Sang Haiquan, Li Tingting, Li Hangyu, Liu Jingang
Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, PR China.
PLoS One. 2013 Nov 28;8(11):e81347. doi: 10.1371/journal.pone.0081347. eCollection 2013.
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.
肝门部胆管癌是一种起源于肝门部胆管上皮的高侵袭性恶性肿瘤。由于有效的综合治疗手段较少，肝门部胆管癌的预后较差。在本研究中，首先采用免疫组织化学方法检测并分析Gab1、VEGFR-2和MMP-9在肝门部胆管癌实体瘤中的表达及其与临床病理特征的关系。此外，利用Gab1和VEGFR-2的小干扰RNA（siRNA）干扰肝门部胆管癌细胞系ICBD-1，然后检测肿瘤细胞的PI3K/Akt信号通路、MMP-9水平及恶性生物学行为。数据显示：1. Gab1、VEGFR-2和MMP-9在肝门部胆管癌组织中高表达且相互呈正相关，这与淋巴结转移和分化有关。2. Gab1或VEGFR-2 siRNA干扰后，ICBD-1细胞中PI3K/Akt通路活性和MMP-9水平降低。同时，细胞增殖减少，细胞周期阻滞于G1期，凋亡增加，侵袭能力下降。这些结果提示，Gab1、VEGFR-2和MMP-9的表达与肝门部胆管癌的恶性生物学行为显著相关。在肝门部胆管癌细胞中，Gab1通过VEGFR-2/Gab1/PI3K/Akt信号通路调节生长、凋亡和侵袭，并通过MMP-9影响肿瘤细胞的侵袭。
