近日,，國際著名雜志Cancer Research在線刊登了哈佛醫(yī)學(xué)院等處研究者的最新研究成果“Loss of Rassf1a Synergizes with Deregulated Runx2 Signaling in Tumorigenesis”，文章中,，研究者揭示了在腫瘤發(fā)生期間,，基因RASSF1A的缺失解除了其對基因Runx2的控制作用。
在人類許多癌癥疾病中,，腫瘤抑制基因RASSF1A都可以通過點突變或者超甲基化而變得失活，研究者Eric O’Neill表示,，在這項研究中,，他們在無基因RASSF1A的小鼠體內(nèi)構(gòu)建了Sleeping Beauty轉(zhuǎn)座子介導(dǎo)的插入突變篩選裝置，目的是為了研究在腫瘤發(fā)生期間基因RASSF1A缺失后的“替補基因”,。
通過篩選,，研究者識別到了10個基因，包括轉(zhuǎn)錄因子Runx2，這是一個Yes相關(guān)蛋白（YAP1）的轉(zhuǎn)錄配偶體,，可以通過與致癌的轉(zhuǎn)錄因子TEA結(jié)構(gòu)域家族（TEAD）競爭從而達到抑制腫瘤發(fā)生的目的,。當(dāng)小鼠體內(nèi)缺失基因RASSF1A后，可以促使致癌YAP1-TEAD復(fù)合物的形成,，而且同時缺少RASSF1A和RUNX2的話,，也可以增加該復(fù)合物的水平。
許多癌癥中,，RUNX2的表達是下調(diào)的,，而且降低該基因的表達可以導(dǎo)致彌散B細(xì)胞或者淋巴瘤病人的低生存率。在前體T細(xì)胞記性成淋巴細(xì)胞性白血病和結(jié)直腸癌患者中,，也可以觀察到明顯的基因RASSF1和RUNX2的水平明顯降低,。
因此研究者在文章中揭示了，基因RASSF1A表達的缺失可以開關(guān)YAP1的功能,，通過調(diào)節(jié)其相關(guān)的轉(zhuǎn)錄因子來使其從腫瘤抑制子變?yōu)榘┌Y基因,，同樣這也是RASSF1A所介導(dǎo)的腫瘤抑制的一個新的分子機制。（生物谷Bioon.com）
doi:10.1158/0008-5472.CAN-11-3343
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Loss of Rassf1a Synergizes with Deregulated Runx2 Signaling in Tumorigenesis
Louise van der Weyden1, Angelos Papaspyropoulos3, George Poulogiannis4, Alistair G. Rust1, Mamunur Rashid1, David J. Adams1, Mark J. Arends2, and Eric O'Neill3
The tumor suppressor gene RASSF1A is inactivated through point mutation or promoter hypermethylation in many human cancers. In this study, we conducted a Sleeping Beauty transposon-mediated insertional mutagenesis screen in Rassf1a-null mice to identify candidate genes that collaborate with loss of Rassf1a in tumorigenesis. We identified 10 genes, including the transcription factor Runx2, a transcriptional partner of Yes-associated protein (YAP1) that displays tumor suppressive activity through competing with the oncogenic TEA domain family of transcription factors (TEAD) for YAP1 association. While loss of RASSF1A promoted the formation of oncogenic YAP1-TEAD complexes, the combined loss of both RASSF1A and RUNX2 further increased YAP1-TEAD levels, showing that loss of RASSF1A, together with RUNX2, is consistent with the multistep model of tumorigenesis. Clinically, RUNX2 expression was frequently downregulated in various cancers, and reduced RUNX2 expression was associated with poor survival in patients with diffuse large B-cell or atypical Burkitt/Burkitt-like lymphomas. Interestingly, decreased expression levels of RASSF1 and RUNX2 were observed in both precursor T-cell acute lymphoblastic leukemia and colorectal cancer, further supporting the hypothesis that dual regulation of YAP1-TEAD promotes oncogenic activity. Together, our findings provide evidence that loss of RASSF1A expression switches YAP1 from a tumor suppressor to an oncogene through regulating its association with transcription factors, thereby suggesting a novel mechanism for RASSF1A-mediated tumor suppression. Cancer Res; 72(15); 3817–27. ©2012 AACR.
