SerpinB3 and Yap Interplay Increases Myc Oncogenic Activity.
SerpinB3 and Yap Interplay Increases Myc Oncogenic Activity.
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DOI：
10.1038/srep17701
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发表时间：
2015-12-04
影响因子：
4.6
通讯作者：
Pontisso P
中科院分区：
文献类型：
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作者：
Turato C;Cannito S;Simonato D;Villano G;Morello E;Terrin L;Quarta S;Biasiolo A;Ruvoletto M;Martini A;Fasolato S;Zanus G;Cillo U;Gatta A;Parola M;Pontisso P
丝氨酸蛋白酶抑制剂B3最近被描述为肝癌发生的早期标志物，但这种丝氨酸蛋白酶抑制剂在肿瘤发展中的潜在机制作用仍然知之甚少。Myc的过表达通常与更具侵袭性的肿瘤形式相关，支持其参与致癌作用。是相关蛋白（雅普），Hippo通路的主要效应子，是增殖的中心调节因子，并且已发现其在肝细胞癌中上调。本研究旨在研究和表征SerpinB 3在肝癌中与Myc的相互作用和功能调节。这项研究的结果表明，Myc上调SerpinB 3通过钙蛋白酶和海马依赖的分子机制，在转基因小鼠和肝癌细胞过度表达人SerpinB 3，也在人肝细胞癌。人重组SerpinB 3能够在体外抑制Calpain的活性，可能降低其切割非致癌Myc-切口胞质形式的Myc的能力。SerpinB 3通过诱导雅普通路间接增加Myc的转录。这些发现首次证明SerpinB 3可以通过直接和间接的机制促进Myc的产生，包括抑制其胞质形式的产生和激活雅普通路。
SerpinB3 has been recently described as an early marker of liver carcinogenesis, but the potential mechanistic role of this serpin in tumor development is still poorly understood. Overexpression of Myc often correlates with more aggressive tumour forms, supporting its involvement in carcinogenesis. Yes-associated protein (Yap), the main effector of the Hippo pathway, is a central regulator of proliferation and it has been found up-regulated in hepatocellular carcinomas. The study has been designed to investigate and characterize the interplay and functional modulation of Myc by SerpinB3 in liver cancer. Results from this study indicate that Myc was up-regulated by SerpinB3 through calpain and Hippo-dependent molecular mechanisms in transgenic mice and hepatoma cells overexpressing human SerpinB3, and also in human hepatocellular carcinomas. Human recombinant SerpinB3 was capable to inhibit the activity of Calpain in vitro, likely reducing its ability to cleave Myc in its non oncogenic Myc-nick cytoplasmic form. SerpinB3 indirectly increased the transcription of Myc through the induction of Yap pathway. These findings provide for the first time evidence that SerpinB3 can improve the production of Myc through direct and indirect mechanisms that include the inhibition of generation of its cytoplasmic form and the activation of Yap pathway.