Effects of Wnt-β-Catenin Signaling and Sclerostin on the Phenotypes of Rat Pheochromocytoma PC12 Cells

Abstract

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 (MAML3) and somatic mutations in cold shock domain containing E1 (CSDE1) 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 (TH), i.e. 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 TH 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, up-regulated expression of sclerostin by BMPs may explain the osteolytic metastatic lesions observed in metastatic PPGLs.

Whole transcriptome analysis of canine pheochromocytoma and paraganglioma

“…Although these specific genes are not differentially expressed between canine PPGL and NAM, we did find significantly increased expression of Wnt Family Member 3 ( WNT3 ; 21-fold overexpressed), Secreted Frizzled Related Protein 2 ( SFRP2 ; 138-fold overexpressed), and NKD Inhibitor of WNT Signaling Pathway 1 ( NKD1 ; 22-fold overexpressed). Overexpression of WNT3 activates the canonical Wnt pathway, and WNT3 treatment enhanced cell proliferation in rat PCC (PC12) cells ( 45 ). SFRP2 can function both as a Wnt antagonist and agonist, whereas NKD1 functions as an inhibitor of the Wnt signaling pathway ( 35 ).…”

A potential tumor marker: Chaperonin containing TCP‑1 controls the development of malignant tumors (Review)

“…The Wnt/β-catenin signaling pathway serves an important role in embryonic development and the homeostasis of cell proliferation and differentiation in adult tissues. Excessive activation of the Wnt signaling pathway has been found in a number of cancer types, including colorectal cancer (CRC), breast cancer, lung cancer and hematological malignancies ( 37 ). In addition, it has been shown that CCT3 target genes are involved in the Wnt signaling pathway ( 34 ).…”