DKK1: Deciphering the Dual Role of a Master Regulator in Development and Disease

The Wnt signaling pathway plays a key role in the development of tumors by promoting tumor cell transformation, growth, invasion and metastasis, and angiogenesis, and has become a hot spot in tumor research [1]. As an important secreted inhibitor of Wnt signaling pathway, the role of DKK1 in tumors has also been gradually paid attention to. The latest research shows that the secretory protein DKK1 (dickkopf-1) is significantly abnormally expressed in a variety of tumors, and its expression is significantly correlated with the pathological stage and prognosis of the tumor, suggesting that DKK1 may become a new tumor marker and It is a therapeutic target and plays an important role in the diagnosis, treatment and recurrence monitoring of tumors [2-4].

What is DKK1?

DKK1 Structure

DKK1 is a protein of 266 amino acids composed of two conservative cysteine-rich domains that are separated by a sequence possessing unknown functions and variable length. First discovered in Xenopus, it was identified as a prominent regulator involved in the induction of head formation in amphibian embryos[5]. Antibody-mediated inhibition of DKK1 confirmed that it was required for head formation[6]. DKK1 has potential N-linked glycosylation at Asn225 and two O-linked glycans attached at Ser30, resulting in a difference between its apparent molecular size and theoretical molecular weight[7]. The C-terminal domain of DKK1 (DKK1c) has been identified as a necessary and sufficient domain for Wnt pathway inhibition, as well as being responsible for binding to LRP6. Conversely, the N-terminal domain does not exhibit the same function as DKK1c and even masks the ability of DKK1c to interact with LRP6[8]. The function of the N-terminal domain may be associated with enhanced invasive activity and an anti-apoptotic signaling pathway that could be neutralized by the anti-DKK1 antibody.

DKK1 Expression and Function

DKK1 is primarily secreted by osteoblasts and osteocytes. It is also expressed to a lesser extent in various tissues and cell types, including placenta, skin, prostate, vascular endothelium, and kidney, among others. As a secreted glycoprotein, DKK1 functions as an antagonist of the Wnt/β-catenin signaling pathway by competitively binding to LRP5/6 receptors alongside Wnt proteins [10-13].

This regulatory role influences crucial cellular processes, such as cell proliferation, differentiation, carcinogenesis, apoptosis, tumor cell invasion, and metastasis. The emerging evidence suggests that DKK1 exhibits diverse characteristics in tumorigenesis and development. Interestingly, even within the same type of cells, it can demonstrate opposing regulatory effects due to different physiological environments, adding complexity to its function [10-13].

Mechanisms of DKK1-Mediated Repression of Wnt Signaling

DKK1 exerts its inhibitory effect on Wnt signaling by interfering with key molecules within the pathway. Specifically, DKK1 employs the following mechanisms to hinder the transmission of Wnt signals:

1. Blocking Wnt-Frizzled Receptor Interaction: The initial step of the Wnt signaling pathway involves the binding of Wnt proteins to Frizzled receptors on the cell surface. DKK1 can bind to the Frizzled receptor, preventing Wnt protein from binding to the receptor and thus impeding signal transduction.
2. Inhibiting Receptor Complex Formation: Under normal conditions, Wnt binding to Frizzled receptors triggers the formation of a complex with LRP5/6 (low-density lipoprotein receptor-related protein 5/6), leading to Wnt signaling activation. DKK1 binds to LRP5/6, disrupting the formation of the receptor complex and hampering subsequent signaling steps.
3. Promoting Receptor Endocytosis: DKK1 facilitates the endocytosis of the Wnt receptor complex, internalizing the receptor from the cell surface and promoting its degradation. As a result, the activity of signal transduction is reduced.

In summary, DKK1 interacts with key molecules, Frizzled receptors, and LRP5/6, within the Wnt signaling pathway. By inhibiting Wnt-receptor binding and the formation of receptor complexes, as well as promoting receptor endocytosis, DKK1 disrupts the transmission of Wnt signals. This disruption prevents cells from properly responding to Wnt signals, ultimately leading to the inhibition of cell proliferation and differentiation. These processes play critical roles in embryonic development, adult tissue maintenance, and the progression of certain diseases.

Clinical application of DKK1

DKK1 has been shown to play a role in a variety of cancers and other diseases. Here are some known diseases where DKK1 may play an important role:

The Role of DKK1 in Colorectal Cancer

1. Promoting Colorectal Cancer Cell Proliferation and Invasion: DKK1's high expression is linked to the increased proliferation and invasion of colorectal cancer cells. By inhibiting Wnt signaling transduction through regulation of the Wnt signaling pathway inhibitor, DKK1 enhances the aggressive behavior of colorectal cancer cells.
2. Upregulation of Stem Cell Markers: DKK1 may play a role in maintaining and promoting the growth of colorectal cancer stem cells. These stem cells are critical for tumor growth and resistance to treatment, highlighting the potential significance of DKK1 in relation to colorectal cancer stem cell properties.
3. Involvement in Metastasis: High DKK1 expression is associated with colorectal cancer metastasis. DKK1 may promote the spread of colorectal cancer cells by influencing cell adhesion and extracellular matrix degradation.
4. Prognostic Implications: Research indicates that elevated DKK1 levels are associated with poor prognosis for colorectal cancer patients, including tumor development, recurrence, and survival rates. As a result, DKK1 may serve as a prognostic marker in colorectal cancer[15].

The Role of DKK1 in Breast Cancer

1. Promoting Proliferation and Invasion of Breast Cancer Cells: DKK1 overexpression is linked to increased proliferation and invasion abilities in breast cancer cells. By inhibiting the Wnt signaling pathway, DKK1 facilitates the growth, migration, and invasion of breast cancer cells.
2. Involvement in Breast Cancer Stem Cells: DKK1 may play a role in maintaining and promoting the growth of breast cancer stem cells. Breast cancer stem cells are a subset of cells with the capacity for self-renewal and differentiation, which are closely associated with tumor recurrence and drug resistance.
3. Correlation with Prognosis: Studies have shown that high DKK1 expression is associated with poor prognosis in breast cancer patients. Elevated DKK1 levels are linked to adverse clinical features in breast cancer, including tumor grade, lymph node metastasis, and distant metastasis.
4. Impact on Drug Resistance: The high expression of DKK1 may contribute to drug resistance in breast cancer, affecting the effectiveness of certain treatment methods.
5. Considering the above findings, DKK1 emerges as a significant therapeutic target and prognostic marker for breast cancer. Inhibiting DKK1 could potentially slow down breast cancer growth and invasion, leading to improved patient outcomes[16-17].

The Role of DKK1 in lung cancer

1. Enhancing Proliferation and Invasion of Lung Cancer Cells: DKK1's high expression is associated with increased proliferation and invasion capabilities of lung cancer cells. By inhibiting the Wnt signaling pathway, DKK1 promotes the growth, migration, and invasion of lung cancer cells.
2. Influence on Lung Cancer Stem Cells: DKK1 may play a role in the maintenance and proliferation of lung cancer stem cells. Lung cancer stem cells constitute a small cell population that plays a crucial role in tumor development and resistance to therapies.
3. Prognostic Implications: Studies suggest that elevated DKK1 levels are associated with a poorer prognosis for lung cancer patients. High DKK1 expression is linked to unfavorable clinical features, such as advanced pathological stage, lymph node metastasis, and distant metastasis in lung cancer.
4. Impact on Drug Resistance: The increased expression of DKK1 may contribute to drug resistance in lung cancer, affecting the effectiveness of certain treatment approaches.
5. Additional Functions: Emerging research indicates that DKK1 may also be involved in biological processes like angiogenesis and immune escape in lung cancer.

The Role of DKK1 in gastric cancer

1. Enhancing Proliferation and Invasion of Gastric Cancer Cells: The high expression of DKK1 is linked to increased proliferation and invasion capabilities of gastric cancer cells. DKK1 promotes the growth, migration, and invasion of gastric cancer cells by inhibiting the Wnt signaling pathway.
2. Implications for Tumor Drug Resistance: Studies indicate that high DKK1 expression is associated with drug resistance in gastric cancer cells, affecting their response to chemotherapy and targeted therapy. This resistance may be related to DKK1's role in promoting stem cell characteristics and enhancing self-renewal ability in gastric cancer stem cells.
3. Prognostic Significance: Research suggests that high DKK1 expression is associated with a poorer prognosis in gastric cancer patients. Elevated DKK1 levels are linked to adverse clinical features, including advanced pathological stage, lymph node metastasis, and distant metastasis in gastric cancer.
4. Impact on Tumor Angiogenesis: DKK1 may play a role in regulating tumor angiogenesis, potentially influencing the growth and metastasis of gastric cancer.
5. Additional Functions: Emerging findings indicate that DKK1 may also be involved in biological processes like immune escape and epithelial-mesenchymal transition in gastric cancer[18-19].

The Role of DKK1 in pancreatic cancer

1. Enhancing Proliferation and Invasion of Pancreatic Cancer Cells: DKK1's high expression is associated with increased proliferation and invasion abilities of pancreatic cancer cells. By inhibiting the Wnt signaling pathway, DKK1 promotes the growth, migration, and invasion of pancreatic cancer cells.
2. Influence on Pancreatic Cancer Stem Cells: DKK1 may play a role in maintaining and promoting the growth of pancreatic cancer stem cells. These stem cells form a subpopulation of cells with self-renewal and differentiation capabilities that play a crucial role in tumor development and resistance to therapies.
3. Prognostic Significance: Studies indicate that high DKK1 expression is associated with a poorer prognosis in pancreatic cancer patients. Elevated DKK1 levels are linked to unfavorable clinical features, including advanced pathological stage, lymph node metastasis, and distant metastasis in pancreatic cancer.
4. Impact on Drug Resistance: The increased expression of DKK1 may contribute to drug resistance in pancreatic cancer, affecting the effectiveness of certain treatment approaches.
5. Influence on Immune Regulation: DKK1 may be associated with immune regulation in pancreatic cancer, potentially inhibiting the recognition and attack of tumor cells by the immune system.
6. Interaction with the Transforming Growth Factor β (TGF-β) Pathway: Some studies suggest that DKK1 may interact with the TGF-β pathway, thus affecting the proliferation and metastasis of pancreatic cancer cells.

DKK1 and its Role in Other Diseases

1. Potential in Osteoporosis Treatment: The Wnt signaling pathway plays a crucial role in bone formation and regulation of bone density. DKK1, as one of the regulatory proteins of bone destruction, can contribute to osteoporosis when its levels increase. Inhibition of DKK1 shows promise in increasing bone mineral density and may hold value as a treatment approach for osteoporosis.
2. Implications in Neurodegenerative Diseases: The Wnt signaling pathway is vital for the development and protection of the nervous system. Abnormal expression of DKK1 is associated with certain neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. Studying DKK1's role in these conditions could potentially lead to the development of targeted therapeutic strategies.
3. Involvement in Kidney Disease: Recent studies have highlighted the potential role of DKK1 in kidney disease. For instance, DKK1 is believed to be involved in the process of kidney fibrosis, and thus, inhibiting DKK1 may offer a treatment avenue for certain kidney diseases.

DKK1 protein

Recombinant Human Dickkopf-Related Protein 1 (DKK1) Protein (His), Active

The purity was greater than 95% as determined by SDS-PAGE. (Tris-Glycine gel) Discontinuous SDS-PAGE (reduced) with 5% enrichment gel and 15% separation gel.

Excellent Bioactivity Validated by Functional ELISA

Click here for more DKK1

Synonym:Dickkopf-related protein 1, Dickkopf-1, Dkk-1, hDkk-1, SK, DKK1, dickkopf WNT signaling pathway inhibitor 1, Dickkopf 1 Homolog, Dickkopf Related Protein-1, Dickkopf-1 Like, Dickkopf-Like Protein 1, Dickkopf (Xenopus Laevis) Homolog 1, DKK-1.

References:

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