Dickkopf‐1 is overexpressed in human pancreatic ductal adenocarcinoma cells and is involved in invasive growth

Abstract

The protein products of the Dickkopf (DKK) genes are antagonists of Wnt glycoproteins, which participate in tumor development and progression by binding to frizzled receptors. In this study, the expression of DKK-1 was analyzed in a panel of 43 human cultured carcinoma cell lines. DKK-1 expression was consistently and significantly upregulated in pancreatic carcinoma cell lines. Low level of DKK-3 expression was also seen. In contrast, the expression of DKK-2 and -4 was not detectable in most pancreatic carcinoma cell lines. The overexpression of DKK-1 was confirmed in surgically resected human pancreatic cancer tissues, in which the mRNA level was evaluated in paired samples from cancerous and noncancerous pancreatic tissues. In ductal adenocarcinomas (23 cases), DKK-1 mRNA levels were significantly upregulated compared to corresponding noncancerous tissues in a statistically significant level. To test the biological role of DKK-1 in pancreatic carcinoma cells, we performed a knockdown of DKK-1 in SUIT-2 human pancreatic adenocarcinoma cell line and S2-CP8, its metastatic subline, using a retroviral short hairpin RNA expression vector. DKK-1 knockdown resulted in reduced migratory activity of SUIT-2 in vitro. The in vitro growth rate and Matrigel invasion were also suppressed by DKK-1 knockdown in S2-CP8 cells. Collectively, the evidence suggests that, despite of its presumed antagonistic role in Wnt signaling, DKK-1 may have a role in the aggressiveness of pancreatic carcinoma cells and could, therefore, serve as a novel biomarker of pancreatic cancer.The Dickkopf (DKK) genes are Wnt antagonists that were originally identified as inducers of head formation in Xenopus.1 Wnt glycoproteins participate in tumor development and progression by binding to frizzled receptors and signaling through the canonical and noncanonical Wnt pathways. 2The DKK gene family consists of DKK-1, -2, -3, -4, and a unique DKK-3-related gene soggy.2 The expression of these genes is temporally and spatially regulated, and all DKK proteins show distinct and elevated expression patterns in tissues that mediate the epithelial-mesenchymal transformation. 3 This finding suggests that they may participate in the epithelial to mesenchymal transition that is important not only in embryogenesis, but also in cancer progression.4 DKK-1 is a secreted protein that has been clearly defined as a direct inhibitor of Wnt binding to LRP5/6 coreceptors of frizzled. 2Evidence for the potential involvement of DKK-1 inactivation in human cancers is accumulating. The DKK-1 gene is frequently hypermethylated in colorectal cancers, whereas overexpression of DKK-1 reduced the growth of colorectal carcinoma cells. 5,6 The expression of DKK-1 is also reportedly downregulated in melanoma cells, 7 lung cancer cells with neuroendocrine differentiation 8 and in a metastatic subline of hepatocellular carcinoma cell line. 9 In contrast, overexpression of DKK-1 has also been found in some tumors, such as Wilms' tumor, hepatoblastoma, hepatocellular carcinoma and ovarian e...

Dickkopf-3 maintains the PANC-1 human pancreatic tumor cells in a dedifferentiated state

“…PANC-1 cells have previously been shown to express DKK3 at mRNA levels (24). herein, we demonstrate that Dkk-3 supports proliferation of PANC-1 cells as shown by knockdown of Dkk-3 via lentiviral-delivered shRNA.…”

“…The PANC-1 cell line serves as a model for Dkk-3 expressing PDAC due to its expression DKK3 at mRNA levels (24). By confocal immunofluorescence, Western blot analysis and an IEMA based on our monoclonal antibody, Dkk-3 protein expression was confirmed in PANC-1 cells and supernatants.…”

Downregulation of serum DKK-1 predicts poor prognosis in patients with papillary thyroid cancer

“…In addition, high serum DKK-1 levels were shown to be an independent prognostic factor for prostate cancer, suggesting that DKK-1 might act as an oncogene in prostate cancer. Takahashi et al (2010) showed that DKK-1 was overexpressed in both human pancreatic ductal adenocarcinoma tissues and cell lines, and knockdown of DKK-1 could inhibit the proliferative and invasive capability of human pancreatic ductal adenocarcinoma cell lines in vitro. Similarly, the serum level of DKK-1 was elevated in patients with osteosarcoma, and the expression of DKK-1 by the osteosarcoma cells at the periphery of the tumor might be responsible for tumor growth by inhibiting repair of the surrounding bone (Lee et al, 2007).…”

The complex life of DICKKOPF-1 in cancer cells

“…It has recently been shown that both DKK-1 and osteopontin enhance the diagnostic value of alpha-fetoprotein, the most widely used biomarker for HCC [29] . Other tumor types in which enhanced expression of DKK-1 has been reported include prostate, breast, gastric, ovarian, glioma, esophagic or pancreatic cancer [30][31][32][33][34][35][36] . Notably, high expression of DKK-1 frequently correlates with increased invasive and metastatic capacity of a variety of tumors [36][37][38][39] , which suggests that DKK-1 might be a metastasis promoter for some neoplasias.…”