Frizzled homolog proteins, microRNAs and Wnt signaling in cancer

Abstract

Wnt signaling pathways play important roles in tumorigenesis and are initiated by binding of Wnt to various receptors including frizzleds (FZDs). FZDs are one of several families of receptors comprised of FZD/LRP/ROR2/RYK in the Wnt signaling pathway. Expression of some FZD receptors are up regulated, thereby activating the Wnt signaling pathway and is correlated with cancer malignancy and patient outcomes (recurrence and survival) in many cancers. The FZD family contains ten genes in humans and their function has not been completely examined including the regulatory mechanisms of FZD genes in cancer. Knockdown of FZDs may suppress the Wnt signaling pathway resulting in decreased cell growth, invasion, motility and metastasis of cancer cells. Recently a number of microRNAs (miRNAs) have been identified and reported to be important in several cancers. MiRNAs regulate target gene expression at both the transcription and translation levels. The study of miRNA is a newly emerging field and promises to be helpful in understanding the pathogenesis of FZDs in cancer. In addition, miRNAs may be useful in regulating FZDs in cancer cells. Therefore, the aim of this review is to discuss current knowledge of the functional mechanisms of FZDs in cancer, including regulation by miRNAs and the potential for possible use of miRNAs and FZDs in future clinical applications.

Figure 1. Schematics of Wnt signaling pathway in cancer cells

A. Regulation of Wnt signaling pathway in normal cells. Beta-catenin is usually phosphorylated and degradated by a multiprotein complex composed of APC, GSK3, CK1 and AXIN. B. Wnt/beta-catenin pathway. Wnt ligands bind to the complex compromised of FZD/LRP/ROR/RYK, resulting in the constitutive stabilization of beta-catenin. The beta-catenin associates with TCF to activate target genes. C. Wnt/Ca²⁺ pathway (non-canonical pathway). Wnt activates intracellular Ca²⁺ signaling as well as Ca²⁺-dependent protein kinases such as PKC and CaMK II. TAK1 and NLK can interfere with TCF/beta-catenin signaling. D. Wnt/JNK pathway (non-canonical pathway). Receptor stimulation activates DVL, which in turn activates the Rho family of GTPases. Rho stimulates c-Jun expression through phosphorylation of c-Jun by ROCK.

Figure 2

Association of FZD with other Wnt related genes and proteins. Chromosome deletions may cause over-expression of some FZDs thorough loss of a particular miRNA. Expression of sFRP, Dkk and Wif1 is down-regulated because of promoter hypermethylation. Mutation of APC/beta-catenin genes is detected in many cancers.