Morimoto Eisaku, Inagaki Kenichi, Komatsubara Motoshi, Terasaka Tomohiro, Itoh Yoshihiko, Fujisawa Satoshi, Sasaki Erika, Nishiyama Yuki, Hara Takayuki, Wada Jun
Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama, 700-8558, Japan.
J Endocr Soc. 2022 Aug 5;6(10):bvac121. doi: 10.1210/jendso/bvac121. eCollection 2022 Oct 1.
Pheochromocytomas and paragangliomas (PPGLs) are classified into 3 major categories with distinct driver genes: pseudohypoxia, kinase signaling, and Wnt-altered subtypes. PPGLs in the Wnt-altered subtype are sporadic and tend to be aggressive with metastasis, where somatic gene fusions affecting mastermind-like 3 () and somatic mutations in cold shock domain containing E1 () cause overactivation of Wnt-β-catenin signaling. However, the relation between Wnt-β-catenin signaling and the biological behavior of PPGLs remains unexplored. In rat pheochromocytoma PC12 cells, Wnt3a treatment enhanced cell proliferation and suppressed mRNA expression of tyrosine hydroxylase (), the rate-limiting enzyme of catecholamine biosynthesis, and dopamine secretion. We identified the expression of sclerostin in PC12 cells, which is known as an osteocyte-derived negative regulator for Wnt signaling-driven bone formation. Inhibition of endogenous Wnt pathway by XAV939 or sclerostin resulted in attenuated cell proliferation and increased expression. Furthermore, Wnt3a pretreatment suppressed bone morphogenetic protein (BMP)-induced Smad1/5/9 phosphorylation whereas BMPs enhanced sclerostin expression in PC12 cells. In the Wnt-altered subtype, the increased Wnt-β-catenin pathway may contribute the aggressive clinical behavior with reduced catecholamine production. Furthermore, upregulated expression of sclerostin by BMPs may explain the osteolytic metastatic lesions observed in metastatic PPGLs.
嗜铬细胞瘤和副神经节瘤（PPGLs）分为具有不同驱动基因的三大类：假性低氧、激酶信号传导和Wnt改变亚型。Wnt改变亚型的PPGLs是散发性的，往往具有侵袭性并伴有转移，其中影响主脑样3（）的体细胞基因融合和含E1冷休克结构域（）的体细胞突变会导致Wnt-β-连环蛋白信号过度激活。然而，Wnt-β-连环蛋白信号与PPGLs生物学行为之间的关系仍未得到探索。在大鼠嗜铬细胞瘤PC12细胞中，Wnt3a处理可增强细胞增殖，并抑制酪氨酸羟化酶（）的mRNA表达，酪氨酸羟化酶是儿茶酚胺生物合成的限速酶，同时抑制多巴胺分泌。我们在PC12细胞中鉴定出硬化蛋白的表达，硬化蛋白是一种已知的由骨细胞衍生的Wnt信号驱动骨形成的负调节因子。用XAV939或硬化蛋白抑制内源性Wnt通路会导致细胞增殖减弱和表达增加。此外，Wnt3a预处理可抑制骨形态发生蛋白（BMP）诱导的Smad1/5/9磷酸化，而BMP可增强PC12细胞中硬化蛋白的表达。在Wnt改变亚型中，Wnt-β-连环蛋白通路的增强可能导致临床侵袭性行为，同时儿茶酚胺产生减少。此外，BMP上调硬化蛋白的表达可能解释了转移性PPGLs中观察到的溶骨性转移病变。
