CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université, F-63171 Aubière Cedex, France.
Developmental Endocrine Oncology and Genetics, Section on Genetics and Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland 20892-1103, USA.
Nat Commun. 2016 Sep 14;7:12751. doi: 10.1038/ncomms12751.
Adrenal cortex physiology relies on functional zonation, essential for production of aldosterone by outer zona glomerulosa (ZG) and glucocorticoids by inner zona fasciculata (ZF). The cortex undergoes constant cell renewal, involving recruitment of subcapsular progenitors to ZG fate and subsequent lineage conversion to ZF identity. Here we show that WNT4 is an important driver of WNT pathway activation and subsequent ZG differentiation and demonstrate that PKA activation prevents ZG differentiation through WNT4 repression and WNT pathway inhibition. This suggests that PKA activation in ZF is a key driver of WNT inhibition and lineage conversion. Furthermore, we provide evidence that constitutive PKA activation inhibits, whereas partial inactivation of PKA catalytic activity stimulates β-catenin-induced tumorigenesis. Together, both lower PKA activity and higher WNT pathway activity lead to poorer prognosis in adrenocortical carcinoma (ACC) patients. These observations suggest that PKA acts as a tumour suppressor in the adrenal cortex, through repression of WNT signalling.
肾上腺皮质生理学依赖于功能分区，这对于由外层球状带（ZG）产生醛固酮和由内层束状带（ZF）产生糖皮质激素至关重要。皮质不断进行细胞更新，涉及到从皮质下祖细胞募集到 ZG 命运，并随后进行谱系转换以获得 ZF 特征。本文研究表明，WNT4 是 WNT 途径激活以及随后的 ZG 分化的重要驱动因素，并证明 PKA 激活通过 WNT4 抑制和 WNT 途径抑制来防止 ZG 分化。这表明 PKA 在 ZF 中的激活是 WNT 抑制和谱系转换的关键驱动因素。此外，本文还提供了证据表明，PKA 的持续激活抑制了，而 PKA 催化活性的部分失活则刺激了β-连环蛋白诱导的肿瘤发生。总的来说，较低的 PKA 活性和较高的 WNT 途径活性导致肾上腺皮质癌（ACC）患者预后较差。这些观察结果表明，PKA 通过抑制 WNT 信号转导，在肾上腺皮质中作为一种肿瘤抑制因子发挥作用。
