DKK1 overexpression

A "rebound" pattern of DKK1 expression in bone metastasis lesions and the decreasing LRP5 expression in primary lesions of RCC-BM patients suggested that Wnt/β-catenin signaling was inhibited in RCC-BM. The overexpression of DKK1 and reduced expression of LRP5 suggest that these markers may be useful for the early prediction of RCC-BM.

DKK1 functions as a tumour suppressor in colorectal cancer, and 1,25(OH)2D3 upregulates DKK1 expression by inducing demethylation of the DKK1 promoter and 5'UTR in specific colorectal cancer cell lines.

Downregulation of Dkk1 by overexpressed sFRP4 occurs by inhibition of the direct interaction of sFRP4 with the promoter region of Dkk1 as observed with low concentrations of sFRP4. We report for the first time a novel function of the Wnt antagonist sFRP4 acting as a transcription factor for another Wnt antagonist Dkk1, throwing open a new vista in the complex interplay between different antagonists of the Wnt pathway.

GPER is a promising prognostic marker due to its ability to activate apoptosis and inhibit proliferation without promoting migration/invasion in CC cells. G-1 could potentially be a tool in the treatment of this neoplasia.

Moreover, DKN-01 activated the cGAS/STING pathway, while the inactivation of cGAS-STING pathway using RU.521 reversed the inhibition of tumor growth in vivo and macrophage M2 polarization caused by DKN-01. This study reveals that DKN-01 suppresses GC tumor growth through activating cGAS-STING pathway to block macrophage M2 polarization.

In summary, DKK1 can promote the PI3K-AKT signaling pathway in tumor cells and then could induce neuritogenesis and facilitate PNI. MK2206 may be a potential therapeutic target drug for HNSCC patients with PNI.

High expression of DKK1 in lung adenocarcinoma is associated with poor prognosis. DKK1 is closely associated with tumor immune cell infiltration and pathways. DKK1 can be considered as a potential prognostic marker and a novel target for immunotherapy of lung adenocarcinoma.

Collectively, data demonstrates promising clinical activity of a well-tolerated drug, DKN-01, in EC patients with high tumoral DKK1 expression which frequently corresponded to the presence of a Wnt activating mutation. Future development will focus on using DKN-01 in DKK1-high EC patients in combination with immunotherapy.

Taken together, our findings suggest that CDK9 inhibitors are potent tools to target DKK1, which can suppress the metastatic progression of HCC.

Correlation analysis of human HCC tumor specimens further revealed that DKK1 and PD-L1 expression were positively correlated with p-β-catenin expression. Together, our findings revealed that DKK1 promotes PD-L1 expression through the activation of Akt/β-catenin signaling, providing a potential strategy to enhance the clinical efficacy of PD-1/PD-L1 blockade therapy in HCC patients.

DKK1 promotes tumour immune evasion in iCCA through the recruitment of immune suppressive macrophages. Targeting DKK1 with a neutralizing antibody is effective at reducing tumour growth in vivo. As such, DKK1 targeted and immune modulatory therapies may be an effective strategy in iCCA patients with high DKK1 tumour expression or tolerogenic immune phenotypes.