Centre de Recherche sur le Cancer, Université Laval, Québec, Canada.
axe oncologie du Centre de Recherche du Centre Hospitalier, Universitaire de Québec-UL, Québec, Canada.
PLoS Genet. 2020 Mar 20;16(3):e1008674. doi: 10.1371/journal.pgen.1008674. eCollection 2020 Mar.
Epithelial cell polarity defects support cancer progression. It is thus crucial to decipher the functional interactions within the polarity protein network. Here we show that Drosophila Girdin and its human ortholog (GIRDIN) sustain the function of crucial lateral polarity proteins by inhibiting the apical kinase aPKC. Loss of GIRDIN expression is also associated with overgrowth of disorganized cell cysts. Moreover, we observed cell dissemination from GIRDIN knockdown cysts and tumorspheres, thereby showing that GIRDIN supports the cohesion of multicellular epithelial structures. Consistent with these observations, alteration of GIRDIN expression is associated with poor overall survival in subtypes of breast and lung cancers. Overall, we discovered a core mechanism contributing to epithelial cell polarization from flies to humans. Our data also indicate that GIRDIN has the potential to impair the progression of epithelial cancers by preserving cell polarity and restricting cell dissemination.
上皮细胞极性缺陷支持癌症进展。因此，解析极性蛋白网络内的功能相互作用至关重要。在这里，我们表明果蝇 Girdin 及其人类同源物（GIRDIN）通过抑制顶端激酶 aPKC 来维持关键的侧向极性蛋白的功能。GIRDIN 表达的丧失也与无序细胞囊泡的过度生长有关。此外，我们观察到从 GIRDIN 敲低的囊泡和肿瘤球体中细胞的扩散，从而表明 GIRDIN 支持多细胞上皮结构的凝聚力。与这些观察结果一致的是，GIRDIN 表达的改变与乳腺癌和肺癌亚型的整体生存不良有关。总的来说，我们从苍蝇到人类发现了一个有助于上皮细胞极化的核心机制。我们的数据还表明，GIRDIN 通过保持细胞极性和限制细胞扩散，有可能损害上皮癌的进展。
