Turato Cristian, Cannito Stefania, Simonato Davide, Villano Gianmarco, Morello Elisabetta, Terrin Liliana, Quarta Santina, Biasiolo Alessandra, Ruvoletto Mariagrazia, Martini Andrea, Fasolato Silvano, Zanus Giacomo, Cillo Umberto, Gatta Angelo, Parola Maurizio, Pontisso Patrizia
Dept. of Medicine, University of Padova, Italy.
Dept. of Clinical and Biological Sciences, Unit of Experimental Medicine and Interuniversity Center for Liver Pathophysiology, University of Torino, Italy.
Sci Rep. 2015 Dec 4;5:17701. doi: 10.1038/srep17701.
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.
丝氨酸蛋白酶抑制剂B3（SerpinB3）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知之甚少。Myc的过表达通常与更具侵袭性的肿瘤形式相关，这支持了其参与致癌作用。Yes相关蛋白（Yap）是Hippo通路的主要效应器，是增殖的核心调节因子，并且已发现在肝细胞癌中上调。本研究旨在调查和表征SerpinB3在肝癌中对Myc的相互作用和功能调节。该研究结果表明，在过表达人SerpinB3的转基因小鼠和肝癌细胞以及人肝细胞癌中，SerpinB3通过钙蛋白酶和Hippo依赖性分子机制上调Myc。人重组SerpinB3能够在体外抑制钙蛋白酶的活性，可能降低其切割非致癌性Myc-nick细胞质形式的Myc的能力。SerpinB3通过诱导Yap通路间接增加Myc的转录。这些发现首次提供了证据，表明SerpinB3可以通过直接和间接机制提高Myc的产生，这些机制包括抑制其细胞质形式的产生和激活Yap通路。
