Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore.
Department of Hepatobiliary Oncology, Cancer Center, Sun Yat-sen University, Guangzhou 510060, PR China.
J Hepatol. 2015 Oct;63(4):863-73. doi: 10.1016/j.jhep.2015.05.005. Epub 2015 May 14.
BACKGROUND & AIMS: Patients with advanced hepatocellular carcinoma (HCC) continue to have a dismal prognosis. Early recurrence, metastases and angiogenesis are the major obstacles to improve the outcome of HCC. Epithelial-mesenchymal transition (EMT) is a key contributor to cancer metastasis and recurrence, which are the major obstacles to improve prognosis of HCC.
Combining gene expression profiles of HCC samples with or without early recurrence and established cell lines with epithelial or mesenchymal phenotype, EDIL3 was identified as a novel regulator of EMT. The expression of EDIL3 was evaluated by quantitative PCR, Western blotting or immunohistochemistry. The effects of EDIL3 on the angiogenesis and metastasis of HCC cells were examined by wound healing, Matrigel invasion and tube formation assay in vitro and orthotopic xenograft mouse model of HCC in vivo. The signaling pathways of EDIL3 mediated were investigated through microarray and Western blotting analysis.
EDIL3 was identified as a novel regulator of EMT, which contributes to angiogenesis, metastasis and recurrence of HCC. EDIL3 induces EMT and promotes HCC migration, invasion and angiogenesis in vitro. Mechanistically, overexpression of EDIL3, which was regulated by the downregulation of miR-137 in HCC, triggered the activation of ERK and TGF-β signaling through interactions with αvβ3 integrin. Blocking ERK and TGF-β signaling overcomes EDIL3 induced angiogenesis and invasion. Using the orthotopic xenograft mouse model of HCC, we demonstrated that EDIL3 enhanced the tumorigenic, metastatic and angiogenesis potential of HCC in vivo.
EDIL3-mediated activation of TGF-β and ERK signaling could provide therapeutic implications for HCC.
晚期肝细胞癌（HCC）患者的预后仍然很差。早期复发、转移和血管生成是改善 HCC 预后的主要障碍。上皮-间充质转化（EMT）是癌症转移和复发的关键因素，是改善 HCC 预后的主要障碍。
结合 HCC 样本中有无早期复发的基因表达谱和具有上皮或间充质表型的已建立的细胞系，鉴定 EDIL3 是 EMT 的新调节因子。通过定量 PCR、Western blot 或免疫组织化学评估 EDIL3 的表达。通过体外划痕愈合、Matrigel 侵袭和管形成试验以及 HCC 的原位异种移植小鼠模型，研究 EDIL3 对 HCC 细胞血管生成和转移的影响。通过微阵列和 Western blot 分析研究 EDIL3 介导的信号通路。
EDIL3 被鉴定为 EMT 的新调节因子，它有助于 HCC 的血管生成、转移和复发。EDIL3 在体外诱导 EMT，并促进 HCC 迁移、侵袭和血管生成。在机制上，受 HCC 中 miR-137 下调调节的 EDIL3 过表达通过与 αvβ3 整合素相互作用触发 ERK 和 TGF-β 信号的激活。阻断 ERK 和 TGF-β 信号可克服 EDIL3 诱导的血管生成和侵袭。使用 HCC 的原位异种移植小鼠模型，我们证明 EDIL3 在体内增强了 HCC 的致瘤性、转移性和血管生成潜能。
EDIL3 介导的 TGF-β 和 ERK 信号激活可为 HCC 提供治疗意义。
