Dickkopf‐1 inhibits epithelial‐mesenchymal transition of colon cancer cells and contributes to colon cancer suppression

Abstract

This study aimed to determine the expression pattern of dickkopf-1 (Dkk1), a potent inhibitor of Wnt signaling, in colon cancer and to assess the function and mechanism of Dkk1 in tumor progression in vitro and in vivo. We detected the protein expression of Dkk1 and some epithelial-mesenchymal transition (EMT)-associated markers (E-cadherin, vimentin and β-catenin) in 217 tissue samples of human colon cancer, upregulated Dkk1 expression in HCT116 colon cancer cells, and established a nude mouse xenograft model. Dkk1 protein overexpression was inversely related to tumor grade and the presence of metastasis and recurrence of colon cancer. Notably, the expression of Dkk1 was concomitant with reduced immunohistochemical features of EMT (e.g. increased expression of epithelial marker E-cadherin, decreased expression of mesenchymal marker vimentin, and cytoplasmic distribution of β-catenin). Furthermore, Dkk1 overexpression resulted in restoration of the epithelial phenotype, decreased expression of EMT transcription factors Snail and Twist, and decreased expression of markers suggestive of intestinal stem cells (e.g. cluster of differentiation 133 [CD133] and leucine-rich-repeat-containing G-protein-coupled receptor 5 [Lgr5]). Functional analysis showed overexpression of Dkk1 reduced proliferation, migration, and invasion of colon cancer cells. Moreover, upregulation of Dkk1 led to decreased tumor-initiating ability and suppressed colon tumor growth in nude mice. Our findings indicate that Dkk1 can suppress the progression of colon cancer, possibly through EMT inhibition, and could therefore serve as a target for tumor therapy.

Acquired resistance to metformin in breast cancer cells triggers transcriptome reprogramming toward a degradome-related metastatic stem-like profile

“…The MCF-7/MET-R cells notably lost (12-fold downregulation vs. metformin-naïve MCF-7 cells) the expression of the Dickkopf1 (DKK1) gene (Table 2), which encodes a secreted inhibitor of the Wnt/β-catenin pathway and may have tumor suppressor functions. [96][97][98] Exogenous expression of DKK1 in human malignant breast cancer cells with mesenchymallike phenotype significantly reduces the expression of EMTpromoting factors, such as SLUG and TWIST; 99 conversely, silencing DKK1 expression in non-tumorigenic epithelial breast cells leads to increased invasive capacity and decreased E-cadherin expression. 100 Together, these findings strongly suggest that the negative effect of DKK1 on the EMT is part of the suppressive reprogramming that occurs when epithelial MCF-7 breast cancer cells adapt to the continuous presence of metformin.…”

The complex life of DICKKOPF-1 in cancer cells

“…This was an unexpected finding because as a β-catenin/TCF target DKK-1 gene was predicted to be upregulated in a malignancy characterized by a constitutively hyperactivated Wnt/β-catenin pathway. Supporting these data, analysis of DKK-1 expression in human colon tumors demonstrated an inverse correlation with tumor grade, presence of metastasis, and recurrence [45] . Moreover, downregulation of DKK-1 expression is concomitant with reduced epithelial-to-mesenchymal transition (EMT) phenotype [45] , and with reduced angiogenesis and VEGF expression [42] .…”

“…Supporting these data, analysis of DKK-1 expression in human colon tumors demonstrated an inverse correlation with tumor grade, presence of metastasis, and recurrence [45] . Moreover, downregulation of DKK-1 expression is concomitant with reduced epithelial-to-mesenchymal transition (EMT) phenotype [45] , and with reduced angiogenesis and VEGF expression [42] . The complex behavior of DKK-1 as a tumor suppressor or metastasis promoter may rely on the diverse and sometimes opposite actions of Wnt/β-catenin signaling in different tissues, together with other Wnt-independent effects that may add to the array of DKK-1 actions.…”

Paricalcitol Enhances the Chemopreventive Efficacy of 5-Fluorouracil on an Intermediate-Term Model of Azoxymethane-Induced Colorectal Tumors in Rats

“…At this point, approximately 80% of all human colorectal cancers have aberrant overactivations in Wnt/b-catenin signal and its downstream components in the colorectal cells (25). On the other hand, the expression pattern of Dkk-1, an inhibitor of Wnt/b-catenin pathway, by blocking Wnt signaling receptor complexes and contributing to colon cancer suppression, is remarkably downregulated in the colonic biopsies of colorectal cancer patients, and its downregulation is disclosed as a biomarker of chemoresistance and poor clinical outcome (25)(26)(27)(28)(29). Although the overall available data still have discrepancies, Dkk-1 has been found to not only act as an inhibitor of Wnt/ b-catenin signaling but also has additional b-catenin-independent tumor suppressor, antiangiogenesis, and antimetastasis actions in colorectal cancer disease (27,41).…”

“…On the other hand, the expression pattern of Dkk-1, an inhibitor of Wnt/b-catenin pathway, by blocking Wnt signaling receptor complexes and contributing to colon cancer suppression, is remarkably downregulated in the colonic biopsies of colorectal cancer patients, and its downregulation is disclosed as a biomarker of chemoresistance and poor clinical outcome (25)(26)(27)(28)(29). Although the overall available data still have discrepancies, Dkk-1 has been found to not only act as an inhibitor of Wnt/ b-catenin signaling but also has additional b-catenin-independent tumor suppressor, antiangiogenesis, and antimetastasis actions in colorectal cancer disease (27,41). Likewise, CDNK-1A, a tumor suppressor gene encoding a potent cell-cycle inhibitory factor (CDKN1A, p21, or CIP1), is downregulated or even lost in most colorectal cancer cases (30), and some colorectal cancer patients have anti-CDKN1A autoantibodies in their colorectal tissues (31).…”