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

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.

CREB5 promotes invasiveness and metastasis in colorectal cancer by directly activating MET

“…CREB5 has been shown to be a downstream target of LncRNA SNHG5/miR-132-3p [14] and circular RNA circVAPA/miR-125a [26]. In addition, FZD3 inhibits transcriptional networks controlled by CREB5 [25]. However, the alternative mechanisms involved in upregulation of the CREB5 gene and activation of CREB5-mediated signalling require further investigation.…”

“…CREB5 is a CRE-dependent trans-activator downstream of the RAS/ERK signalling pathway since it interacts with c-Jun, which is one of the AP-1 subunits, to form a homodimer or a heterodimer [ 8 ]. Along with FOXD1 and ATF3, CREB5 formed a transcription factor regulatory network that negatively regulates MAPK signalling, which is suppressed by FZD3 in melanoma [ 25 ]. Previous studies have revealed that CREB5 mRNA was upregulated in CRC as demonstrated by bioinformatics analysis or qRT-PCR examination in human cancer tissues [ 13 , 14 ].…”

The role of exosomal miR‐375‐3p: A potential suppressor in bladder cancer via the Wnt/β‐catenin pathway

“…Through bioinformatics prediction and dual luciferase reporter assays, FZD8 was verified the miR‐375‐3p target gene in BC cells. The members of the FZD receptor family, which include FZD2, 53 FZD3, 54 FZD4, 55 FZD7, 56 and FZD10, 57 have been revealed to be involved in many types of cancers. Among them, FZD8 is a classical receptor of Wnt with multiple functions; it can activate canonical or noncanonical Wnt/β‐catenin pathways and plays a pro‐inflammatory role in chronic bronchitis, 58 is involved in brain development and size 59 ; and enhances cell‐cycle dynamics in the developing neocortex 60 .…”

WNT Signaling in Melanoma

“…FZD3 has been found to be associated with β-catenin-independent-signaling and upregulation of this receptor is associated with melanoma progression and a reduced patient survival, whereas down-regulation of FZD3 suppresses growth and metastasis of melanoma [138]. Overexpressed FZD3 has been detected in 20% of melanoma patients whose tumors were deprived of infiltrating T cells indicating the importance of this receptor in immune evasion [139].…”

“…Moreover, it has been observed that FZD3 effectively modulates the activity of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway that is critical for melanoma maintenance. Therefore, FZD3 blocking agents may enhance the efficacy of melanoma treatment when used in combination with available kinase inhibitors and immunotherapy [138,139].…”