Abstract
Hilar cholangiocarcinoma is a highly aggressive malignancy originating from the hilar biliary duct epithelium. Due to few effective comprehensive treatments, the prognosis of hilar cholangiocarcinoma is poor. In this study, immunohistochemistry was first used to detect and analyze the expression of Gab1, VEGFR-2, and MMP-9 in hilar cholangiocarcinoma solid tumors and the relationships to the clinical pathological features. Furthermore, Gab1 and VEGFR-2 siRNA were used to interfere the hilar cholangiocarcinoma cell line ICBD-1 and then detect the PI3K/Akt signaling pathway, MMP-9 levels and malignant biological behaviors of tumor cells. The data showed that 1. Gab1, VEGFR-2, and MMP-9 were highly expressed and positively correlated with each other in hilar cholangiocarcinoma tissues, which were related to lymph node metastasis and differentiation. 2. After Gab1 or VEGFR-2 siRNA interference, PI3K/Akt pathway activity and MMP-9 levels were decreased in ICBD-1 cells. At the same time, cell proliferation decreased, cell cycle arrested in G1 phase, apoptosis increased and invasion decreased. These results suggest that the expression of Gab1, VEGFR-2, and MMP-9 are significantly related to the malignant biological behavior of hilar cholangiocarcinoma. Gab1 regulates growth, apoptosis and invasion through the VEGFR-2/Gab1/PI3K/Akt signaling pathway in hilar cholangiocarcinoma cells and influences the invasion of tumor cells via MMP-9.
Highlights
Hilar cholangiocarcinoma originates from the hilar biliary duct epithelium and is highly invasive, accounting for 50%-60% of cholangiocarcinomas [1,2]
VEGFR-2, Gab1 and MMP-9 expression levels in hilar cholangiocarcinoma tissues were positively correlated with each other. These results demonstrate that VEGFR-2, Gab1 and MMP-9 are all highly expressed in hilar cholangiocarcinoma tissues and closely related to the malignant biological behaviors of hilar cholangiocarcinoma and are correlated with each other
Hilar cholangiocarcinoma relapses after surgery and is insensitive to radiotherapy and chemotherapy [4,7,8,9], with a low overall 5-year survival rate
Summary
Hilar cholangiocarcinoma originates from the hilar biliary duct epithelium and is highly invasive, accounting for 50%-60% of cholangiocarcinomas [1,2]. Hilar cholangiocarcinoma is the most common malignant tumor of the biliary system [2]. Epidemiologic study results have shown an increasing incidence of hilar cholangiocarcinoma, which has become one of the major malignancies threatening human health in recent years [3]. Radical surgical resection is the most effective therapy available to treat hilar cholangiocarcinoma [4]. Most clinical patients have middle or advanced stage hilar cholangiocarcinoma with metastatic invasion to adjacent tissues by the time they seek medical care, resulting in a low radical resection rate [5,6]. Effective comprehensive therapies have not yet been established to treat hilar cholangiocarcinoma. To improve the therapeutic effects of hilar cholangiocarcinoma, mechanisms regarding molecular regulation associated with occurrence, infiltration and metastasis should be studied in addition to early intervention
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