美国加州大学旧金山分校Hani Goodarzi研究组发现一个促进肿瘤转移的剪接程序。这一研究成果发表在2021年5月14日出版的国际学术期刊《科学》上。

研究人员对RNA结构编码进行了解析，这些RNA结构编码在乳腺癌转移过程中塑造病理性剪接。研究人员发现了一个以前未知的结构剪接增强子，该增强子在盒式外显子附近富集，并在高度转移的细胞中具有更高的出现率。研究人员表明，剪接体蛋白小核糖核糖核蛋白多肽A'（SNRPA1）与这些增强子相互作用，从而促进盒式外显子的包含。

这种相互作用增强了转移性肺部定植和癌细胞的侵袭，部分是通过SNRPA1介导的PLEC选择性剪接调节，这可以通过剪接调节吗啉代物来抵消。这项发现确立了SNRPA1作为乳腺癌促转移剪接增强子的非经典调节作用。

据悉，异常的可变剪接是癌症的标志，但是控制该过程的基本调控程序仍然未知。

附：英文原文

Title: A prometastatic splicing program regulated by SNRPA1 interactions with structured RNA elements

Author: Lisa Fish, Matvei Khoroshkin, Albertas Navickas, Kristle Garcia, Bruce Culbertson, Benjamin Hnisch, Steven Zhang, Hoang C. B. Nguyen, Larisa M. Soto, Maria Dermit, Faraz K. Mardakheh, Henrik Molina, Claudio Alarcón, Hamed S. Najafabadi, Hani Goodarzi

Issue&Volume: 2021/05/14

Abstract: Aberrant alternative splicing is a hallmark of cancer, yet the underlying regulatory programs that control this process remain largely unknown. Here, we report a systematic effort to decipher the RNA structural code that shapes pathological splicing during breast cancer metastasis. We discovered a previously unknown structural splicing enhancer that is enriched near cassette exons with increased inclusion in highly metastatic cells. We show that the spliceosomal protein small nuclear ribonucleoprotein polypeptide A′ (SNRPA1) interacts with these enhancers to promote cassette exon inclusion. This interaction enhances metastatic lung colonization and cancer cell invasion, in part through SNRPA1-mediated regulation of PLEC alternative splicing, which can be counteracted by splicing modulating morpholinos. Our findings establish a noncanonical regulatory role for SNRPA1 as a prometastatic splicing enhancer in breast cancer.

DOI: 10.1126/science.abc7531

Source: https://science.sciencemag.org/content/372/6543/eabc7531