TCF21 inhibits tumor-associated angiogenesis and suppresses the growth of cholangiocarcinoma by targeting PI3K/Akt and ERK signaling
TCF21 inhibits tumor-associated angiogenesis and suppresses the growth of cholangiocarcinoma by targeting PI3K/Akt and ERK signaling
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DOI：
10.1152/ajpgi.00264.2018
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发表时间：
2019-06-01
影响因子：
4.5
通讯作者：
Xiao, Shuang
中科院分区：
文献类型：
--
作者：
Duan, Hua-Xin;Li, Bo-Wen;Xiao, Shuang
肿瘤相关血管生成在胆管癌的发病机制中起着重要作用。在这项研究中，我们研究了转录因子21（TCF 21）在CCA相关血管生成中的生物学作用和分子机制。采用实时定量PCR和Western blot方法比较15对癌旁正常组织和CCA组织以及正常胆管上皮细胞和两种CCA细胞系（QBC-939和TFK-1）之间TCF 21的表达。利用两种CCA细胞系作为模型系统，我们通过慢病毒转导稳定表达TCF 21（Lv-TCF 21）。在体内，我们监测异种移植生长从不同的CCA细胞，测量肿瘤相关的血管生成的组织学分析，并确定表达和循环水平的VEGFA和PDGF-BB的免疫组化和ELISA，分别。在体外，我们评估了收集自不同CCA细胞的条件培养基对内皮细胞的活力、迁移和管形成的影响，并探讨了磷脂酰肌醇3-激酶/蛋白激酶B（PI 3 K/Akt）以及ERK 1/2信号在此过程中的意义。TCF 21在CCA组织或细胞系中显著下调。CCA细胞中TCF 21的异位表达抑制异种移植物生长或体内肿瘤相关血管生成，并靶向促血管生成因子VEGFA和PDGF-BB的表达和分泌。在体外，从Lv-TCF 21 CCA细胞收集的条件培养基显著降低了内皮细胞的活力、迁移和管形成。在分子水平上，TCF 21的抗血管生成活性主要是通过靶向PI 3 K/Akt和ERK 1/2信号通路实现的。TCF 21具有生长抑制和抗血管生成活性，因此TCF 21表达的升高可能为CCA提供治疗益处。dNEW & NOTEWORTHY转录因子21（TCF 21）在胆管癌（CCA）组织或细胞中下调。TCF 21抑制源自CCA细胞的异种移植物的生长。TCF 21抑制体内肿瘤相关的血管生成。TCF 21靶向CCA细胞中促血管生成因子的表达和产生。TCF 21的抗血管生成作用是通过靶向磷脂酰肌醇3-激酶/蛋白激酶B和ERK 1/2信号通路实现的。
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 transduction (Lv-TCF21). In vivo, we monitored xenograft growth from different CCA cells, measured tumor-associated angiogenesis by histological 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 endothelial cells and explored the significance of phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), as well as ERK1/2 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 ERK1/2 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.dNEW & NOTEWORTHY Transcription factor 21 (TCF21) is downregulated in cholangiocarcinoma (CCA) tissues or cells. TCF21 inhibits the growth of xenografts derived from CCA cells. TCF21 suppresses in vivo tumor-associated angiogenesis. TCF21 targets expression and production of proangiogenic factors from CCA cells. The targeting of phosphatidylinositol 3-kinase/protein kinase B and ERK1/2 signaling mediates the anti-angiogenesis of TCF21.