Dickkopf-1 expression is associated with tumorigenity and lymphatic metastasis in human hilar cholangiocarcinoma.
Dickkopf-1 (DKK1) is involved in tumorigenesis and the invasion of several tumors. However, its biological function in human hilar cholangiocarcinoma (HCCA) has not yet been documented. This study was designed to investigate the clinical significance and biological function of DKK1 in HCCA. The expression of DKK1 was investigated in thirty-seven human HCCA biopsy samples by immunohistochemistry. To further explore the biological effects of DKK1 in HCCA, transient and stable knockdown of DKK1 in two human HCCA cells (QBC939 and FRH0201) were established using small interfering or short hairpin RNA expression vector. In the present study, immunohistochemistry revealed that DKK1 was up-regulated in human HCCA tissues (24/37, 64.9%). High levels of DKK1 in human HCCA correlated with metastasis to the hilar lymph nodes (P=0.038). Genetic depletion of DKK1 in HCCA cells resulted in significantly inhibited proliferation, colony formation and migration compared with controls. Most importantly, DKK1 down-regulation impaired tumor formation capacity of HCCA cells in vivo. Subsequent investigations revealed that β-catenin is an important target of DKK1 and DKK1 exerts its pro-invasion function at least in part through the β-catenin/ matrix metalloproteinase-7 (MMP-7) signaling pathway. Consistently, in human HCCA tissues, DKK1 level was positively correlated with β-catenin and MMP-7 expression, as well as tumor hilar lymphatic metastasis. Taken together, our findings indicate that DKK1 may be a crucial regulator in the tumorigenicity and invasion of human HCCA, DKK1 exerts its pro-invasion function at least in part through the β-catenin/ MMP-7 signaling pathway, suggesting DKK1 as a potential therapeutic target for HCCA.
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation and Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
Xiang-de
XD
Shi
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation and Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
Xian-Huan
XH
Yu
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation and Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
Wen-Rui
WR
Wu
Department of Ultrasound, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
Xiao-Lin
XL
Xu
Department of Hematology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
Jie-Yu
JY
Wang
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation and Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
Lei-Bo
LB
Xu
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation and Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.|Faculty of Medicine, Department of Gastroenterology and Hepatology, University Duisburg-Essen, Essen, 45147, Germany.
Rui
R
Zhang
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation and Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
Chao
C
Liu
D001650:Bile Duct Neoplasms / Q000209:etiology* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018281:Cholangiocarcinoma / Q000209:etiology* / Q000473:pathology; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D008207:Lymphatic Metastasis; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D051176:beta Catenin / Q000032:analysis / Q000502:physiology
C495270:CTNNB1 protein, human; C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D051176:beta Catenin; D020783:Matrix Metalloproteinase 7
DKK1; HCCA; lymphatic metastasis; tumorigenesis