Abstract
Gallbladder cancer (GBC) is a common malignancy of biliary tract cancers and its incidence has been rising rapidly worldwide. The prognosis for this disease is dismal as most of the symptoms are non-specific leading to a definitive diagnosis only at a late stage. Loss of DKK3 gene is associated with a possible tumor suppressor role in human cancers. The role and regulation of DKK3 in GBC have not been studied. We found that DKK3 expression levels were low in GBC patients and cell lines. Treatment of GBC cell lines with demethylating agent 5-Aza- 2'-deoxycytidine enhances its expression, establishing impact of methylation on DKK3 expression. We observed low expression of DKK3 in gallbladder adenocarcinoma tumors and highly invasive GBC cell lines. We showed that overexpression of DKK3 can decrease cell invasion, proliferation, and colony forming ability of GBC cells. Our data thus demonstrated the DKK3 gene is a potential tumor suppressor gene in GBC and aberrant promoter methylation could be involved in its downregulation, which may play a role in the tumorigenesis and aggressiveness of GBC.
Highlights
Gallbladder cancer (GBC) is the most common, aggressive malignancy of the biliary tract and its incidence has been rising rapidly in recent decades
Our results indicate that the expression of Dickkopf Homolog 3 (DKK3) is significantly down regulated in highly invasive GBC cell line G-415 in comparison to non-invasive or less invasive cell lines
DKK3 belongs to DKK family comprising of DKK1, DKK2, and DKK4, which are known as a potent antagonist of Wnt/β-catenin signaling pathway [24]
Summary
Gallbladder cancer (GBC) is the most common, aggressive malignancy of the biliary tract and its incidence has been rising rapidly in recent decades. Both genetic and epigenetic modifications are known to contribute in the tumorigenesis process [1, 2]. CpG hypermethylation in the promoter regions of tumor suppressor genes is commonly observed in various cancers. The increasing number of genes inactivated by CpG island hypermethylation is important step in cancer development. Wnt signaling pathway is a hallmark in multiple cancers and its downstream effector regulators are important for cancer progression, including tumor initiation, tumor growth, cell death, and metastasis [3]. DKK1, DKK2, and DKK4 are DKK3 Is a Novel Tumor Suppressor in GBC antagonists of Wnt signaling and interact with Wnt coreceptors, LDL receptor-related protein 5/6 (LRP5/6) and kremen proteins [6, 7]
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