TCF21 inhibits tumor-associated angiogenesis and suppresses the growth of cholangiocarcinoma by targeting PI3K/Akt and ERK signaling

摘要

Tumor-associated angiogenesis plays a critical role in the pathogenesis of cholangiocarcinoma (CCA). In this study, we examined the biological effects and molecular mechanisms of transcription factor 21 (TCF21) on CCA-associated angiogenesis. TCF21 expression was compared between 15 pairs of peritumor normal tissues and CCA tissues and also between normal bile duct epithelial cells and two CCA cell lines (QBC-939 and TFK-1) using real-time PCR and Western blot. With the use of both CCA cell lines as the model system, we stably expressed TCF21 by lentiviral trans-duction (Lv-TCF21). In vivo, we monitored xenograft growth from different CCA cells, measured tumor-associated angiogenesis by his-tological analysis, and determined the expressions and circulatory levels of VEGFA and PDGF-BB by immunohistochemistry and ELISA, respectively. In vitro, we assessed the effects of conditioned medium collected from different CCA cells on the viability, migration, and tube formation of endolhelial cells and explored the significance of phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), as well as ERK 1/2 signaling in this process. TCF21 was significantly downregulated in CCA tissues or cell lines. Ectopic expression of TCF21 in CCA cells inhibited xenograft growth or tumor-associated angiogenesis in vivo and targeted the expression and secretion of proangiogenic factors, VEGFA and PDGF-BB. In vitro, the conditioned medium collected from Lv-TCF21 CCA cells significantly reduced the viability, migration, and tube formation of endothelial cells. On the molecular level, the targeting of PI3K/Akt and ERK 1/2 signaling mediated the anti-angiogenic activity of TCF21. TCF21 presents growth-inhibitory and anti-angiogenic activities, and thus the elevation of TCF21 expression may provide therapeutic benefits for CCA.