Dickkopf-1 expression is associated with tumorigenity and lymphatic metastasis in human hilar cholangiocarcinoma
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Xiang-de Shi1,*, Xian-huan Yu1,*, Wen-rui Wu1,*, Xiao-lin Xu2, Jie-Yu Wang3, Lei-bo Xu1, Rui Zhang1,4, Chao Liu1
1Guangdong 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
2Department of Ultrasound, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
3Department of Hematology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
4Faculty of Medicine, Department of Gastroenterology and Hepatology, University Duisburg-Essen, Essen, 45147, Germany
*These authors contributed equally to this work
Rui Zhang, email: email@example.com
Chao Liu, email: firstname.lastname@example.org
Keywords: DKK1, HCCA, tumorigenesis, lymphatic metastasis
Received: February 15, 2016 Accepted: August 24, 2016 Published: September 06, 2016
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.
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