重写脚本：针对替代RNA剪接以治疗癌症

通过确定要保留哪些序列以及要切割的序列，编辑器可以从同一原材料中创建戏剧，喜剧甚至惊悚片。

California [US], March 16 : Alternative RNA splicing is similar to a movie editor cutting and rearranging scenes from the same video to produce distinct versions of a film. By deciding which sequences to keep and which to cut, the editor can create a drama, a comedy, or even a thriller from the same raw material.

加利福尼亚[美国]，3月16日：替代性RNA剪接类似于电影编辑的剪裁和重新排列的场景，从同一视频中产生了不同版本的电影。通过确定要保留哪些序列以及要切割的序列，编辑器可以从同一原材料中创建戏剧，喜剧甚至惊悚片。

Similarly, cells splice RNA in various ways to make a wide range of proteins from a single gene, fine-tuning their activity to meet specific needs. However, when cancer rewrites the script, this process is disrupted, promoting tumor growth and survival.

同样，细胞以各种方式将RNA剪接，以从单个基因中制成各种蛋白质，从而微调其活性以满足特定需求。但是，当癌症重写脚本时，此过程会破坏，从而促进肿瘤的生长和生存。

In a recent study, scientists from The Jackson Laboratory (JAX) and UConn Health not only show how cancer hijacks this tightly regulated splicing and rearranging of RNA but also introduce a potential therapeutic strategy that could slow or even shrink aggressive and hard-to-treat tumors. This discovery could transform how we treat aggressive cancers, such as triple-negative breast cancer and certain brain tumors, where current treatment options are limited.

在最近的一项研究中，来自杰克逊实验室（JAX）和UCONN健康的科学家不仅表明了癌症如何劫持这种严格调节的RNA的剪接和重新排列，而且还引入了潜在的治疗策略，可能会减慢或什至会缩短侵略性且难以治疗的肿瘤。这一发现可能会改变我们如何治疗侵略性癌症，例如三阴性乳腺癌和某些脑肿瘤，而当前治疗选择受到限制。

At the heart of this work, led by Olga Anczukow, an associate professor at JAX and co-program leader at the NCI-designated JAX Cancer Center, are tiny genetic elements called poison exons, nature's own "off switch" for protein production. When these exons are included in an RNA message, they trigger its destruction before a protein can be madepreventing harmful cellular activity. In healthy cells, poison exons regulate the levels of key proteins, keeping the genetic machinery in check. But in cancer, this safety mechanism often fails.

这项工作的核心是由JAX的副教授，NCI指定的JAX癌症中心的联合计划领导者Olga Anczukow领导，是称为Poison Exons的微小遗传元素，这是Nature's自然的“ Off Switch”用于蛋白质生产。当这些外显子包含在RNA消息中时，它们会触发其破坏，然后蛋白质可能会使有害的细胞活性疯狂。在健康的细胞中，毒物外显子调节关键蛋白的水平，从而控制遗传机械。但是在癌症中，这种安全机制常常失败。

Anczukow and her team, including Nathan Leclair, an MD/PhD graduate student at UConn Health and The Jackson Laboratory who spearheaded the research, and Mattia Brugiolo, a staff researcher who contributed his expertise, discovered that cancer cells suppress poison exon activity in a critical gene called TRA2b. As such, levels of TRA2b protein increase inside cancer cells, causing tumor proliferation.

Anczukow和她的团队，包括UConn Health的医学博士/博士学位研究生Nathan Leclair和带头研究的Jackson实验室，以及贡献他的专业知识的员工研究人员Mattia Brugiolo发现癌细胞抑制了一个称为Tra2b的重要基因中的毒药外显子活性。因此，Tra2b蛋白质的水平增加了癌细胞内部，导致肿瘤增殖。

Furthermore, the team found a correlation between levels of poison exons and patient outcomes. "We've shown for the first time that low levels of poison exon inclusion in the TRA2b gene are associated with poor outcomes in many different cancer types, and especially in aggressive and difficult-to-treat cancers," said Anczukow. These include breast cancer, brain tumors, ovarian cancers, skin cancers, leukemias, and colorectal cancers, Anczukow explained.

此外，该小组发现毒药外显子和患者结局之间存在相关性。 Anczukow说：“我们首次表明，在TRA2B基因中，低水平的毒物外显子包含在许多不同的癌症类型中，尤其是在侵略性且难以治疗的癌症中的结果。” Anczukow解释说，其中包括乳腺癌，脑肿瘤，卵巢癌，皮肤癌，白血病和结直肠癌。

Anczukow, Leclair, and Brugiolo then went on to see if they could increase the inclusion of the poison exon in the TRA2b gene and reactivate the kill switch. They found their answer in antisense oligonucleotides (ASOs)synthetic RNA fragments that can be designed to increase poison exon inclusion in specific ways. When introduced into cancer cells, ASOs effectively flipped the genetic switch, restoring the body's natural ability to degrade excess TRA2b RNA and inhibit tumor progression.

然后，Anczukow，Leclair和Brugiolo继续看看他们是否可以增加Tra2b基因中的毒物外显子的包含并重新激活杀伤开关。他们在反义寡核苷酸（ASOS）合成RNA片段中发现了答案，这些片段可以设计以增加毒物外显子的包含。当被引入癌细胞时，ASO有效地翻转了遗传转换，从而恢复了人体降解多余的TRA2B RNA并抑制肿瘤进展的自然能力。

"We found that ASOs can rapidly boost poison exon inclusion, essentially tricking the cancer cell into turning off its own growth signals," said Leclair. "These poison exons work like a rheostat, quickly adjusting protein levelsand that could make ASOs a highly precise and effective therapy for aggressive cancers."

Leclair说：“我们发现ASO可以迅速增加毒物外显子的包含，从本质上欺骗癌细胞，转化为自身的生长信号。” “这些毒物外显子像变阻器一样工作，迅速调整蛋白质水平并可以使ASO成为高度精确且有效的侵略性癌症的疗法。”

Interestingly, when researchers completely removed TRA2b proteins using CRISPR gene editing, tumors continued to growsuggesting that targeting the RNA rather than the protein could be a more effective approach. "This tells us that poison-exon-containing RNA doesn't just silence TRA2b," explained Anczukow. "It likely sequesters other RNA-binding proteins, creating an even more toxic environment for cancer cells."

有趣的是，当研究人员使用CRISPR基因编辑完全去除TRA2B蛋白时，肿瘤继续增长，将靶向RNA而不是蛋白质的靶向可能是一种更有效的方法。 Anczukow解释说：“这告诉我们，含毒药的RNA不仅使Tra2b保持沉默。” “它可能会隔离其他RNA结合蛋白，从而为癌细胞创造更具毒性的环境。”

Further studies will refine ASO-based therapies and explore their delivery to tumors. However, preliminary data suggest that ASOs are highly specific and do not interfere with normal cellular function, making them promising candidates for future cancer treatments.

进一步的研究将完善基于ASO的疗法，并探索它们向肿瘤的分娩。但是，初步数据表明，ASO是高度特异性的，并且不会干扰正常的细胞功能，从而使他们有望接受未来的癌症治疗。

Disclaimer: This post has been auto-published from an agency feed without any modifications to the text and has not been reviewed by an editor

免责声明：该帖子已从代理商提要中自动发布而没有任何修改文本，也没有由编辑进行审查