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

Chen Li, Vincent Nguyen, Kaitlyn N. Clark, Tara Zahed, Shawn Sharkas, Fabian V. Filipp, Alexander D. Boiko

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

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-feedback mechanism that activates MAPK signal transduction network, critical to melanoma carcinogenesis. Importantly, high levels of FZD3 mRNA were found to be correlated with melanoma advancement to metastatic stages and limited patient survival. Changes in gene-expression patterns mediated by FZD3 activity occur in the absence of nuclear β-catenin function, thus representing an important therapeutic target for the melanoma patients whose disease progresses independent of canonical WNT signaling.

Original languageEnglish
Pages (from-to)4548-4557
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number10
DOIs
StatePublished - 2019

Keywords

  • Frizzled
  • Gene expression
  • MAPK
  • Melanoma
  • Systems biology

Fingerprint

Dive into the research topics of 'Down-regulation of FZD3 receptor suppresses growth and metastasis of human melanoma independently of canonical WNT signaling'. Together they form a unique fingerprint.

Cite this