LATS2 Is a Tumor Suppressor Gene of Malignant Mesothelioma
LATS2 Is a Tumor Suppressor Gene of Malignant Mesothelioma
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DOI：
10.1158/0008-5472.can-10-2164
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发表时间：
2011-02-01
期刊：
影响因子：
11.2
通讯作者：
Sekido, Yoshitaka
中科院分区：
文献类型：
--
作者：
Murakami, Hideki;Mizuno, Tetsuya;Sekido, Yoshitaka
恶性间皮瘤（MM）是一种与石棉接触有关的侵袭性肿瘤。我们用14个MM细胞系进行了基于全基因组阵列的比较基因组杂交分析。三个细胞系显示染色体13 q12处的重叠纯合缺失，其含有LATS 2（大肿瘤抑制基因同源物2）基因。在其他6个MM细胞系和25个MM肿瘤中，我们在45个MM中发现了10个LATS 2的失活纯合缺失或突变。LATS 2编码丝氨酸/苏氨酸激酶，这是Hippo肿瘤抑制信号通路的一个组成部分，我们在MM细胞中转导LATS 2及其突变。LATS 2的转导通过磷酸化使癌蛋白雅普（一种转录辅激活因子）失活，并抑制MM细胞生长。我们还对LATS 2进行了化学分析，发现45例MM肿瘤中有13例LATS 2表达较低。由于NF 2在40%至50%的MM中发生遗传突变，我们的数据表明Hippo通路失调在MM细胞中频繁发生，LATS 2或该通路的上游调节因子Merlin（由NF 2编码）失活。因此，我们的研究结果表明LATS 2的失活是雅普组成性激活的关键机制之一，其诱导MM细胞增殖的失调。Cancer Res; 71（3）; 873-83.（C）2011年《非洲标准化评论》。
Malignant mesothelioma (MM) is an aggressive neoplasm associated with asbestos exposure. We carried out genome-wide array-based comparative genomic hybridization analysis with 14 MM cell lines. Three cell lines showed overlapping homozygous deletion at chromosome 13q12, which harbored the LATS2 (large tumor suppressor homolog 2) gene. With 6 other MM cell lines and 25 MM tumors, we found 10 inactivating homozygous deletions or mutations of LATS2 among 45 MMs. LATS2 encodes a serine/threonine kinase, a component of the Hippo tumor-suppressive signaling pathway, and we transduced LATS2 in MM cells with its mutation. Transduction of LATS2 inactivated oncoprotein YAP, a transcriptional coactivator, via phosphorylation, and inhibited MM cell growth. We also analyzed LATS2 immunohistochemically and found that 13 of 45 MM tumors had low expression of LATS2. Because NF2 is genetically mutated in 40% to 50% of MM, our data indicate that Hippo pathway dysregulation is frequent in MM cells with inactivation of LATS2 or an upstream regulator of this pathway, Merlin, which is encoded by NF2. Thus, our results suggest that the inactivation of LATS2 is one of the key mechanisms for constitutive activation of YAP, which induces deregulation of MM cell proliferation. Cancer Res; 71(3); 873-83. (C)2011 AACR.