Background: Recently several reports have indicated that elevated expression of DKK1 is tightly associated with the progression of hepatocellular carcinoma (HCC). However, the biological function of DKK1 in HCC has not yet been well documented. Methods: In this study, the role of DKK1 in tumor cell proliferation, migration and invasion was investigated using MTT, colony formation, wound scratch, transwell assays, and also human HCC samples. Results: Both gain- and loss-of-function studies showed that DKK1 did not influence the tumor cell proliferation and colony formation, while dramatically promoted HCC cell migration and invasion. Subsequent investigations revealed that β-catenin was an important target of DKK1. The blocking of β-catenin by pharmacological inhibitor antagonized the function of DKK1, whereas introduction of β-catenin by transfection with plasmids or treatment with GSK3β inhibitor phenocopied the pro-migration and pro-invasion effects of DKK1. We further disclosed that DKK1 exerted its pro-invasion function, at least in part, by promoting β-catenin expression, in turn, upregulating the expression of matrix metalloproteinase 7 (MMP7), which was independent of the canonical Wnt signaling pathway. Moreover, introduction of MMP7 significantly enhanced the ability of HCC cells to invade extracellular matrix gel in vitro. Consistently, in human HCC tissues, DKK1 level was positively correlated with β-catenin expression, as well as tumor metastasis. Conclusion: Taken together, these results demonstrated that DKK1 is overexpressed in HCC; moreover, ectopic expression DKK1 promotes HCC cell migration and invasion at least partly through β-catenin/MMP7 signaling axis, suggesting that DKK1 may be a promising target for HCC therapy.

Spermidine/spermine N 1 -acetyltransferase regulates cell growth and metastasis via AKT/-catenin signaling pathways in hepatocellular and colorectal carcinoma cells

DKK1 has been reported to act as a tumor suppressor in breast cancer. However, the mechanism of DKK1 inhibits breast cancer migration and invasion was still unclear. Western blot and real time PCR was used to detect the expression of DKK1, β-catenin and MMP7 in breast cancer cells. Wound scratch assay and transwell assay was employed to examine migration and invasion of breast cancer cell. DKK1 overexpression dramatically inhibits breast cancer cell migration and invasion. Knockdown of DKK1 promotes migration and invasion of breast cancer cells. DKK1 suppressed breast cancer cell migration and invasion through suppression of β-catenin and MMP7 expression. XAV-939, an inhibitor of β-catenin accumulation could reverse DKK1 silencing-induced MMP7 expression in breast cancer cells. Meanwhile, XAV-939 also could reverse the increase in the cell number invaded through Matrigel when DKK1 was knockdown. Furthermore, depletion of MMP7 also could reverse DKK1 knockdown-induced increase in the cell number invaded through Matrigel. DKK1 inhibits migration and invasion of breast cancer cell through suppression of β-catenin/MMP7 pathway, our findings offered a potential alternative for breast cancer prevention and treatment.

Growth factor–induced parallel pathways stimulate DKK1 expression and metastasis in liver cancer.