Role of DKK4 in Tumorigenesis and Tumor Progression

Abstract

Tumor is the most public health problem. The Wnt signal pathway extensively participates in diverse progresses containing embryonic development, maintenance of homeostasis and tumor pathogenesis. The Wnt signal pathway consists of canonical signal pathway, noncanonical Wnt/PCP pathway and noncanonical Wnt/Ca2+ pathway. The deletion of the ligand of Wnts results in cytoplasmic β-catenin phosphorylation, stopping entry of β-catenin to nuclear in canonical Wnt signaling. Instead, binding of Wnts to frizzled (FZ/FZD) as well as LRP5/6 causes activation of Wnt signal pathways. This facilitates entry of β-catenin to nuclear. The Dickkopf proteins (DKKs) have been known as the antagonist of Wnt signal pathway. A number of research of DKK1, 2, 3 have been reported, however, the effect of DKK4 on tumor process is still mysterious. A more distinct comprehension about the effect of DKK4 on tumorigenesis and tumor process will shed light on biomedical research of DKK4 and tumor research. This review summarizes the current knowledge of DKK4 in various kinds of tumors.

Keywords: DKK4; Tumor; Wnt signal pathway; β-catenin.

Figure 1

Role of DKK4 in different signal pathway. Binding of TR to nucleotides 1645-1629 of promoter of DKK4 gene is related to T3-dependent DKK4 transcription. Triiodothyronine (T3) and TR up-regulate the mRNA and protein levels of DKK4 expression. 1α, 25-dihydroxyvitamin D3 might be able to inhibit DKK4 expression. There may be 2 mechanisms: (a) bonding of vitamin D receptor with DKK4 promoter; (b) mediately by the TCF/ β-catenin-connection sites. DKK4 inhibites activity of TCF/LEF and down-regulates nuclear β-catenin entry. As the downstream effector, c-Myc as well as cyclin D1 also expressed at a low level. Meanwhile DKK4 decreases levels of phosphorylated GSK3β and up-regulates levels of phosphorylated β-catenin to antagonize the canonical Wnt signaling. Activating canonical Wnt signaling can induce expression of DKK4 as a negative feedback loop. DKK4 up-regulates and phosphorylates c-Jun and activates the non-canonical JNK signaling. DKK4 can activate the MAPK signal pathway through coexpression with MAPK3.