重寫腳本：針對替代RNA剪接以治療癌症

通過確定要保留哪些序列以及要切割的序列，編輯器可以從同一原材料中創建戲劇，喜劇甚至驚悚片。

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.

加利福尼亞[美國]，3月16日：替代性RNA剪接類似於電影編輯的剪裁和重新排列的場景，從同一視頻中產生了不同版本的電影。通過確定要保留哪些序列以及要切割的序列，編輯器可以從同一原材料中創建戲劇，喜劇甚至驚悚片。

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.

同樣，細胞以各種方式將RNA剪接，以從單個基因中製成各種蛋白質，從而微調其活性以滿足特定需求。但是，當癌症重寫腳本時，此過程會破壞，從而促進腫瘤的生長和生存。

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.

在最近的一項研究中，來自傑克遜實驗室（JAX）和UCONN健康的科學家不僅表明了癌症如何劫持這種嚴格調節的RNA的剪接和重新排列，而且還引入了潛在的治療策略，可能會減慢或什至會縮短侵略性且難以治療的腫瘤。這一發現可能會改變我們如何治療侵略性癌症，例如三陰性乳腺癌和某些腦腫瘤，而當前治療選擇受到限制。

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.

這項工作的核心是由JAX的副教授，NCI指定的JAX癌症中心的聯合計劃領導者Olga Anczukow領導，是稱為Poison Exons的微小遺傳元素，這是Nature's自然的“ Off Switch”用於蛋白質生產。當這些外顯子包含在RNA消息中時，它們會觸發其破壞，然後蛋白質可能會使有害的細胞活性瘋狂。在健康的細胞中，毒物外顯子調節關鍵蛋白的水平，從而控制遺傳機械。但是在癌症中，這種安全機制常常失敗。

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和她的團隊，包括UConn Health的醫學博士/博士學位研究生Nathan Leclair和帶頭研究的Jackson實驗室，以及貢獻他的專業知識的員工研究人員Mattia Brugiolo發現癌細胞抑制了一個稱為Tra2b的重要基因中的毒藥外顯子活性。因此，Tra2b蛋白質的水平增加了癌細胞內部，導致腫瘤增殖。

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，該小組發現毒藥外顯子和患者結局之間存在相關性。 Anczukow說：“我們首次表明，在TRA2B基因中，低水平的毒物外顯子包含在許多不同的癌症類型中，尤其是在侵略性且難以治療的癌症中的結果。” Anczukow解釋說，其中包括乳腺癌，腦腫瘤，卵巢癌，皮膚癌，白血病和結直腸癌。

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.

然後，Anczukow，Leclair和Brugiolo繼續看看他們是否可以增加Tra2b基因中的毒物外顯子的包含並重新激活殺傷開關。他們在反義寡核苷酸（ASOS）合成RNA片段中發現了答案，這些片段可以設計以增加毒物外顯子的包含。當被引入癌細胞時，ASO有效地翻轉了遺傳轉換，從而恢復了人體降解多餘的TRA2B RNA並抑制腫瘤進展的自然能力。

"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說：“我們發現ASO可以迅速增加毒物外顯子的包含，從本質上欺騙癌細胞，轉化為自身的生長信號。” “這些毒物外顯子像變阻器一樣工作，迅速調整蛋白質水平並可以使ASO成為高度精確且有效的侵略性癌症的療法。”

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，當研究人員使用CRISPR基因編輯完全去除TRA2B蛋白時，腫瘤繼續增長，將靶向RNA而不是蛋白質的靶向可能是一種更有效的方法。 Anczukow解釋說：“這告訴我們，含毒藥的RNA不僅使Tra2b保持沉默。” “它可能會隔離其他RNA結合蛋白，從而為癌細胞創造更具毒性的環境。”

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.

進一步的研究將完善基於ASO的療法，並探索它們向腫瘤的分娩。但是，初步數據表明，ASO是高度特異性的，並且不會干擾正常的細胞功能，從而使他們有望接受未來的癌症治療。

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