Worldwide, malignant tumors have jeopardized public health (Siegel et al., 2021). WNT signaling plays a critical role in the progress of multiple cancer types (Bian et al., 2020; Peng et al., 2021; Sun et al., 2021). Aberrant WNT signaling may subvert cancer immunosurveillance (Spranger and Gajewski, 2015; Augustin et al., 2016; Hong et al., 2016). Dickkopf-1 (DKK1), as a WNT signaling pathway inhibitor, is involved in the development of several types of cancers (Lu et al., 2017; Zhuang et al., 2017; Igbinigie et al., 2019). DKK1 had decreased expression in both gastric cancer (GC) and colorectal cancer (CRC), but increased expression in breast cancer (BRCA) and non-small cell lung cancer (NSCLC) (Aguilera et al., 2006; Sato et al., 2007; Li et al., 2013; Jia et al., 2016; Kasoha et al., 2018). In esophageal cancer (ESCA), DKK1 promoted cell proliferation through the cytoskeleton-associated protein 4 (CKAP4)-related pathway (Shinno et al., 2018). DKK1 was also involved in the invasion and metastasis of intrahepatic cholangiocarcinoma (ICC) cells and lymph node metastasis (Shi et al., 2013). Various studies also demonstrated the effect of DKK1 on the prognosis of certain cancers, such as head and neck squamous carcinoma (HNSC), NSCLC, and pancreatic adenocarcinoma (PAAD) (Yamabuki et al., 2007; Han et al., 2015; Gao et al., 2018). In liver hepatocellular carcinoma (LIHC), DKK1 could be induced by an active WNT/β-catenin signal and further contributed to patient’s poor prognosis (Yu et al., 2009). Some reports also presented that DKK1 might serve as a target for immunotherapy (Qian et al., 2012; Betella et al., 2020). DKK1 could affect the function of immune cells, such as T lymphocytes and bone marrow-derived suppressor cells (Katoh and Katoh, 2017). By activating CD4⁺ and CD8⁺ T lymphocytes, DKK1 could eliminate myeloma cells in mouse models (Qian et al., 2012). DKK1 also inhibited the secretion of IFN-γ in Th1 cells and induced the production of interleukin (IL)-4, IL-5, IL-10, and IL-13 in Th2 cells (Bais et al., 2005). The inflammation caused by tumor-specific Th1 cells could prevent cancer, but Th2 cells have the opposite function (Kennedy and Celis, 2008; Lefrancois et al., 2020). By inhibiting β-catenin to prevent clearance by natural killer (NK) cells, DKK1 helps to sustain the stem cell-like properties of cancer cells (Malladi et al., 2016). Based on these findings, it is necessary to evaluate the role of DKK1 in the cancer immune microenvironment.

For several years, numerous studies have been conducted to explore the role of DKK1 in various cancers and revealed the different roles of DKK1 in different cancer types. In this study, we evaluated the pan-cancer expression of DKK1 using The Cancer Genome Atlas (TCGA) dataset. Subsequently, we investigated the association of DKK1 expression with the survival time of patients with different cancers. Finally, we analyzed the effect of DKK1 expression on immune cell infiltration and immune cell markers. The overall process of this research is shown in Figure 1. Our findings deepened our understanding of the roles of DKK1 in cancer progression and prognosis.

DKK1 is a well-established crucial participant in the WNT signal pathway and also acts as a major target in drug design. DKN-01, an anti-DKK1 mAb, could block the immunosuppressive effects of DKK1 in the tumor microenvironment (TME) (Haas et al., 2021) and also perform potential antiangiogenic and immunomodulatory activity in combination therapy with gemcitabine/cisplatin in advanced biliary tract cancer (Goyal et al., 2020). Other clinical trials using anti-DKK1 mAb, such as BHQ880 (Fulciniti et al., 2009) and PF-04840082 (Betts et al., 2010) were also carried out to treat certain cancers.

The differential expression of DKK1 has been reported in many different cancers; however, there is a lack of comprehensive pan-cancer analysis of DKK1. In the current study, after analyzing the expression level of DKK1 in cancer and normal tissues of 33 cancer types, we found that DKK1 was upregulated in CHOL, ESCA, HNSC, LIHC, LUSC, and STAD, but downregulated in BLCA, KICH, KIRP, and PRAD. Similarly, several studies demonstrated that DKK1 was differentially expressed in a variety of cancers and affected cancer progression by changing cancer proliferation and invasion capabilities (Shi et al., 2013; Zhuang et al., 2017; Fezza et al., 2019). Our prognostic analysis showed that in most cancers (ACC, HNSC, LAML, LUAD, MESO, PAAD, and STAD), the upregulated expression of DKK1 was associated with poor prognosis. This further supported the results from previous studies which also confirmed the relationship between the overexpression of DKK1 and the lower overall survival in HNSC (Gao et al., 2018), NSCLC (Yamabuki et al., 2007), and PAAD (Han et al., 2015). However, in ESCA and KIRC, our data showed that a lower DKK1 level contributed to poor prognosis. Other pan-cancer analysis also provided evidence that the same gene could result in a controversial consequence in different kinds of cancer. For example, a pan-cancer study showed that there was a significant different expression of NLRP3 in 15 different cancers, and it was used as an independent posterior factor of SKCM (Ju et al., 2021). Similarly, when comparing the expression level of Fam20C in cancer tissues with that in neighboring normal tissues, we found a large variation across different kinds of cancers which indicated the different roles in different cancers (Liu et al., 2021).

The effect of DKK1 on various cancers may be the result of abnormal activation of WNT signaling (Niida et al., 2004). Our PPI analysis and the pathway enrichment analysis showed that the genes interacting with DKK1 were mainly involved in the WNT signaling pathway, basal cell carcinoma, breast cancer, gastric cancer, and liver cancer. DKK1 has been reported to inhibit the interaction of LRP 5/6 with a WNT signal and the formation of the Fzd-WNT-LRP5/6 complex (Wirths et al., 2003; Ahn et al., 2011). By interfering with DKK1, the activated WNT3a/β-catenin signal had a great influence on cell proliferation, cell cycle acceleration, invasion, and migration (Ren et al., 2021). These results suggested that DKK1 may participate in cancer progression through the WNT signaling pathway.

To unravel the potential mechanism of the predictive value of DKK1 alterations for the tumor immune microenvironment, types of infiltrating immune cells were surveyed. Chronic inflammation is a well-acknowledged risk factor of cancers, we hypothesized that DKK1 influenced cancer prognosis through immune cell infiltration. After conducting immune infiltration analysis, we found that the expression DKK1 was correlated with certain immune cell markers on Th1 and Th2 cells. Wang’s study showed that Th2 cells were identified as prognostic immune cells in gastric cancer (Wang et al., 2020). Th2 cells also demonstrated therapeutic potential for adoptive cell therapy (ACT) (Lorvik et al., 2016). Recent studies demonstrated that Th2 responses played a critical role in the pathogenesis of cancers, such as luminal breast cancer (Zhang et al., 2015), prostate and advanced melanoma cancer (Dulos et al., 2012), and myeloma (Tian et al., 2019). The deep understanding of the relationship between DKK1 and Th2 responses will help us comprehend the mechanism of local antitumor response. In recent years, with the development of immune checkpoint inhibitors, infiltrating immune cell markers can not only be used as prognostic markers, but also have received extensive attention as a new type of treatment (Ladanyi, 2015).

Taken together, our study annotated DKK1 expression in a pan-cancer manner and identified that DKK1 could be used as an independent prognosis factor. DKK1 was significantly expressed in various cancers, and it might also be a biomarker for tumor immunity or even targeted therapy. This study also provided evidence of the effect of DKK1 on immune cell infiltration. However, this study has its limitations. Since all analyses were based on online datasets, experimental confirmation from a laboratory is still needed.