PDIA6

来自巴塞罗那科技学院等机构的科学家们通过研究识别出了参与黑色素瘤进展的多种蛋白质，黑色素瘤是一种最致命的人类皮肤癌。研究者表示，其中一种名为PDIA6的蛋白质对于驱动癌变非常重要。 RNA结合蛋白（RBPs）在癌症研究中一直被忽略，尽管其对几乎所有的癌症特征都有贡献，近日，一篇发表在国际杂志Nucleic Acids Research上题为“Melanoma RBPome identification reveals PDIA6 as an unconventional RNA-binding protein involved in metastasis”的研究报告中，来自巴塞罗那科技学院等机构的科学家们通过研究识别出了参与黑色素瘤进展的多种蛋白质，黑色素瘤是一种最致命的人类皮肤癌。研究者表示，其中一种名为PDIA6的蛋白质对于驱动癌变非常重要，对小鼠进行实验结果表明，PDIA6水平降低的黑色素瘤细胞转移到肺部中的能力或许会受损。 研究者发现，PDIA6或能通过与肿瘤细胞内的RNA分子结合来促进黑色素瘤恶变，此外，研究人员还识别出了PDIA6表面与RNA分子结合的特殊区域，进一步研究后，这一信息或能帮助设计出新型治疗性化合物，从而预防黑色素瘤从机体一个部位扩散到另一个部位。此前研究人员发现PDIA6与淋巴瘤、乳腺癌和肺癌的进展有关，如果进一步研究发现PDIA6能结合其它癌症类型中的RNA，那么研究人员或许有望开发出一种治疗性策略来靶向作用不同肿瘤中的相同作用机制。 这一研究发现得益于研究人员开发的一种名为“RNA钓鱼”（RNA fishing）的技术，该技术尤其能帮助识别RNA结合蛋白，其是一类能发挥多种生物学功能的特殊蛋白，在癌症中，其能通过帮助细胞适应不断改变的环境并对外来威胁快速反应来赋予细胞可塑性，从而促进癌变以及对疗法耐受性。这种技术也被称为RNA交互组捕获技术（RNA interactome capture），其主要涉及从一个细胞中捞出所有的信使RNAs，随后研究人员就会观察哪种蛋白质会吸附到RNA上，这或许就告知了细胞中所发生的RNA结合活动的水平和多样性。 科学家开发出“RNA钓鱼”技术 或能揭示黑色素瘤恶变和转移的新型驱动子。 图片来源：Nucleic Acids Research (2022). DOI: 10.1093/nar/gkac605 研究者Fatima Gebauer解释道，RNA结合蛋白具有很大的治疗性意义，本文研究中研究人员所采用的技术能帮助测定RNA结合蛋白的活性，而这是传统方法不可能在这种规模上所做到的，当用于比较肿瘤和非肿瘤细胞时，这种方法就能帮助识别哪些蛋白在癌症进展过程中扮演重要角色，通过进一步实验也能告诉研究人员其是如何发挥作用的，研究人员利用这一蓝图揭示了黑色素瘤的新弱点，他们希望后期能帮助发现其它类型癌症中的新型治疗性靶点。 在该技术确定的数百个RNA结合蛋白汇总，研究人员选择了24个利用不同的标准选择来进一步分析，比如，因为其RNA结合能力并没有被描述过，或者此前并未发现其与癌症进展相关，研究人员挑选出了PDIA6来进一步分析其功能，包括在小鼠模型中进行移植实验，未来研究中研究人员还将会继续对其它23种蛋白质进行深入分析。 研究者表示，我们对RNA结合蛋白能作为治疗性靶点的研究还仅仅是在表面上做文章，通过功能性方法来识别RNA结合活动，随后在分子层面上理解其能力，或许就为设计新型抑制剂来改善癌症个体化疗法提供一定的思路和希望。综上，本文研究结果揭示了研究人员如何利用其所开发的新技术来发现癌细胞的新型弱点或易感性。（生物谷Bioon.com） 原始出处： Neus Mestre-Farràs, Santiago Guerrero, Nadine Bley，et al. Melanoma RBPome identification reveals PDIA6 as an unconventional RNA-binding protein involved in metastasis, Nucleic Acids Research (2022). DOI: 10.1093/nar/gkac605

Researchers have identified several proteins involved in the progression of melanoma. One of the proteins -- PDIA6 -- was found to be particularly important for driving malignancy. Experiments with mice showed that melanoma cells with reduced levels of PDIA6 had an impaired ability to metastasize to the lung. The findings could lead to new therapeutic strategies that prevent the spread of melanoma from one part of the body to another. Researchers at the Centre for Genomic Regulation (CRG) have identified several proteins involved in the progression of melanoma, the deadliest form of skin cancer. One of the proteins -- PDIA6 -- was found to be particularly important for driving malignancy. Experiments with mice showed that melanoma cells with reduced levels of PDIA6 had an impaired ability to metastasize to the lung. The researchers found that PDIA6 promoted melanoma malignancy by binding to RNA molecules inside the tumour's cell. The authors of the study, published in the journal Nucleic Acids Research with the support of "La Caixa" Foundation identified the region on the surface of PDIA6 that binds to RNA molecules. With further research, this information can help design new therapeutic compounds that prevent the spread of melanoma from one part of the body to another. PDIA6 has been previously linked to the progression of lymphoma, breast and lung cancer. If further research finds that PDIA6 also binds to RNA in these other cancer types, it could lead to a therapeutic strategy that targets the same mechanism of action across different tumours. The finding was made possible thanks to an 'RNA fishing' technique specifically designed to identify RNA-binding proteins. These are a class of proteins that carry out a variety of biological functions, an in cancer, confer resilience to cells by helping them adapt to changing environments and quickly respond to external threats, promoting cancer malignancy and resistance to therapy. The technique, also known as RNA interactome capture, involves fishing out all messenger RNAs in a cell. Researchers then see which proteins are attached to them, which informs on the level and diversity of RNA-binding activities taking place inside the cells. "RNA-binding proteins are of great therapeutic interest. The technique in this study can help us measure their activity, something not possible at such global scale with conventional methods. When used to compare tumour and non-tumour cells, the approach helps us identify which proteins might play important roles in cancer progression, and carrying out further experiments tells us how they work. We used this blueprint to uncover new vulnerabilities in melanoma, and we hope this can be repeated to find new therapeutic targets in other types of cancers too," explains Dr. Fátima Gebauer, researcher at the CRG and senior author of the study. Out of the hundreds of RNA-binding proteins identified by the technique, the researchers selected 24 to carry out further analysis using varied criteria, for example because their RNA-binding activity had not been described or they were not previously linked to cancer progression. The researchers singled-out PDIA6 to further characterize its function, including transplantation experiments in mouse models. Future studies could delve into the roles of the other 23 proteins found. "We are just scratching the surface of the potential of RNA-binding proteins as therapeutic targets. Identifying RNA-binding activities through functional methods, followed by detailed molecular understanding of their capacities, will pave the way for the design of inhibitors that may greatly improve personalized therapy for cancer," concludes Dr. Gebauer. The work was carried out in collaboration with the University of Halle in Germany and the University of Oxford in the United Kingdom, with the support of the "la Caixa" foundation via a CaixaResearch Health grant. The project started in 2014 funded by "La Marató de TV3."