Abstract
Wip1 has been shown to correlate with the metastasis/invasion of several tumors. This study was designed to investigate the clinical significance and biological function of Wip1 in intrahepatic cholangiocarcinoma (ICC). The expression of Wip1 was investigated in sixty human ICC biopsy samples by immunohistochemistry. Transient and stable knockdown of Wip1 in two human ICC cells (ICC-9810 and SSP25) were established using short hairpin RNA expression vector. Immunohistochemistry revealed that Wip1 was up-regulated in human ICC tissues (47/60, 78.3%). High levels of Wip1 in human ICC correlated with metastasis to the lymph metastasis (P=0.022). Genetic depletion of Wip1 in ICC cells resulted in significantly inhibited proliferation and invasion compared with controls. Most importantly, Wip1 down-regulation impaired tumor migration capacity of ICC cells in vivo. Subsequent investigations revealed that matrix metalloproteinase-2 (MMP-2) is an important target of Wip1. Consistently, in human ICC tissues, Wip1 level was positively correlated with MMP-2 expression. Taken together, our founding indicates that Wip1 may be a crucial regulator in the tumorigenicity and invasion of human ICC, Wip1 exerts its pro-invasion function at least in part through the MMP-2 signaling pathway, suggesting Wip1 as a potential therapeutic target for ICC.
Highlights
Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with poor prognosis that makes up 10-25% of all primary hepatic cancers
The expression of Wip1 was elevated in intrahepatic cholangiocarcinoma (ICC) tissues and associated with hepatic hilar lymph nodes metastasis
Immunohistochemistry data showed that Wip1 expression was significantly up-regulated in ICC tissues compared with the normal samples (Figure 1)
Summary
Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with poor prognosis that makes up 10-25% of all primary hepatic cancers. ICC arises from the intrahepatic biliary tree and continues to be characterized by a poor prognosis, less than 20% to 50% of the patients alive years after curative resection, and a high recurrence/ metastasis rate [2, 3]. Wip dephosphorylates many proteins, including ataxia-telangiectasia mutated (ATM), p53, p38, Mdm, Mdm, Chk, Chk, and UNG2 [12, 13] [7]. These proteins that belong DDR/checkpoint markers, are often decreased in DNA damage response pathways, which contribute to sensing and repairing DNA damage. We investigated the roles of Wip expression in biologic behavior of ICC cells
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