Cancer Res：肿瘤抑制基因RASSF1A的缺失或引发新癌基因的诞生

近日，国际著名杂志Cancer Research在线刊登了哈佛医学院等处研究者的最新研究成果“Loss of Rassf1a Synergizes with Deregulated Runx2 Signaling in Tumorigenesis”，文章中，研究者揭示了在肿瘤发生期间，基因RASSF1A的缺失解除了其对基因Runx2的控制作用。

在人类许多癌症疾病中，肿瘤抑制基因RASSF1A都可以通过点突变或者超甲基化而变得失活，研究者Eric O’Neill表示，在这项研究中，他们在无基因RASSF1A的小鼠体内构建了Sleeping Beauty转座子介导的插入突变筛选装置，目的是为了研究在肿瘤发生期间基因RASSF1A缺失后的“替补基因”。

通过筛选，研究者识别到了10个基因，包括转录因子Runx2，这是一个Yes相关蛋白（YAP1）的转录配偶体，可以通过与致癌的转录因子TEA结构域家族（TEAD）竞争从而达到抑制肿瘤发生的目的。当小鼠体内缺失基因RASSF1A后，可以促使致癌YAP1-TEAD复合物的形成，而且同时缺少RASSF1A和RUNX2的话，也可以增加该复合物的水平。

许多癌症中，RUNX2的表达是下调的，而且降低该基因的表达可以导致弥散B细胞或者淋巴瘤病人的低生存率。在前体T细胞记性成淋巴细胞性白血病和结直肠癌患者中，也可以观察到明显的基因RASSF1和RUNX2的水平明显降低。

因此研究者在文章中揭示了，基因RASSF1A表达的缺失可以开关YAP1的功能，通过调节其相关的转录因子来使其从肿瘤抑制子变为癌症基因，同样这也是RASSF1A所介导的肿瘤抑制的一个新的分子机制。

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.