SURF4

来自釜山国立大学等机构的科学家们通过研究发现了能调节白血病发生和进展的新基因。 白血病是一种人类血液癌症，2015年其在全球影响着大约230万人的健康，急性髓性白血病（AML，Acute myeloid leukemia）是一种侵袭性的白血病，其通常开始发生于机体骨髓，当干细胞无法分化为白细胞时，就会导致机体中健康血液细胞数量的减少，进而促使免疫系统功能衰弱以及其它问题的发生。 鉴于这种疾病的普遍性和影响，目前很多研究都重点关注了白血病的发生和进展机制，近日，一篇发表在国际杂志Cancer Communications上题为“Novel endogenous endoplasmic reticulum transmembrane protein SURF4 suppresses cell death by negatively regulating the STING‐STAT6 axis in myeloid leukemia”的研究报告中，来自釜山国立大学等机构的科学家们通过研究发现了能调节白血病发生和进展的新基因，文章中，研究人员发现了一种名为干扰素基因刺激子（STING，stimulator of interferon genes）的特殊蛋白，其能与另外两种蛋白（TANK结合激酶1-TBK1和信号转导及转录激活子6-STAT6）相互作用从而在血液癌症中施加抗癌效应。 科学家发现一种能调节白血病发生和进展的新型关键基因。 图片来源：Cancer Communications (2022). DOI:10.1002/cac2.12390 研究者观察到，名为surfeit 4 (SURF4)的特殊基因在白血病细胞中会高度表达，其所表达的蛋白质SURF4能结合STING；然而，目前他们仍然并不清楚SURF4如何影响STING-TBK1-STAT6轴以及SURF4在白血病中扮演什么样的角色，因此，这项研究中，研究人员就开始着手理解其中的具体过程。研究人员发现，遭受AML复发的儿童很少能够存活，这或许就使得研究AML发生的机制非常重要，揭示诸如SURF4等蛋白的影响效应或有望帮助开发治疗AML的新型疗法策略。 首先，研究人员利用多种多发夹RNA构建物来靶向作用SURF4，从而就能抑制白血病细胞中SURF4的表达，同时研究者将其与白血病对照细胞进行比较，前者显示出了细胞分化、细胞死亡和ROS积累的增加，而包含这些细胞的肿瘤则在接种到小鼠体内后表现出了生长的停滞。此外，研究者还比较了AML患者机体中SURF4的表达水平，结果发现，携带高水平SURF4表达的患者的生存期会明显缩短，他们还观察到，SURF4的表达在遭受AML折磨的患者中要比健康人群高得多，相关研究结果表明，SURF4能调节AML患者中细胞的死亡和分化，有意思的是，SURF4的沉默并不会影响细胞的周期状态。 研究者Lee说道，我们揭示了SURF4在髓性白血病中所扮演的关键角色，其能负向调节STING-TBK1-STAT6轴并抑制癌细胞的死亡，而且剔除SURF4还能与抗癌药物一起协同作用从而减少患者机体骨髓白血病细胞的负担。因此，利用单克隆抗体和/或核酸适体（aptamers）来抑制SURF4的表达或许能作为一种更好的癌症疗法策略来代替当前摧毁宿主机体免疫系统并产生多种副作用的癌症疗法，而且其也有望作为一种治疗人类血液系统疾病更有希望的选择。（生物谷Bioon.com） 原始出处： Jayoung Kim, Hansong Lee, Chae Mi Hong, et al. Novel endogenous endoplasmic reticulum transmembrane protein SURF4 suppresses cell death by negatively regulating the STING‐STAT6 axis in myeloid leukemia, Cancer Communications (2022). DOI:10.1002/cac2.12390

The findings of this study may lead to a new therapeutic strategy for acute myeloid leukemia for the first time in four decades BUSAN, South Korea, Feb. 1, 2023 /PRNewswire/ -- Leukemia, a type of blood cancer, affected around 2.3 million people around the world in 2015. Acute myeloid leukemia (AML)—a particularly aggressive disease—generally starts in the bone marrow, when stem cells cannot differentiate into white blood cells, which reduces the number of healthy blood cells in the body, leading to a very weak immune system, among other problems. Given the prevalence and implications of this disease, there has been a lot of research on the development and progression of leukemia. This has led to the discovery of a protein, stimulator of interferon genes (STING), which interacts with two other proteins—TANK-binding kinase 1 (TBK1) and signal transducer and activator of transcription 6 (STAT6)—to exert anti-cancer effects in blood cancers. Researchers have also observed that a particular gene—surfeit 4 (SURF4)—is highly expressed in leukemic cells, and its protein, SURF4, binds to STING. However, we are still unclear about how SURF4 affects the STING-TBK1-STAT6 axis, and what role it plays in leukemia. So, a team of researchers from Pusan National University, Republic of Korea set out to understand this. They were led by Professors Dongjun Lee and Yun Hak Kim, who explain the rather humanitarian motive for their research. "Children who suffer from AML relapses seldom survive. This makes studying the mechanisms of AML very important. Uncovering the effects of proteins like SURF4 may lead to new therapeutic strategies for AML, which hasn't happened in four decades". The team ran a series of experiments, the findings of which are detailed in a letter to the editor, published on 6 November 2022 in Cancer Communications. First, using multiple short hairpin RNA constructs to target SURF4, the team suppressed its expression in myeloid leukemic cells and compared these to control leukemic cells. The former showed increased cell differentiation, cell death, and accumulation of ROS. Tumors containing these cells also displayed arrested growth when inoculated in mice. The researchers additionally compared SURF4 expression levels among patients with AML and saw that patients with higher SURF4 expression levels had significantly shorter survival. It was also observed that SURF4 expression was much higher in patients suffering from AML compared to healthy people. These observations suggest that SURF4 regulates cell death and differentiation in AML. Interestingly, SURF4 silencing did not affect the cell cycle status. "Our research shows the role played by SURF4 in myeloid leukemia. It negatively regulates the STING-TBK1-STAT6 axis and inhibits the death of cancer cells. We also found that depletion of SURF4 synergistically works with anti-cancer drugs to reduce myeloid leukemic cell burden," says Prof. Lee. "Therefore," Prof. Kim concludes, "inhibiting SURF4 expression using monoclonal antibodies and/or aptamers may present a better alternative to current cancer therapies that wipe out the immune system and have multiple side effects. This is a promising option for the treatment of hematological cancers." Overall, their findings have increased our understanding of AML and have opened new avenues for the treatment of not only AML but also other blood cancers. Reference Title of original paper: Novel endogenous endoplasmic reticulum transmembrane protein SURF4 suppresses cell death by negatively regulating the STING-STAT6 axis in myeloid leukemia Journal: Cancer Communications DOI: *Corresponding author's email: Dongjun Lee: lee.dongjun@pusan.ac.kr Yun Hak Kim: yunhak10510@pusan.ac.kr About Pusan National University Website: Contact: Jae-Eun Lee 82 51 510 7928 352949@email4pr.com

研究团队证实了一氧化氮也可以靶向和抑制PCSK9，从而降低胆固醇。他们发现了一种小分子药物，能够增加PSCK9的一氧化氮失活。接受这种小分子药物治疗的小鼠的低密度脂蛋白胆固醇（坏胆固醇）降低了70%。 低密度脂蛋白（LDL），是一种富含胆固醇的脂蛋白，当过量时，它携带的胆固醇会积存在动脉壁上，容易引起动脉硬化等心血管疾病。因此低密度脂蛋白（LDL）也被称为“坏胆固醇”。目前应用最广泛的他汀类药物，是一类羟甲基一戊二酰辅酶A还原酶抑制剂，通过抑制肝脏内胆固醇合成，从而降低坏胆固醇水平，保护血管内皮细胞，预防心血管疾病。 PCSK9基因表达的PCSK9蛋白能与肝脏细胞表面的低密度脂蛋白受体（LDL-R）结合并使其降解，从而升高血浆中低密度脂蛋白胆固醇水平。因此，降低PCSK9基因的表达或抑制PCSK9蛋白与LDL-R的结合，就能降低血浆中坏胆固醇水平，从而预防心血管疾病的发生。 近年来，PCSK9抑制剂（包括靶向PCSK9蛋白的单克隆抗体，靶向PCSK9 mRNA 的siRNA）成为新一代降低胆固醇药物，能够高效从血液中清除多余胆固醇。但与他汀类药物不同的是，PCSK9抑制剂只能以注射的方式给药，这为它们的应用带来了一定障碍。 近日，凯斯西储大学的研究人员在 Cell Reports 期刊发表了题为：A multienzyme S-nitrosylation cascade regulates cholesterol homeostasis 的研究论文。 该研究开发了一种口服小分子药物，能够在小鼠模型中降低PCSK9水平，并降低70%的胆固醇，这些研究结果代表了一种此前未被证实的调控胆固醇的策略。此外，该研究还提示了靶向PCSK9有望改善癌症免疫治疗。 论文通讯作者 Jonathan Stamler 教授表示，心脏病是发病率和死亡率的头号原因，降低胆固醇是我们延长生命和保护人们远离心脏病的最重要的治疗方法之一。而该研究发现了一种靶向PSCK9并降低胆固醇的新方法。 胆固醇调节的核心是低密度脂蛋白受体（LDL-R），它位于肝细胞表面，能够从血液中清除胆固醇，从而降低血清水平。血液中的PCSK9蛋白通过结合并降解低LDL-R来控制其数量。因此，PCSK抑制剂能够增加LDL-R的数量，从而促进胆固醇的清除。 ，在这项最新研究中，研究团队证实了一氧化氮也可以靶向和抑制PCSK9，从而降低胆固醇。他们发现了一种小分子药物，能够增加PSCK9的一氧化氮失活。接受这种小分子药物治疗的小鼠的低密度脂蛋白胆固醇（坏胆固醇）降低了70%。 SAR1作为SURF4的亚硝基化酶，SURF4作为PCSK9的亚硝基化酶，抑制PCSK9的分泌，而蛋白质脱硝基化酶SCoR2通过促进PCSK9的脱硝基化，来抵消亚硝基化酶的活性。研究团队发现，蛋白质脱硝基化酶SCoR2缺乏的小鼠，PCSK9蛋白分泌减少，从而导致胆固醇显著降低。 众所周知，一氧化氮（NO）能够通过扩张血管来预防心脏病发作。该研究表明，一氧化氮也可以靶向和抑制PCSK9，从而降低胆固醇。而一氧化氮对PCSK9的抑制需要硝基化酶活性，SCoR2的小分子抑制剂能够增加PSCK9的一氧化氮失活，接受这种小分子药物治疗的小鼠的低密度脂蛋白胆固醇（坏胆固醇）降低了70%。