Institute of Zoology-Developmental Biology, University of Cologne, Germany.
Cell and Developmental Biology, Center of Human and Molecular Biology (ZHMB), Saarland University, Faculty of Medicine, Homburg/Saar, Germany.
PLoS Genet. 2023 Aug 11;19(8):e1010873. doi: 10.1371/journal.pgen.1010873. eCollection 2023 Aug.
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.
异常上调的 II 型跨膜蛋白酶 Matriptase-1 的活性与一系列上皮来源的癌的发生和发展有关，多种信号通路可以介导 Matriptase 依赖性肿瘤发生事件。在哺乳动物癌变过程中，Matriptase 活性的增加通常是由于 Matriptase 与其膜结合抑制剂 Hai1 的不平衡比例所致。同样，在斑马鱼中，由于 hai1a 的缺失导致不受限制的 Matriptase 活性，在胚胎发生期间就会导致表皮前肿瘤。在这里，基于我们之前发现的 Na+/K+-泵β亚基 ATP1b1a 具有相似的肿瘤抑制作用，我们确定上皮极性缺陷和全身低渗应激是体内斑马鱼表皮中另一种异常 Matriptase 激活的模式。然而，在这种情况下，激活的是另一种致癌途径，其中包含 PI3K、AKT 和 NFkB，而不是 EGFR 和 PLD（如 hai1a 突变体）。引人注目的是，只有当角蛋白细胞中的上皮极性缺陷（导致 Matriptase 亚细胞定位紊乱）与全身低渗应激（导致 Matriptase 蛋白水解活性增加）同时发生时，才会诱导表皮前肿瘤。在人 MCF-10A 上皮乳腺细胞中，Matriptase-1 的活性水平也获得了类似的低渗性和上皮极性缺失的组合效应。总的来说，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启动子（这里是 ATP1a1b）分支出来，并可以在同一个介质（这里是 Matriptase）水平再次汇聚。总之，我们的数据表明，渗透压和上皮细胞极性是 Matriptase 活性的进化保守调节剂，其失调可能构成体内 Matriptase 依赖性致癌作用的另一种模式。
