Abstract
The incidence and mortality of intrahepatic cholangiocarcinoma (ICC) are increasing worldwide in recent decades. Osteopontin (OPN) plays an important role in cancer metastasis, but its functional mechanism in ICC is not clear yet. In this study, we found that OPN level was elevated both in plasma and tumor tissues of ICC patients, which was closely related to a shorter overall survival (OS) and high probability of tumor relapse after curative resection. The gain- and loss-of-function studies determined that OPN could promote ICC growth and metastasis. OPN selectively interacted with β-Catenin and knockdown of β-Catenin abrogated the effects induced by OPN. OPN recruited MAPK1 and activated MEK–MAPK1 pathway to mediate the S675 phosphorylation of β-Catenin and nucleus accumulation, which induced the activation of Wnt signaling. Moreover, a significant correlation between OPN and β-Catenin was found in ICC tissues. OPN, β-Catenin, and their combination were independent prognostic indicator for ICC patients. In conclusion, OPN promotes ICC progression through recruiting MAPK1 and activating the Wnt/β-Catenin pathway and can serve as a novel prognostic marker and therapeutic target for ICC.
Highlights
Intrahepatic cholangiocarcinoma (ICC), arising from the intrahepatic bile ducts, is the second most common primary liver cancer[1,2]
High OPN expression is associated with dismal outcomes of patients with ICC The plasma OPN levels of ICC patients were remarkably increased compared with the healthy volunteers detected by enzyme-linked immunosorbent assay (ELISA) (Fig. 1a)
Univariate analysis showed that OPN expression, regional lymph node metastasis, and tumor differentiation were significantly associated with overall survival (OS) and possibilities of tumor recurrence of ICC patients
Summary
Intrahepatic cholangiocarcinoma (ICC), arising from the intrahepatic bile ducts, is the second most common primary liver cancer[1,2]. The incidence and mortality rate of ICC have been increasing in the world[3]. ICC is characterized as a devastating disease with very dismal prognosis[4]. Surgical resection and liver transplantation are the main treatment options; the 5-year survival rate is still very low due to the high probability of metastasis and relapse[5,6]. The pathogenesis of ICC is very complicated. To date no molecular targeted therapy is effective for ICC6. It is urgent to define the molecular mechanism involved in the progression of ICC
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