Wip1 is associated with tumorigenity and metastasis through MMP-2 in human intrahepatic cholangiocarcinoma

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.

MicroRNA-129-2-3p directly targets Wip1 to suppress the proliferation and invasion of intrahepatic cholangiocarcinoma

“…Our previous findings indicate that Wip1 is involved in the tumorigenicity and invasion of human ICC at least in part through the MMP-2 signaling pathway [17]. Our further data show that both iNOS and Wip1 promote ICC cell migration and invasion by up-regulating MMP expression [18].…”

“…Accumulating studies identified that high Wip1 expression disrupted the homeostasis maintained by the p38 MAPK-p53-Wip1 pathway, which caused downstream Wnt-p53 inactivation through p38 MAPK dephosphorylation, and promoted the development of malignant in humans by reducing p16 protein levels [33,34]. Our previous data have indicated that Wip1 is oncogenic and is involved in invasive growth in renal cancer cells and ICC cells [12,17]. Our data also show Wip1 involved in the tumorigenicity and invasion of human ICC in part through the MMP-2 signaling pathway [17].…”

“…Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy with poor prognosis [17,20]. Despite improvements in its diagnosis and therapy, the prognosis for ICC patients remains poor.…”

“…Despite improvements in its diagnosis and therapy, the prognosis for ICC patients remains poor. An improved understanding of ICC tumorigenicity and consequential identification of novel therapeutic targets would improve the prognosis of ICC patients [17]. MicroRNAs (miRNAs) are a class of highly conserved, small endogenous non-coding RNAs that regulate gene expression at the posttranscriptional level and participate in important cellular processes, including development, apoptosis, proliferation, differentiation, metabolism [9,21].…”

“…Others and our previous studies showed that Wip1 were over expression in a wide range of tumor tissues including kidney [12], breast [13], lung [14], ovarian [15], neuroblastoma [16]. Our previous research showed that Wip1 was highly expressed in ICC tissues and cell lines and may be a key regulator in the tumorigenicity and invasion of human ICC [17,18]. However, the potential mechanism is unknown.…”