Down-Regulation of Gab1 Inhibits Cell Proliferation and Migration in Hilar Cholangiocarcinoma

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.

Gab1 regulates proliferation and migration through the PI3K/Akt signaling pathway in intrahepatic cholangiocarcinoma

“…Gab1, VEGFR-2, and MMP-9 are significantly overexpressed in primary intrahepatic cholangiocarcinoma tissues, and the VEGFR-2/Gab1/PI3K/Akt pathway is able to regulate the malignant biological behaviors [i.e., growth, apoptosis, and invasion] in an intrahepatic cholangiocarcinoma cell line. As a multisubstrate adapter protein, Gab1 upregulates proto-oncogene expression via amplification of signaling pathways related to tumorigenesis [11][12][13][14]. Using immunohistochemistry, we found high expression of Gab1 in intrahepatic cholangiocarcinoma tissues from 24 patients and demonstrated that Gab1 was correlated with lymphatic metastasis and TNM stage.…”

“…VEGFR-2 is critical for VEGF-mediated tumor angiogenesis and lymphangiogenesis [18,19], and its expression is associated with tumor invasion and metastasis [14,20,29,30]. A VEGFR-2 antagonist can significantly inhibit VEGFinduced tumor growth and metastasis [31].…”

“…One such potential factor is Gab1 (Grb2-associated binding protein 1), which is involved in the development of tumors, including digestive system tumors [11][12][13][14]. Gab1 is an adapter protein that plays a role in the intracellular signal transduction process [15].…”

“…Gab1 also interacts with vascular endothelial growth factor receptor 2 (VEGFR-2), which plays a key role in angiogenesis and lymphangiogenesis, enhancing the growth, invasion, and metastasis of malignant tumors and resulting in poor prognosis [18][19][20]. VEGFR-2 activates the PI3K/Akt signaling pathway through its interaction with Gab1, contributing to tumor c e l l i n v a s i o n t h r o u g h i n d u c t i o n o f m a t r i x metallopeptidase 9 (MMP-9) [14,[21][22][23][24]. MMP-9 is able to degrade the extracellular matrix (ECM) and the basement membrane to promote tumor invasion and metastasis [25,26].…”

Expression of Gab1 Is Associated with Poor Prognosis of Patients with Epithelial Ovarian Cancer

“…As reported, Gab1 can up-regulate the proto-oncogene expression through interactions with Grb2, protein-tyrosine phosphatase SHP2, phosphatidylinositol 3-kinase (PI3K) and phosphatidylinositol (3,4,5)-trisphosphate (PIP3), therefore it plays an important role in the tumor development and progression (Oka et al 2008;Wohrle et al 2009;Felici et al 2010). Although there have been several studies demonstrated that Gab1 is involved in the development of chondrosarcoma (Fan et al 2016), cholangiocarcinoma (Sang et al 2013(Sang et al , 2015, colorectal cancer (Seiden-Long et al 2008) and mammary tumor (Gillgrass et al 2003), there are no published reports describing the correlation between Gab1 and the biological behaviors of EOC.…”