与Matriptase-1型II跨膜蛋白酶的异常上调活性有关的，已经与多种上皮源性癌症的发展和进展相关联，并且多种信号通路可以介导Matriptase依赖的肿瘤发生事件。在哺乳动物的致癌过程中，Matriptase活性的增加往往是由于Matriptase与其配体跨膜抑制剂Hai1之间比例失衡导致的。类似地，在斑马鱼中，由于 hai1a 的丢失导致Matriptase活性不受限制，已在胚胎发育过程中形成表皮癌前病变。基于我们之前发现的钠钾泵β亚单位ATP1b1a在抑制肿瘤方面的类似作用，我们在此确认了上皮细胞极性缺陷和全身性低渗应力作为斑马鱼胚胎表皮中异常Matriptase激活的另一种方式。然而，在这种情况下，激活了另一种包含PI3K、AKT和NFkB的致癌通路，而不是EGFR和PLD（如 hai1a 突变体）。令人惊讶的是，只有当角质细胞中的上皮细胞极性缺陷（导致Matriptase亚细胞定位障碍）与全身低渗应力（导致Matriptase的蛋白酶活性增加）相结合时，才会诱导表皮癌前病变。在人类MCF-10A上皮乳腺细胞中，低渗和丧失上皮细胞极性也对Matriptase-1的活性水平产生了类似的联合效应。总之，我们的数据表明环境渗透性和上皮细胞极性作为Matriptase活性的进化保守调控因子，当失调时可以构成Matriptase依赖性癌症发生的一种替代方式。版权所有：© 2023 Hatzold等人。本文是根据知识共享署名许可证开放获取的文章，允许无限制使用、分发和再制作，前提是保留原始作者和来源的署名。

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.Copyright: © 2023 Hatzold et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.