游调节因子，为癌症中癌细胞干性的失调提供了见解（图 9）。 hnRNPA2B1介导的NEAT1表达调节对GC化疗耐药性影响的模型 研究结论 03 本研究探讨了hnRNPA2B1在GC化疗耐药中的潜在作用和机制。 我们发现 GC 中 hnRNPA2B1 的上调与不良的临床结果有关，并且 hnRNPA2B1 可以通过与 NEAT1 相互作用并以 m6A 依赖性方式增加其稳定性来诱导化疗耐药性。此外，hnRNPA2B1 和 NEAT1 通过 Wnt/β-catenin 途径协同增强干性特性并加剧化疗耐药性。 本研究表明，癌症干性相关hnRNPA2B1/NEAT1轴可能代表了GC化疗耐药的新机制。靶向该轴可能为化疗耐药性GC提供一种新颖有效的治疗策略。 参考资料： https://onlinelibrary-wiley-com.libproxy1.nus.edu.sg/doi/full/10.1002/cac2.12534 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｜06月14日-16日 ▶ 第六届上海国际癌症大会将于6月14-16日在上海举办，学科交叉，共同推进肿瘤研究与诊治多模态！ 🕓 北京｜09月20日-21日 ▶ 第五届单细胞技术应用研讨会暨空间组学前沿研讨会欢迎您的参与！ 点击对应文字 查看详情

语言是人类沟通传递关于世界信息的重要方式，也是知识传承的重要载体。有一种观点认为语言的灵活运用赋予了智人强大的力量，从众多人种中脱颖而出【1】。 语言是人类沟通传递关于世界信息的重要方式，也是知识传承的重要载体。有一种观点认为语言的灵活运用赋予了智人强大的力量，从众多人种中脱颖而出【1】。从20世纪60年代，一些科学家猜测人类拥有复杂的语言能力是否和基因有很大的关系【2】；在20世纪90年代，在英国发现有一个叫“KE家族”的家庭，该家族中大约有一半的成员存在语言功能障碍，他们不能很好的组织理解语言和运用语法【3】，这说明人类的语言障碍是可以遗传的。2001年Lai等人，确定了该家族成员中FXOP2基因的一个R553H的点突变造成了该家族成员语言功能的紊乱【4】，这暗示着诚如人类复杂的语言也可以由单基因来控制。随后一系列的研究围绕着FOXP2调控的基因展开，如SPRX2,MEF2C,CNTNAP2等。是否存在其他不同于FOXP2的基因同样也调控人类着语言的功能？ 将病人中FOXP2 R553H点突变引入小鼠中，不但损害了幼年小鼠的发声，也影响成年小鼠的发声交流【5】；而将人源版本的FOXP2引入小鼠中，增加了小鼠发声音节的复杂度【6】。这说明可以通过研究小鼠发声在一定程度上来理解人类语言的分子机制。 最近，Molecular Psychiatry杂志发表了清华大学医学院贾怡昌教授课题组题为 TCF7L2 acts as a molecular switch in midbrain to control mammal vocalization through its DNA binding domain but not transcription activation domain 的研究论文。该研究揭示了调控小鼠发声的分子机制。 研究人员首先通过正向遗传学筛选，确定Tcf7l2基因的点突变损害了幼年小鼠的发声。进一步，研究人员用发情的雌鼠来诱导野生型和Y337H点突变的成年雄鼠发声，发现突变小鼠与雌鼠的交流明显减少，发出音节的复杂度也降低了，并且影响了不同音节之间的转换，突变小鼠发出的声音序列更容易被中断。随后，作者通过立体定位注射的方法，发现TCF7L2在控制发声的关键脑区PAG (periaqueductal gray) 起作用,失去Tcf7l2造成了PAG脑区神经元不正常的突触传递。更进一步，研究人员发现Tcf7l2含有β-catenin结合位点和不含β-catenin结合位点的转录本对发声均是必须的，结合双荧光素酶报告实验，表明Tcf7l2的转录抑制活性对小鼠正常发声是至关重要的。将自闭症病人的Tcf7l2的两个点突变引入小鼠，同样造成小鼠严重的发声障碍。而含有Tcf7l2点突变的病人也被报道表现出语言发育的延迟。这些数据暗示Tcf7l2可能和人类自闭症和语言障碍有一定的联系。 图2 Tcf7l2调控小鼠发声的模式图 综上所述，该研究揭示了调控小鼠发声的关键基因以及其可能的调控机制。该研究有助于科学家们深入理解Tcf7l2在神经系统中的新功能，为理解人类语言和其相关疾病的发声机制提供了分子遗传的理论基础。 原文链接： https://www-nature-com.libproxy1.nus.edu.sg/articles/s41380-023-01993-5

A growing body of research suggests that the disease may also flow from defects in glia, important support cells found in the brain. The new study expands our understanding of the underlying mechanisms of the disease, and reinforces the potential of therapies that target glia cells. Huntington's disease -- a hereditary and fatal genetic disorder -- has long been considered a neuronal disease due to the permanent loss of medium spiny motor neurons, the death of which over time is responsible for the clinical hallmarks of the disease: involuntary movements, problems with coordination, cognitive decline, depression, and psychosis. However, a growing body of research, including a new study appearing in the journal Cell Reports, suggests that the disease may also flow from defects in glia, important support cells found in the brain. The new study expands our understanding of the underlying mechanisms of the disease, and reinforces the potential of therapies that target glia cells. Years of research in the lab of University of Rochester Medical Center (URMC) neurologist Steve Goldman, M.D., Ph.D., have shown that the two populations of glia found in the brain -- astrocytes and oligodendrocytes -- are dysfunctional in Huntington's disease, and may trigger much of the neuronal pathology seen in the disease. Goldman is co-director of the URMC Center for Translational Neuromedicine and senior author of the new study. Glia cells play a critical role in maintaining the health of neurons and facilitating the chemical signaling between nerve cells. In Huntington's, glia are unable to perform these functions, leading to a breakdown in communication between neurons and, over time, cell death. "Huntington's is a complex disease that impacts both neurons and support cells. To use an analogy, not only is the patient sick, but so are the doctor and the nurse," said Abdellatif Benraiss, Ph.D., a research associate professor in the URCM Department of Neurology and first author of the study. "While the loss of neurons gives rise to the symptoms and the ultimate fatal nature of the disease, reversing glial dysfunction may give us an opportunity to intervene early in the course of the disease, keeping neurons healthy for longer and slowing disease progression." The new study focuses on oligodendrocytes and identifies how the suppression of a specific transcription gene called Tcf7l2 triggers a series of changes that impair the function of oligodendrocyte progenitor cells (OPCs). These cells constantly resupply the brain with oligodendrocytes, which, in turn, refresh the myelin insulation that helps signals travel in the brain more crisply. In Huntington's, OPCs are not able to meet demand, leading to deficient myelination in the brain, which can be observed in Huntington's patients in the form of white matter atrophy. When the researchers overexpressed Tcf7l2 in mice with the Huntington's disease mutation, their OPCs recovered and restored the myelin that had been lost to the disease. A sister paper from the Goldman lab, which appeared in Cell Reports last year, examined how the genetic defect that lies at the heart of the disease impacts the development and function of astrocytes, which support neurons and their synaptic connections. That paper highlighted genetic pathways aligned with Tcf7l2, found in both mouse and human Huntington's astrocytes, that is a major contributor to synaptic dysfunction in Huntington's, which in turn leads to the behavioral and psychiatric symptoms of the disease. Taken together, these papers provide a clearer picture of the genetic mechanisms by which Huntington's disease impairs glial cell function and ultimately leads to neurological disability, while providing new cellular and molecular targets for potential treatment. The researchers believe that these findings put new therapies within reach. Replacing or "fixing" defective glia cells may prove a far easier proposition than replenishing neurons lost in the disease. A study from Goldman's lab in 2018 showed the complexity of the genetic defects in Huntington's glia, and pointed to the utility of swapping out sick cells with healthy ones, an approach that the lab had shown effective in mouse models of the disease in an earlier study in 2016. Taken together, this series of studies has laid the foundation for targeting glial cells for treatment, and potentially outright replacement, in Huntington disease. Additional authors of the study include John Mariani, Ashley Tate, Pernille Madsen, Kathleen Clark, Kevin Welle, Renee Solly, Laetitian Capellano, Karen Bentley, and Devin Chandler-Militello with URMC. The research was funded with support from National Institute of Neurological Disorders and Stroke, the Hereditary Disease Foundation, CHDI, and Sana Biotechnology.