小柯机器人

以色列希伯来大学Rotem Karni课题组发现，RBFOX2调控胰腺癌中可变剪接的一种转移特征。这一研究成果于2023年3月22日在线发表在国际学术期刊《自然》上。

研究人员分析了一大批原发性和转移性胰腺导管腺癌（PDA）肿瘤的RNA剪接数据，以确定与PDA进展相关的不同剪接事件。对这些事件进行从头模体分析，研究人员发现与RBFOX2模体高度相似的模体富集。在患者来源的异种移植（PDX）转移性PDA细胞系中过量表达RBFOX2，大大降低了这些细胞在体外和体内的转移潜力，而在原发性胰腺肿瘤细胞系中敲除RBFOX2则增加了这些细胞的转移潜力。

这些发现支持RBFOX2在PDA中作为一种有效的转移抑制因子的作用。对RBFOX2靶基因的RNA测序和剪接分析显示RHO GTP酶途径中的基因富集，这表明RBFOX2剪接活动在细胞骨架组织和焦点粘附形成中的作用。改变RBFOX2调节的剪接事件，如通过肌球蛋白磷酸酶RHO-交互蛋白（MPRIP），与PDA转移、细胞骨架组织的改变和诱导局灶粘附的形成有关。这些研究结果表明，RBFOX2的剪接调控功能是PDA的肿瘤抑制因子，并提出了转移性PDA的治疗方法。

据介绍，PDA的特点是积极的局部侵袭和转移性扩散，导致高致死率。虽然PDA进展过程中的驱动基因突变是保守的，但没有特定的突变与转移灶的传播相关。

附：英文原文

Title: RBFOX2 modulates a metastatic signature of alternative splicing in pancreatic cancer

Author: Jbara, Amina, Lin, Kuan-Ting, Stossel, Chani, Siegfried, Zahava, Shqerat, Haya, Amar-Schwartz, Adi, Elyada, Ela, Mogilevsky, Maxim, Raitses-Gurevich, Maria, Johnson, Jared L., Yaron, Tomer M., Ovadia, Ofek, Jang, Gun Ho, Danan-Gotthold, Miri, Cantley, Lewis C., Levanon, Erez Y., Gallinger, Steven, Krainer, Adrian R., Golan, Talia, Karni, Rotem

Issue&Volume: 2023-03-22

Abstract: Pancreatic ductal adenocarcinoma (PDA) is characterized by aggressive local invasion and metastatic spread, leading to high lethality. Although driver gene mutations during PDA progression are conserved, no specific mutation is correlated with the dissemination of metastases1,2,3. Here we analysed RNA splicing data of a large cohort of primary and metastatic PDA tumours to identify differentially spliced events that correlate with PDA progression. De novo motif analysis of these events detected enrichment of motifs with high similarity to the RBFOX2 motif. Overexpression of RBFOX2 in a patient-derived xenograft (PDX) metastatic PDA cell line drastically reduced the metastatic potential of these cells in vitro and in vivo, whereas depletion of RBFOX2 in primary pancreatic tumour cell lines increased the metastatic potential of these cells. These findings support the role of RBFOX2 as a potent metastatic suppressor in PDA. RNA-sequencing and splicing analysis of RBFOX2 target genes revealed enrichment of genes in the RHO GTPase pathways, suggesting a role of RBFOX2 splicing activity in cytoskeletal organization and focal adhesion formation. Modulation of RBFOX2-regulated splicing events, such as via myosin phosphatase RHO-interacting protein (MPRIP), is associated with PDA metastases, altered cytoskeletal organization and the induction of focal adhesion formation. Our results implicate the splicing-regulatory function of RBFOX2 as a tumour suppressor in PDA and suggest a therapeutic approach for metastatic PDA.

DOI: 10.1038/s41586-023-05820-3

Source: https://www.nature.com/articles/s41586-023-05820-3

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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