Expression and Role of Dickkopf-1 (Dkk1) in Tumors: From the Cells to the Patients

Figures & data

Figure 1 Summary of the research findings on the role of Dkk1 in cancers from in vitro and in vivo experiments as well as from studies using serum from human patients.

Table 1 Studies in Human Cancer Revealing the Role of Dkk1 as a Cancer Biomarker

Study	Cancer Type	Experimental Approach	Metastasis in vitro (Cell Migration and Invasion)	Metastasis in vivo	Correlation with Malignant or Meta-Static Phenotype	Correlation with Decreased Survival	Suggested Mechanism of Action via the Pathway of
21–29	Non-Small Cell Lung Cancer (NSCLC)	Analysis of tumor tissue samples from 205 patients with lung cancer.^Citation27 The serum levels of Dkk1 autoantibodies were measured by ELISA in 206 patients with NSCLC and 99 healthy controls. And followed up for 3 years.^Citation28 Serum Dkk1 levels were quantified and analyzed in 470 patients with NSCLC (140 bone metastases, 178 extraosseous metastases and 152 complete remission).^Citation29	Yes	Yes	Yes	Yes	Dkk1 promotes VM formation by inducing EMT-related proteins and developing CSC properties in NSCLC.
30–45	Hepatocellular carcinoma (HCC)	By comparing the serum Dkk1 levels of 831 test cohort participants and 453 verification cohort participants, the contents of Dkk1mRNA and protein in liver tissues of patients with HCC and non-cancer patients were compared.^Citation38 Evaluation of the effects of exogenous Dkk1 on angiogenesis and EnMT by cell test.^Citation39 Retrospectively analyzed the changes of serum Dkk1 and circulating tumor cell (CTC) in 155 HCC patients treated with TACE.^Citation44	N/A	N/A	N/A	Yes	Dkk1 induces angiogenesis by regulating VEGFR2 independent of Wnt signal transduction pathway.
46–52	Esophageal carcinoma (EC)	The expression of Dkk1 in esophageal cancer tissues, matched normal esophageal tissues and esophageal cancer cell lines was detected by RT-PCR and Western blot methods. Serum Dkk1 levels of 90 ESCC patients and 85 healthy patients were compared by ELISA.^Citation49 The expression of Dkk1 protein in surgical specimens of 170 patients with ESCC was compared with various clinical data.^Citation51	Yes	N/A	Yes	Yes	N/A
53–62	Gastric cancer (GC)	Comparison of serum Dkk1 levels in 153 GC patients and 173 healthy controls, and comparison of Dkk1 expression levels in 144 cancer specimens of 153 patients and 265 GC specimens.^Citation55 ELISA was used to detect the expression of serum Dkk1 protein in 90 cases of gastric cancer, 50 cases of gastric benign diseases and 40 healthy persons, and to monitor the changes of serum Dkk1 protein in patients with gastric cancer after radical operation for a month.^Citation56 Detection of the relationship between the co-expression of Dkk1 and β-catenin in gastric cancer and clinical prognosis.^Citation59 To verify whether Dkk1 can effectively inhibit endogenous Wnt/β-catenin signal transduction in CD44^+GC cells.^Citation60	Yes	N/A	Yes	Yes	Wnt/β-catenin signal pathway
63–75	Colorectal cancer (CRC)	Immunohistochemistry was used to detect the expression of Dkk1 in 476 colon specimens. HCT116 cells overexpressing Dkk1 were cultured in vitro and tumorigenesis was carried out in vitro.^Citation69 Knock out CSN5 gene in SW480 cells and detect the expression of Dkk1.^Citation70 The relationship between miR-410 and Dkk1 expression was demonstrated in SW-480 and HCT-116 CRC cell lines in vitro.^Citation71	Yes	Yes	Yes	Yes	CSN5actively drives abnormal Wnt signals by inhibiting Dkk1. Overexpression of miR-410 inhibits the expression of Dkk1 in CRC cells, thus promoting the proliferation, migration and invasion of CRC cells. HotTipregulates the metastasis of colorectal cancer cells by down-regulating the expression of tumor suppressor gene Dkk1.
76–87	Pancreatic cancer (PC)	The expression levels of Dkk1 protein and mRNA in normal pancreatic cells, PC cell lines, normal pancreatic tissues and PC tumor tissues were compared. Tumor invasiveness was detected after Dkk1 knockout in vitro.^Citation73 Co-immunoprecipitation and knockout methods were used to prove that GATA6 negatively regulates Dkk1 transcription by directly binding to the GATA motif in the Dkk1 promoter region at the cellular level.^Citation78 140 patients with pancreatic adenocarcinoma and 92 patients without PC were followed up for 2 years to evaluate the levels of serum Dkk1 and CA19-9 and tumor progression.^Citation79 Detection of Dkk1 expression in PDAC tissues and matched normal tissues, and comparison with clinical data items of patients.^Citation80 The expression of LINC01133 and Dkk1 and their effects on tumor cells were detected by ectopic expression test, gene knockout test and gene reporting test.^Citation81 The interaction between CKAP4 and Dkk1 and its effect on PDAC cells were detected by texture detection and tumor formation in vitro.^Citation84	Yes	Yes	Yes	Yes	GATA6 negatively regulates Dkk1 transcription by directly binding to the GATA motif in the Dkk1 promoter region. INC01133 can down-regulate the expression of Dkk1 to inhibit the Wnt signal pathway, thus promoting the growth and metastasis of pancreatic cancer.
88–96	Cervical cancer (CC)	Explore the epigenetic characteristics of Dkk1 in CC cell line.^Citation90 Testing serum Dkk1 levels in patients with CC and comparing them with patient clinical information.^Citation91 Simultaneous testing of serum Dkk1 in normal subjects, patients with CIN, and patients with CC and follow-up of subsequent disease progression.^Citation92 Demonstration at the cellular level that SNHG7 epigenetically silences Dkk1 through the Wnt/β-catenin signaling pathway.^Citation93	N/A	N/A	Yes	Yes	SNHG7 epigenetically silences Dkk1 through the Wnt/β-catenin signaling pathway to exacerbate CC malignancy
97–114	Ovarian cancer	STAT3 was demonstrated in EOC cells to regulate tumor progression via miR-92a/β-1 and to interconnect with Wnt/Dkk1-catenin signals.^Citation100TET1 was demonstrated in EOC cells to inhibit the Wnt/β-catenin pathway through demethylation of Dkk1 and thus tumor suppression.^Citation105 Cell-level validation of cordycepin inhibits ovarian cancer cell growth through synergistic autophagy and Dkk1/β-catenin signaling.^Citation109	Yes	Yes	Yes	N/A	STAT3 regulates tumor cell metabolism by regulating miR-92a/β-1 and combining the Wnt/Dkk1-catenin signaling pathway. TET1 activates Dkk1 and inhibits Wnt/β-catenin pathway for tumor suppression through demethylation. Cordycepsin inhibits ovarian cancer cell growth through synergistic autophagy and Dkk1/β-catenin signaling.
115–127	Breast cancer	Comparison of serum Dkk1 in normal subjects, breast cancer patients, and patients with bone metastases.^Citation114,Citation115,Citation121,Citation122 In vivo experiments use drugs to interfere with Dkk1 and thereby suppress tumors.^Citation119,Citation123 In vivo and in vitro experiments demonstrate that PMSC-secreted Dkk1 inhibits breast cancer cell growth through the Wnt/β-catenin pathway.^Citation120	Yes	Yes	Yes	Yes	Possible role of p38 in regulating Dkk1 in osteolytic breast cancer tumors. PMSC-secreted Dkk1 inhibits breast cancer cell growth through the Wnt/β-catenin pathway. Statins in combination with zoledronic acid at low concentrations may inhibit tumor growth by reducing Dkk1 levels. The small molecule dorsomorphin may produce tumor suppression by reducing the transcriptional level of Dkk1.
128–134	Bladder urothelial cancer (BUC)	Detecting Dkk1 levels in BUC patients before surgery.^Citation127 Determination of serum Dkk1 levels in normal subjects and BUC patients and comparison of clinical data.^Citation128 Investigating the role of miR-543-3p on tumors via Dkk1 in BUC cells.^Citation129	N/A	N/A	Yes	Yes	Upregulation of miR-543-3p in bladder cancer activates Wnt/β-catenin signaling by directly targeting Dkk1.

Figure 2 Analysis of differential expression of Dkk1 in tumor tissues and normal tissues based on TCGA and GTEx database.

Abbreviations: ACC, adrenocortical carcinoma; BLCA, bladder Urothelial Carcinoma; BRCA, breast invasive carcinoma; CESC, cervical squamous cell carcinoma and endocervical adenocarcinoma; CHOL, cholangiocarcinoma; COAD, colon adenocarcinoma; ESCA, esophageal carcinoma; GBM, glioblastoma multiforme; HNSC, head and neck squamous cell carcinoma; KICH, kidney chromophobe; KIRC, kidney renal clear cell carcinoma; KIRP, kidney renal papillary cell carcinoma; LAML, acute myeloid leukemia; LGG, brain lower grade glioma; LIHC, liver hepatocellular carcinoma; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; OV, ovarian serous cystadenocarcinoma; PAAD, pancreatic adenocarcinoma; PRAD, prostate adenocarcinoma; READ, rectum adenocarcinoma; SKCM, skin cutaneous melanoma; STAD, stomach adenocarcinoma; TGCT, testicular germ cell tumors; THCA, thyroid carcinoma; UCEC, uterine corpus endometrial carcinoma; UCS, uterine carcinosarcoma.

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