Dickkopf-1 expression is associated with tumorigenity and lymphatic metastasis in human hilar cholangiocarcinoma.
Dickkopf-1 expression is associated with tumorigenity and lymphatic metastasis in human hilar cholangiocarcinoma.
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Dickkopf-1 表达与人肝门胆管癌的致瘤和淋巴转移相关
DOI：
10.18632/oncotarget.11859
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发表时间：
2016-10-25
期刊：
影响因子：
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通讯作者：
Liu C
中科院分区：
文献类型：
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作者：
Shi XD;Yu XH;Wu WR;Xu XL;Wang JY;Xu LB;Zhang R;Liu C
Dickkopf-1（DKK 1）参与多种肿瘤的发生和侵袭。然而，其在人肝门部胆管癌（HCCA）中的生物学功能尚未被证实。本研究旨在探讨DKK 1在HCCA中的临床意义和生物学功能。采用免疫组织化学方法检测37例人HCCA活检标本中DKK 1的表达。为了进一步研究DKK 1在HCCA中的生物学作用，我们利用小干扰RNA（small interfering RNA，siRNA）和短发夹RNA（short hairpin RNA，shRNA）表达载体，在两个人HCCA细胞（QBC 939和FRH 0201）中建立了DKK 1的瞬时和稳定敲低。免疫组化结果显示，DKK 1在人HCCA组织中表达上调（24/37，64.9%）。人HCCA中高水平的DKK 1与肝门淋巴结转移相关（P=0.038）。与对照组相比，HCCA细胞中DKK 1的基因缺失导致细胞增殖、集落形成和迁移显著抑制。最重要的是，DKK 1下调损害了HCCA细胞在体内的肿瘤形成能力。随后的研究表明，β-catenin是DKK 1的重要靶点，并且DKK 1至少部分地通过β-catenin/基质金属蛋白酶-7（MMP-7）信号通路发挥其促侵袭功能。结论：在人肝癌组织中，DKK 1表达水平与β-catenin、MMP-7的表达及肝门淋巴结转移呈正相关。综上所述，我们的研究结果表明，DKK 1可能是人类HCCA致瘤性和侵袭性的关键调节因子，DKK 1至少部分通过β-catenin/ MMP-7信号通路发挥其促侵袭功能，提示DKK 1是HCCA潜在的治疗靶点。
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.