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.

Aberrant accumulation of Dickkopf 4 promotes tumor progression via forming the immune suppressive microenvironment in gastrointestinal stromal tumor

“…Wnt pathway is well‐known for contributing to tumor malignancy in multiple cancers, which also serves as the pivotal mechanism driving tumor progression in GIST, announced by several previous evidences . As a canonical Wnt pathway antagonist, DKK4 belonging to dickkopf (DKK) families is also transcriptionally activated by Wnt pathway transcriptional factor, forming an ideal regulatory loop . Some earlier studies pointed that DDK4 drove the antitumor effects by antagonist of Wnt signaling .…”

“…19,20 As a canonical Wnt pathway antagonist, DKK4 belonging to dickkopf (DKK) families is also transcriptionally activated by Wnt pathway transcriptional factor, forming an ideal regulatory loop. [21][22][23][24] Some earlier studies pointed that DDK4 drove the antitumor effects by antagonist of Wnt signaling. [25][26][27] However, emerging evidence demonstrate that DKK4, upregulated by activated Wnt pathway, contributes to tumor malignancy in variable tumors, promoting tumor cells invasion and progression.…”

Expression and function of dinkkopf 4 in oral squamous cell carcinoma and in vitro

“…The expression of DKK4 is increased in colorectal cancer, gastric cancer, pancreatic cancer, renal cell carcinoma, ovarian cancer, esophageal cancer and endometrial carcinoma [19] . Pendas-Franco et al…”

“…It was found that the expression of DKK3 in OSCC was higher than that in NOM, and DKK3 might promote the proliferation, invasion and metastasis of squamous cell carcinoma. However, the study of DKK4, another member of DKK family, in OSCC has not been reported [20,21] .The expression of DKK4 is up-regulated in colorectal cancer, gastric cancer, pancreatic cancer, renal cell carcinoma, ovarian cancer, esophageal cancer and endometrial carcinoma [19] . DKK4 enhances the migration, invasion and angiogenic potential of colon cancer cells [22] .…”

“…Dickkopf (DKK) family consists of four secretory proteins DKK1, DKK2, DKK3 and DKK4, containing 255-350 amino acids and 2 conserved sequences of CRD. The CRD sequence of DKK4 is located in the regions of C24-73 and C128-201 [19] . The DKK family induces endocytosis of the Wnt/LRP5/6 complex by interacting with LRP5/6 receptors, inhibiting the activity of Wnt/β-catenin signal pathway [8,9] .…”