Matriptase-dependent epidermal pre-neoplasm in zebrafish embryos caused by a combination of hypotonic stress and epithelial polarity defects.

IF 4.5 2区 生物学 Q1 Agricultural and Biological Sciences PLoS Genetics Pub Date : 2023-08-11 eCollection Date: 2023-08-01 DOI:10.1371/journal.pgen.1010873
Julia Hatzold, Verena Nett, Stephanie Brantsch, Jin-Li Zhang, Joy Armistead, Heike Wessendorf, Rebecca Stephens, Patrick O Humbert, Sandra Iden, Matthias Hammerschmidt
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Abstract

Aberrantly up-regulated activity of the type II transmembrane protease Matriptase-1 has been associated with the development and progression of a range of epithelial-derived carcinomas, and a variety of signaling pathways can mediate Matriptase-dependent tumorigenic events. During mammalian carcinogenesis, gain of Matriptase activity often results from imbalanced ratios between Matriptase and its cognate transmembrane inhibitor Hai1. Similarly, in zebrafish, unrestrained Matriptase activity due to loss of hai1a results in epidermal pre-neoplasms already during embryogenesis. Here, based on our former findings of a similar tumor-suppressive role for the Na+/K+-pump beta subunit ATP1b1a, we identify epithelial polarity defects and systemic hypotonic stress as another mode of aberrant Matriptase activation in the embryonic zebrafish epidermis in vivo. In this case, however, a different oncogenic pathway is activated which contains PI3K, AKT and NFkB, rather than EGFR and PLD (as in hai1a mutants). Strikingly, epidermal pre-neoplasm is only induced when epithelial polarity defects in keratinocytes (leading to disturbed Matriptase subcellular localization) occur in combination with systemic hypotonic stress (leading to increased proteolytic activity of Matriptase). A similar combinatorial effect of hypotonicity and loss of epithelial polarity was also obtained for the activity levels of Matriptase-1 in human MCF-10A epithelial breast cells. Together, this is in line with the multi-factor concept of carcinogenesis, with the notion that such factors can even branch off from one and the same initiator (here ATP1a1b) and can converge again at the level of one and the same mediator (here Matriptase). In sum, our data point to tonicity and epithelial cell polarity as evolutionarily conserved regulators of Matriptase activity that upon de-regulation can constitute an alternative mode of Matriptase-dependent carcinogenesis in vivo.

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由低张应激和上皮极性缺陷联合引起的斑马鱼胚胎中基质蛋白酶依赖性表皮前肿瘤。
II型跨膜蛋白酶基质蛋白酶-1活性异常上调与一系列上皮衍生癌的发展和进展有关,多种信号通路可介导基质蛋白酶依赖性致瘤事件。在哺乳动物致癌过程中,基质酶活性的增加通常是由于基质酶与其同源跨膜抑制剂Hai1之间的比例不平衡造成的。同样,在斑马鱼中,由于hai1a的缺失而导致的无限制的基质酶活性导致胚胎发生过程中的表皮前肿瘤。在此,基于我们先前发现的Na+/K+-泵β亚基ATP1b1a具有类似的肿瘤抑制作用,我们确定上皮极性缺陷和全身低张应激是体内胚胎斑马鱼表皮中基质蛋白酶异常激活的另一种模式。然而,在这种情况下,一种不同的致癌途径被激活,它包含PI3K、AKT和NFkB,而不是EGFR和PLD(如在hai1a突变体中)。引人注目的是,只有当角质形成细胞中的上皮极性缺陷(导致基质蛋白酶亚细胞定位紊乱)与系统性低张应激(导致基质酶的蛋白水解活性增加)相结合时,才会诱导表皮前肿瘤。对于人MCF-10A乳腺上皮细胞中基质蛋白酶-1的活性水平,也获得了类似的低张力和上皮极性丧失的组合效应。总之,这符合致癌作用的多因素概念,即这些因素甚至可以从同一个引发剂(此处为ATP1a1b)分支出来,并可以在同一个介体(此处为基质酶)的水平上再次聚集。总之,我们的数据表明,张力和上皮细胞极性是基质酶活性的进化保守调节因子,在去调节后,可以构成体内基质酶依赖性致癌的另一种模式。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
PLoS Genetics
PLoS Genetics 生物-遗传学
CiteScore
8.10
自引率
2.20%
发文量
438
审稿时长
1 months
期刊介绍: PLOS Genetics is run by an international Editorial Board, headed by the Editors-in-Chief, Greg Barsh (HudsonAlpha Institute of Biotechnology, and Stanford University School of Medicine) and Greg Copenhaver (The University of North Carolina at Chapel Hill). Articles published in PLOS Genetics are archived in PubMed Central and cited in PubMed.
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