Pan-Cancer Analyses Reveal Oncogenic and Immunological Role of Dickkopf-1 (DKK1)

Abstract

WNT signaling pathway inhibitor Dickkopf-1 (DKK1) is related to cancer progression; however, its diagnostic and prognostic potential have not been investigated in a pan-cancer perspective. In this study, multiple bioinformatic analyses were conducted to evaluate therapeutic value of DKK1 in human cancers. The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) project served as data resources. The Wilcoxon rank test was performed to evaluate the expression difference of DKK1 between cancer tissues and normal tissues. A Kaplan-Meier curve and Cox regression were used for prognosis evaluation. Single-sample gene set enrichment analysis (ssGSEA) was used to evaluate the association of DKK1 expression with the immune cell infiltration. The potential function of DKK1 was explored by STRING and clusterProfiler. We found that the expression level of DKK1 is significantly different in different cancer types. Importantly, we demonstrated that DKK1 is an independent risk factor in ESCA, LUAD, MESO, and STAD. Further analysis revealed that DKK1 had a large effect on the immune cell infiltration and markers of certain immune cells, such as Th1 and Th2 cells. PPI network analysis and further pathway enrichment analysis indicated that DKK1 was mainly involved in the WNT signaling pathway. Our findings suggested that DKK1 might serve as a marker of prognosis for certain cancers by affecting the WNT signaling pathway and tumor immune microenvironment.

Prognostic Analysis of Cuproptosis-related Genes in Gastric Cancer

“…As a repressor of WNT signaling pathway, DKK1 is involved in the development of various cancers [44]. Moreover, studies have shown that the expression of DKK1 is up-regulated in malignant tumors and further leads to poor prognosis [45]. In addition, in the analysis of gene mutations, we found that the frequency of TTN and TP53 mutations was the highest in both high-risk and low-risk groups.…”

Construction of a Novel Prognostic Model in Lung Adenocarcinoma Based on 7-Methylguanosine-Related Gene Signatures

“…ARNTL2 is a paralog of the circadian transcription factor ARNTL and has recently been discovered to also act as a modifier of immune cell infiltration in malignancies ( 66 – 68 ). Meanwhile, the Wnt antagonist DKK1 (Dickkopf-1) has been implicated in the modulation of immune cell activities as well as the immunosuppressive microenvironment in cancers and has become a promising target for cancer immunotherapy ( 69 , 70 ). Together, these findings confirmed the reliability and precision of our prognostic model.…”

Multiomics of Colorectal Cancer Organoids Reveals Putative Mediators of Cancer Progression Resulting from SMAD4 Inactivation

“…The DKK protein family is traditionally known to regulate WNT signaling, but all four members are associated with the modulation of the antitumor immune response as well (Table ). − We found that DKK3, but not DKK4, was able to negatively affect the killing capacity of NK cells for CRC cells, but that neither was able to decrease the activity of CTLs in a patient-derived colon cancer model. Both DKK3 and DKK4 have been reported to dampen the antitumor response in CTLs, but not in the context of CRC, providing a possible explanation for the absence of an effect on CTL response.…”