Down-regulation of FZD3 receptor suppresses growth and metastasis of human melanoma independently of canonical WNT signaling

Proceedings of the National Academy of Sciences of the United States of America
Chen LiAlexander D Boiko

Abstract

Frizzled 3 receptor (FZD3) plays an important role in the homeostasis of the neural crest and its derivatives, which give rise to pigment-synthesizing cells, melanocytes. While the role for FZD3 in specification of the melanocytic lineage from neural crest is well established, its significance in the formation of melanoma, its associated malignancy, is less understood. In this study we identified FZD3 as a critical regulator of human melanoma tumorigenesis. Down-regulation of FZD3 abrogated growth, colony-forming potential, and invasive capacity of patient-derived melanoma cells. Xenotransplantation of tumor cells with down-regulated FZD3 levels originating from melanomas carrying the BRAF(V600) mutation uniformly suppressed their capacity for tumor and metastasis formation. FZD3 knockdown leads to the down-regulation of the core cell cycle protein components (cyclins D1, E2, B1, and CDKs 1, 2, and 4) in melanomas with a hyperactive BRAF oncogene, indicating a dominant role of this receptor during melanoma pathogenesis. Enriched pathway analysis revealed that FZD3 inhibits transcriptional networks controlled by CREB5, FOXD1, and ATF3, which suppress the activity of MAPK-mediated signaling. Thus, FZD3 establishes a positive-feed...Continue Reading

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Citations

Jul 28, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Qi LiWei Zhang
Jul 15, 2020·International Journal of Molecular Sciences·Anna Gajos-Michniewicz, Malgorzata Czyz
May 24, 2019·Scientific Reports·Fabian V FilippAlexander D Boiko
Aug 28, 2020·Journal of Experimental & Clinical Cancer Research : CR·Shuyang WangWenting Liao
Feb 16, 2021·Frontiers in Cell and Developmental Biology·Yagmur AzbazdarGunes Ozhan

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Methods Mentioned

BETA
xenograft
PCA
RNA-Seq
PCR
biopsies
nuclear translocation
transfection

Software Mentioned

Ingenuity Pathway Analysis
Bioconductor toolbox
EdgeR
Bowtie

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