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.27 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.28 Serum Dkk1 levels were quantified and analyzed in 470 patients with NSCLC (140 bone metastases, 178 extraosseous metastases and 152 complete remission).29	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.38 Evaluation of the effects of exogenous Dkk1 on angiogenesis and EnMT by cell test.39 Retrospectively analyzed the changes of serum Dkk1 and circulating tumor cell (CTC) in 155 HCC patients treated with TACE.44	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.49 The expression of Dkk1 protein in surgical specimens of 170 patients with ESCC was compared with various clinical data.51	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.55 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.56 Detection of the relationship between the co-expression of Dkk1 and β-catenin in gastric cancer and clinical prognosis.59 To verify whether Dkk1 can effectively inhibit endogenous Wnt/β-catenin signal transduction in CD44+GC cells.60	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.69 Knock out CSN5 gene in SW480 cells and detect the expression of Dkk1.70 The relationship between miR-410 and Dkk1 expression was demonstrated in SW-480 and HCT-116 CRC cell lines in vitro.71	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.73 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.78 140 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.79 Detection of Dkk1 expression in PDAC tissues and matched normal tissues, and comparison with clinical data items of patients.80 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.81 The interaction between CKAP4 and Dkk1 and its effect on PDAC cells were detected by texture detection and tumor formation in vitro.84	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.90 Testing serum Dkk1 levels in patients with CC and comparing them with patient clinical information.91 Simultaneous testing of serum Dkk1 in normal subjects, patients with CIN, and patients with CC and follow-up of subsequent disease progression.92 Demonstration at the cellular level that SNHG7 epigenetically silences Dkk1 through the Wnt/β-catenin signaling pathway.93	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.100TET1 was demonstrated in EOC cells to inhibit the Wnt/β-catenin pathway through demethylation of Dkk1 and thus tumor suppression.105 Cell-level validation of cordycepin inhibits ovarian cancer cell growth through synergistic autophagy and Dkk1/β-catenin signaling.109	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.114,115,121,122 In vivo experiments use drugs to interfere with Dkk1 and thereby suppress tumors.119,123 In vivo and in vitro experiments demonstrate that PMSC-secreted Dkk1 inhibits breast cancer cell growth through the Wnt/β-catenin pathway.120	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.127 Determination of serum Dkk1 levels in normal subjects and BUC patients and comparison of clinical data.128 Investigating the role of miR-543-3p on tumors via Dkk1 in BUC cells.129	N/A	N/A	Yes	Yes	Upregulation of miR-543-3p in bladder cancer activates Wnt/β-catenin signaling by directly targeting Dkk1.