TGF-β synergizes with defects in the Hippo pathway to stimulate human malignant mesothelioma growth.
TGF-β synergizes with defects in the Hippo pathway to stimulate human malignant mesothelioma growth.
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DOI：
10.1084/jem.20111653
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发表时间：
2012-03-12
期刊：
影响因子：
--
通讯作者：
Sekido Y
中科院分区：
文献类型：
--
作者：
Fujii M;Toyoda T;Nakanishi H;Yatabe Y;Sato A;Matsudaira Y;Ito H;Murakami H;Kondo Y;Kondo E;Hida T;Tsujimura T;Osada H;Sekido Y
Hippo 和 TGF-β 与 CTGF 汇聚，促进恶性间皮瘤。恶性间皮瘤（MM）是一种无法治愈的恶性肿瘤，由接触石棉引起，并伴有严重的纤维化。由于多发性骨髓瘤 (MM) 诊断时通常已是晚期，且早期病变的临床识别困难，其分子发病机制尚未完全阐明。近 75% 的 MM 病例在 NF2（2 型神经纤维瘤病；Merlin）基因或 Hippo 信号级联的下游信号分子中存在失活突变，该突变对转录因子 Yes 相关蛋白 (YAP) 产生负调节。在这项研究中，我们证明了 Hippo 和 TGF-β 通路在调节结缔组织生长因子 (CTGF) 方面的功能相互作用。 MM 细胞中 CTGF 的表达是通过在 CTGF 启动子上形成 YAP-TEAD4-Smad3-p300 复合物来诱导的。降低 MM 细胞中的 CTGF 表达可延长异种移植小鼠的存活时间，并且在 MM 异种移植物和患者组织标本中发现 CTGF 表达与细胞外基质沉积之间存在显着关联。我们进一步认为，由于在人类 MM 组织中观察到不同的组织学表达模式，CTGF 可能会影响间皮瘤的恶性程度。这些数据表明，CTGF 是 MM 生长和病理学的重要调节剂，代表了该疾病的新治疗靶点。
Hippo and TGF-β converge on CTGF to promote malignant mesothelioma. Malignant mesothelioma (MM) is an incurable malignancy that is caused by exposure to asbestos and is accompanied by severe fibrosis. Because MM is usually diagnosed at an advanced stage and clinical identification of early lesions is difficult, its molecular pathogenesis has not been completely elucidated. Nearly 75% of MM cases have inactivating mutations in the NF2 (neurofibromatosis type 2; Merlin) gene or in downstream signaling molecules of the Hippo signaling cascade, which negatively regulates the transcription factor Yes-associated protein (YAP). In this study, we demonstrate a functional interaction between the Hippo and TGF-β pathways in regulating connective tissue growth factor (CTGF). Expression of CTGF in MM cells was induced by the formation of a YAP–TEAD4–Smad3–p300 complex on the CTGF promoter. Knocking down CTGF expression in MM cells prolonged the survival of xenografted mice, and a significant association was seen between CTGF expression and extracellular matrix deposition in MM xenografts and in patient tissue specimens. We further suggest that CTGF may influence the malignancy of mesothelioma because of the different histological expression patterns observed in human MM tissues. These data suggest that CTGF is an important modulator of MM growth and pathology and represents a novel therapeutic target for this disease.
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