Division of Molecular Oncology, Aichi Cancer Center Research Institute, Nagoya, Japan.
Cancer Res. 2011 Feb 1;71(3):873-83. doi: 10.1158/0008-5472.CAN-10-2164. Epub 2011 Jan 18.
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.
恶性间皮瘤（MM）是一种与石棉暴露有关的侵袭性肿瘤。我们对 14 种 MM 细胞系进行了基于全基因组芯片的比较基因组杂交分析。三种细胞系在染色体 13q12 上表现出重叠的纯合性缺失，该区域包含 LATS2（大肿瘤抑制物同源物 2）基因。在另外 6 种 MM 细胞系和 25 种 MM 肿瘤中，我们在 45 种 MM 中发现了 10 种 LATS2 的失活性纯合缺失或突变。LATS2 编码一种丝氨酸/苏氨酸激酶，是 Hippo 肿瘤抑制信号通路的一个组成部分，我们将携带突变的 LATS2 转导到 MM 细胞中。通过磷酸化，转导 LATS2 使癌蛋白 YAP（一种转录共激活因子）失活，并抑制 MM 细胞生长。我们还通过免疫组织化学分析了 LATS2，发现 45 种 MM 肿瘤中有 13 种 LATS2 表达水平较低。由于 NF2 在 40%至 50%的 MM 中发生遗传突变，我们的数据表明，在 LATS2 失活或其上游通路调节因子 Merlin（由 NF2 编码）的 MM 细胞中，Hippo 通路失调很常见。因此，我们的结果表明，LATS2 的失活是 YAP 持续激活的关键机制之一，这会导致 MM 细胞增殖的失调。
