CDH2

本文为转化医学网原创，转载请注明出处 作者：Jerry 导读： RNF214是一种未被充分研究的泛素连接酶，对其生物学功能或蛋白质底物知之甚少。 6月11日，浙江大学研究团队在期刊《Nature Communications》上发表了题为“The RNF214-TEAD-YAP signaling axis promotes hepatocellular carcinoma progression via TEAD ubiquitylation”的研究论文， 研究数据揭示了RNF214是Hippo信号通路中的关键组分，并形成了RNF214-TEAD-YAP的信号转导轴，这表明RNF214是肝癌的致癌基因，可能是肝癌治疗的潜在药物靶点。 https://www-nature-com.libproxy1.nus.edu.sg/articles/s41467-024-49045-y#Sec9 研究背景 01 泛素是一种可以与蛋白质底物共价结合的小型信号蛋白。这一过程被称为泛素化或泛素化修饰，是真核生物中最主要的蛋白质翻译后修饰之一。泛素化反应依次由泛素激活酶（E1）、泛素共价连接酶（E2）和泛素连接酶（E3）催化。到目前为止，已在人类中检测到至少43948个泛素化位点，涉及14692种泛素化蛋白质，这表明泛素化与复杂的生物学过程有关。 泛素化是一个非常特异的过程，底物特异性主要由泛素连接酶决定。人类基因组编码超过600种泛素连接酶，它们含有RING指或HECT结构域。这些酶可以对许多人类蛋白质进行泛素化修饰，其中包括各种信号通路的组分。 研究进展 02 研究人员采用免疫组织化学（IHC）方法比较了浙江省人民医院176对肝癌组织样本和癌旁组织样本中RNF214的表达水平，发现在92对样本中，RNF214在肿瘤组织中过表达，占52.3%，这意味着超过一半的肝癌患者的肿瘤组织中RNF214蛋白水平上调。同时，研究人员根据IHC结果分析了275例肝癌患者中RNF214表达水平与不同分化程度之间的相关性，发现超过一半的中等或低分化程度的病例（IHC评分≥6）显示RNF214高表达（R值为0.26），这表明RNF214可能参与了肝癌的恶性进程。基于RNF214表达与Edmonson-Steiner分级（肝癌另一个重要的预后指标）之间的相关性也获得了类似的结果。在这种情况下，III级和IV级的患者中分别有79.6%和43.3%的患者RNF214表达水平较高（IHC评分≥6）。此外，研究人员观察到RNF214蛋白水平与真正的肝癌生物标志物甲胎蛋白（AFP）的血清表达水平密切相关。为了进一步巩固临床分析，研究人员采用蛋白质印迹法对HCC细胞系中的RNF214表达情况进行了测量，并注意到在考察的7种HCC细胞系中，RNF214蛋白水平均高于正常肝细胞系HL7702。 然后，研究人员研究了RNF214与肝癌样本中Hippo信号通路调控的基因表达之间的相关性。通过TCGA队列的斯皮尔曼等级相关分析，研究人员观察到RNF214与YAP/TAZ-TEAD靶基因（如AMOTL2、CTGF、CYR61、ANKRD1、AXL、BCL2、CCND1和CDH2）呈正相关。此外，RNF214的表达与YAP和TAZ的表达以及TEAD1至TEAD4的表达呈正相关。 总之，这些数据表明RNF214可能是一个关键的致癌基因，与增强YAP/TAZ-TEAD转录活性有关，从而促进HCC肿瘤的发生。 RNF214 的过度表达与 HCC 的预后不良相关 研究结论 03 Hippo通路与肿瘤的发生有关，MST1/2和LATS1/2激酶是肿瘤抑制基因，而YAP/TAZ和TEADs是癌基因。YAP和TEADs已被认为是肿瘤治疗中有前景的治疗靶点。事实上，作为抗癌药物，干扰TEADs和YAP之间相互作用的小分子抑制剂正在开发中。通过结合临床数据和生物分析，研究人员证明了RNF214是HCC的癌基因，也是YAP-TEAD转录复合物的重要调节因子。因此，将RNF214添加到YAP-TEAD轴上，可以为开发独特的抗癌工具提供有希望的视角，通过管理TEAD和YAP/TAZ复合物的转录活性，特别是通过杀死HCC细胞来实现。 参考资料： https://www-nature-com.libproxy1.nus.edu.sg/articles/s41467-024-49045-y#Sec9 【关于投稿】 转化医学网（360zhyx.com）是转化医学核心门户，旨在推动基础研究、临床诊疗和产业的发展，核心内容涵盖组学、检验、免疫、肿瘤、心血管、糖尿病等。如您有最新的研究内容发表，欢迎联系我们进行免费报道（公众号菜单栏-在线客服联系），我们的理念：内容创造价值，转化铸就未来！ 转化医学网（360zhyx.com）发布的文章旨在介绍前沿医学研究进展，不能作为治疗方案使用；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20日 ▶ 【日程公布】合成生物学前沿技术与临床应用研讨会 🕓 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

Regenerative heart therapies involve transplanting cardiac muscle cells into damaged areas of the heart to recover lost function. However, the risk of arrhythmias following this procedure is reportedly high. In a recent study, researchers tested a novel approach that involves injecting 'cardiac spheroids,' cultured from human stem cells, directly into damaged ventricles. The highly positive outcomes observed in primate models highlight the potential of this strategy. Regenerative heart therapies involve transplanting cardiac muscle cells into damaged areas of the heart to recover lost function. However, the risk of arrhythmias following this procedure is reportedly high. In a recent study, researchers from Japan tested a novel approach that involves injecting 'cardiac spheroids,' cultured from human stem cells, directly into damaged ventricles. The highly positive outcomes observed in primate models highlight the potential of this strategy. Cardiovascular diseases are still among the top causes of death worldwide, and especially prevalent in developed countries. Myocardial infarctions, commonly known as "heart attacks," are on the rise, resulting in a significant number of deaths each year. Heart attacks typically kill millions of cardiac muscle cells, leaving the heart in a weakened state. Since mammals cannot regenerate cardiac muscle cells on their own, heart transplants are currently the only clinically viable option for patients suffering (or likely to suffer) heart failure. Given that full heart transplants are expensive and donors difficult to come by, it is no surprise that alternative therapies are highly sought after by the medical community. One promising strategy that has been steadily gaining traction is using human induced pluripotent stem cells (HiPSCs) for regenerative heart therapy. Simply put, HiPSCs are cells derived from mature cells that can be effectively 'reprogrammed' into a completely different cell type, such as cardiac muscle cells (cardiomyocytes). By transplanting or injecting cardiomyocytes derived from HiPSCs into damaged areas of the heart, it is possible to recover some lost functionality. Unfortunately, studies have reported that this approach can increase the risk of arrythmias, posing a major hurdle to clinical trials. In a recent study, a Japanese research team from Shinshu University and Keio University School of Medicine, tested a new strategy for regenerative heart therapy that involves injecting 'cardiac spheroids' derived from HiPSCs into monkeys with myocardial infarction. This study, published on April 26, 2024, in the journal Circulation, was led by Professor Yuji Shiba from the Department of Regenerative Science and Medicine, Shinshu University. The team included Hideki Kobayashi, the first author, and Koichiro Kuwahara from the Department of Cardiovascular Medicine, Shinshu University School of Medicine, as well as Shugo Tohyama, and Keiichi Fukuda from the Department of Cardiology, Keio University School of Medicine, among others. In their novel approach, the researchers cultivated HiPSCs in a medium that led to their differentiation into cardiomyocytes. After carefully extracting and purifying cardiac spheroids (three-dimensional clusters of cardiac cells) from the cultures, they injected approximately 6 × 107 cells into the damaged hearts of crab-eating macaques (Macaca fascicularis). They monitored the condition of the animals for twelve weeks, taking regular measurements of cardiac function. Following this, they analyzed the monkeys' hearts at the tissue level to assess whether cardiac spheroids could regenerate the damaged heart muscles. First, the team verified the correct reprogramming of HiPSCs into cardiomyocytes. They observed, via cellular-level electrical measurements, that the cultured cells exhibited potential patterns typical of ventricular cells. The cells also responded as expected to various known drugs. Most importantly, they found that the cells abundantly expressed adhesive proteins such as connexin 43 and N-cadherin, which would promote their vascular integration into an existing heart. Afterwards, the cells were transported from the production facility at Keio University to Shinshu University, located 230 km away. The cardiac spheroids, which were preserved at 4 °C in standard containers, withstood the four-hour journey without problem. This means that no extreme cryogenic measures would be needed when transporting the cells to clinics, which would make the proposed approach less expensive and easier to adopt. Finally, the monkeys received injections of either cardiac spheroids or a placebo directly into the damaged heart ventricle. During the observation period, the researchers noted that arrythmias were very uncommon, with only two individuals experiencing transient tachycardia (fast pulse) in the first two weeks among the treatment group. Through echocardiography and computed tomography exams, the team confirmed that the hearts of monkeys that received treatment had better left ventricular ejection after four weeks compared to the control group, indicating a superior blood pumping capability. Histological analysis ultimately revealed that the cardiac grafts were mature and properly connected to pre-existing existing tissue, cementing the results of previous observations. "HiPSC-derived cardiac spheroids could potentially serve as an optimal form of cardiomyocyte products for heart regeneration, given their straightforward generation process and effectiveness," remarks Assistant Professor Kobayashi. "We believe that the results of this research will help solve the major issue of ventricular arrhythmia that occurs after cell transplantation and will greatly accelerate the realization of cardiac regenerative therapy," he further adds. Although tested in monkeys, it is worth noting that the cardiac spheroid production protocol used in this study was designed for clinical application in humans. "The favorable results obtained thus far are sufficient to provide a green light for our clinical trial, called the LAPiS trial. We are already employing the same cardiac spheroids on patients with ischemic cardiomyopathy," comments Asst. Prof. Kobayashi. Let us all hope for a resounding success in the LAPiS trial, paving the way for expanded and effective treatment avenues for people suffering from heart problems.

ROOT, Switzerland--(BUSINESS WIRE)-- Novocure (NASDAQ: NVCR) today announced 20 presentations on Tumor Treating Fields (TTFields) therapy will be delivered at the American Association for Cancer Research (AACR) Annual Meeting 2024, to be held April 5 to 10 in San Diego. The presentations, describing preclinical investigations, include new insights on how TTFields therapy can potentially enhance the immune system’s ability to combat cancer cells and on TTFields therapy’s effects and mechanisms in pancreatic cancer. “The research we and our collaborators are presenting at the AACR Annual Meeting underscores the potential of Tumor Treating Fields therapy in treating various solid tumor types,” said Moshe Giladi, Ph.D., Novocure’s Chief Science Officer. “We continually explore the science of TTFields therapy to improve our product and make a difference in the lives of patients with cancer, and we are eager to discuss some of our latest insights with leading cancer investigators.” Highlights include: A preclinical study in a murine model of pancreatic cancer showing that TTFields applied concurrently with standard chemotherapy led to significantly enhanced therapeutic effects. When used alongside gemcitabine and nab-paclitaxel (Gem/NabP), TTFields significantly reduced tumor growth compared to the control group, and a complete regression of tumors was observed in a number of animals. This is a treatment regimen similar to the PANOVA-3 clinical trial examining the efficacy of TTFields in patients with locally advanced pancreatic cancer. A preclinical study demonstrating a novel immunomodulatory role for TTFields by promoting in vitro pro-inflammatory polarization of macrophages. Macrophages exposed to TTFields showed an increase in markers and chemicals that indicate a shift towards a pro-inflammatory, tumor-fighting mode. The study suggests TTFields can potentially modulate macrophages to better attack cancer cells by pushing them toward a state more hostile to tumors. An in vitro study suggesting concomitant application of TTFields and PARP inhibitors in BRCA wild type pancreatic cancer cells leads to improvement over monotherapy. Applied individually, both PARP inhibitors and TTFields killed cancer cells, stopped them from multiplying, and triggered apoptosis. These effects were amplified when TTFields and PARP inhibitors were applied together. These findings contribute to existing data suggesting that TTFields induce a state of BRCAness in cancer cells. Presentations from Novocure-sponsored and partner programs include: Tumor Treating Fields (TTFields) targeted self assembling nanoparticles for pancreatic cancer treatment: In vitro and in vivo assessment. Presenter: P.P. Desai. 1:30 p.m. PDT on Sunday, April 7. Tumor Treating Fields induce the integrated stress response, alter the transcriptional signatures of cellular metabolism, and modulate immune-related cytokines dependent and independent of p53. Presenter: P.R. Srinivasan. 1:30 p.m. PDT on Sunday, April 7. Tumor Treating Fields (TTFields) disrupt cancer cell invasion by impacting cell-ECM traction forces. Presenter: S.M. Short. 9 a.m. PDT on Monday, April 8. N-cadherin-mediated activation of PI3K/Akt pathway following application of Tumor Treating Fields (TTFields). Presenter: T. Voloshin. 9 a.m. PDT on Monday, April 8. Genomic and proteomic analysis of glioblastoma recurrences during TTFields exposure. Presenter: M. Mazzanti. 9 a.m. PDT on Monday, April 8. Co-treatment with KRAS G12D inhibitor MRTX1133 plus TTFields against human pancreatic and Colorectal cancer cell lines results in synergistic up-regulation of cleaved PARP in KRAS G12D & unexpectedly in KRAS G12V as well. Presenter: V. Tajiknia. 9 a.m. PDT on Monday, April 8. Tumor Treating Fields (TTFields) for spinal metastasis: Clinical trial concept for use of conductive implants as waveguides to enhance TTFields strength. Presenter: C.E. Tatsui. 9 a.m. PDT on Monday, April 8. Tumor Treating Fields (TTFields) increase cancer cell membrane permeability and improve sensitivity to doxorubicin in vitro and in vivo. Presenter: T. Voloshin. 9 a.m. PDT on Tuesday, April 9. Development of paclitaxel-loaded nanoparticles with high charge density. Presenter: K.Y. Bang. 1:30 p.m. PDT on Tuesday, April 9. Tumor Treating Fields alter PDGFR-β localization in immortalized human pericytes in an in vitro model of the blood-brain barrier. Presenter: C. Hagemann. 1:30 p.m. PDT on Tuesday, April 9. Designing arrays for delivering Tumor Treating Fields (TTFields) to the mouse head. Presenter: I Tzchori. 1:30 p.m. PDT on Tuesday, April 9. Tumor Treating Fields (TTFields) induce an anti-tumor immune response in a pancreatic cancer mouse model. Presenter: T. Voloshin. 9 a.m. PDT on Wednesday, April 10. Macrophage pro-inflammatory phenotype skewing by the application of Tumor Treating Fields (TTFields). Presenter: T. Voloshin. 9 a.m. PDT on Wednesday, April 10. Quantitative proteomics reveal the mechanism of TTFields therapy for glioblastoma. Presenter: Q. Mei. 9 a.m. PDT on Wednesday, April 10. Treatment of pancreatic cancer cells with Tumor Treating Fields (TTFields) and PARP inhibitors. Presenter: E. Dor-On. 9 a.m. PDT on Wednesday, April 10. Preclinical effects of Tumor Treating Fields (TTFields) with PARP inhibitors in ovarian cancer. Presenter: E. Dor-On. 9 a.m. PDT on Wednesday, April 10. Preclinical investigations of concomitant Tumor Treating Fields (TTFields) with cisplatin for treatment of cervical cancer. Presenter: I. Tzschori. 9 a.m. PDT on Wednesday, April 10. Tumor Treating Fields (TTFields) can induce immunogenic cell death in GBM resulting in enhanced immune modulation. Presenter: R.T. Nitta. 9 a.m. PDT on Wednesday, April 10. Tumor Treating Fields (TTFields) show efficacy in Triple-Negative breast cancer (TNBC) cells alone and in combination with PARP inhibitor Talazoparib. Presenter: M. Ghandali. 9 a.m. PDT on Wednesday, April 10. TTFields and imipridone ONC206 co-treatment inhibits p-AKT and spheroid growth and upregulates caspase-10 in human GBM cell lines. Presenter: V. Tajiknia. 9 a.m. PDT on Wednesday, April 10. ABOUT TUMOR TREATING FIELDS THERAPY Tumor Treating Fields (TTFields) are electric fields that exert physical forces to kill cancer cells via a variety of mechanisms. TTFields do not significantly affect healthy cells because they have different properties (including division rate, morphology, and electrical properties) than cancer cells. The multiple, distinct mechanisms of TTFields therapy work together to selectively target and kill cancer cells. Due to its multimechanistic actions, TTFields therapy can be added to cancer treatment modalities in approved indications and demonstrates enhanced effects across solid tumor types when used with chemotherapy, radiotherapy, immune checkpoint inhibition, or PARP inhibition in preclinical models. TTFields therapy provides clinical versatility that has the potential to help address treatment challenges across a range of solid tumors. To learn more about Tumor Treating Fields therapy and its multifaceted effect on cancer cells, visit tumortreatingfields.com. ABOUT NOVOCURE Novocure is a global oncology company working to extend survival in some of the most aggressive forms of cancer through the development and commercialization of its innovative therapy, Tumor Treating Fields. Novocure’s commercialized products are approved in certain countries for the treatment of adult patients with glioblastoma, malignant pleural mesothelioma and pleural mesothelioma. Novocure has ongoing or completed clinical studies investigating Tumor Treating Fields in brain metastases, gastric cancer, glioblastoma, liver cancer, non-small cell lung cancer, pancreatic cancer and ovarian cancer. Headquartered in Root, Switzerland and with a growing global footprint, Novocure has regional operating centers in Portsmouth, New Hampshire and Tokyo, as well as a research center in Haifa, Israel. For additional information about the company, please visit Novocure.com and follow @Novocure on LinkedIn and Twitter. FORWARD-LOOKING STATEMENTS In addition to historical facts or statements of current condition, this press release may contain forward-looking statements. Forward-looking statements provide Novocure’s current expectations or forecasts of future events. These may include statements regarding anticipated scientific progress on its research programs, clinical study progress, development of potential products, interpretation of clinical results, prospects for regulatory approval, manufacturing development and capabilities, market prospects for its products, coverage, collections from third-party payers and other statements regarding matters that are not historical facts. You may identify some of these forward-looking statements by the use of words in the statements such as “could” “anticipate,” “estimate,” “expect,” “project,” “intend,” “plan,” “believe” or other words and terms of similar meaning. Novocure’s performance and financial results could differ materially from those reflected in these forward-looking statements due to general financial, economic, environmental, regulatory and political conditions and other more specific risks and uncertainties facing Novocure such as those set forth in its Annual Report on Form 10-K filed on February 22, 2024, and subsequent filings with the U.S. Securities and Exchange Commission. Given these risks and uncertainties, any or all of these forward-looking statements may prove to be incorrect. Therefore, you should not rely on any such factors or forward-looking statements. Furthermore, Novocure does not intend to update publicly any forward-looking statement, except as required by law. Any forward-looking statements herein speak only as of the date hereof. The Private Securities Litigation Reform Act of 1995 permits this discussion. View source version on businesswire.com: Contacts INVESTORS & MEDIA: Ingrid Goldberg investorinfo@novocure.com media@novocure.com 610-723-7427 Source: Novocure View this news release online at: