Elevated autocrine EDIL3 protects hepatocellular carcinoma from anoikis through RGD-mediated integrin activation.
Elevated autocrine EDIL3 protects hepatocellular carcinoma from anoikis through RGD-mediated integrin activation.
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自分泌 EDIL3 升高通过 RGD 介导的整合素激活保护肝细胞癌免受失巢凋亡
DOI：
10.1186/1476-4598-13-226
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发表时间：
2014-10-01
期刊：
影响因子：
37.3
通讯作者：
Xia Q
中科院分区：
文献类型：
--
作者：
Feng MX;Ma MZ;Fu Y;Li J;Wang T;Xue F;Zhang JJ;Qin WX;Gu JR;Zhang ZG;Xia Q
背景：基质细胞蛋白异常表达导致肝癌微环境重塑，促进肝癌进展。整合素介导的细胞-基质相互作用在肿瘤微环境中起重要作用。表皮生长因子样重复序列和盘状蛋白I样结构域3（EDIL 3）是一种具有血管生成和抗炎作用的细胞外基质（ECM）蛋白，在HCC中异常高表达。本研究旨在分析EDIL 3在肝组织和肝癌组织中的表达，探讨其在肝癌发生发展中的作用机制。分析EDIL 3与临床结局之间的相关性。使用免疫荧光和ELISA检查EDIL 3表达和定位的模式。对一组细胞系中EDIL 3的过表达或敲低进行与增殖、侵袭和失巢凋亡相关的测定，以研究该基质蛋白在HCC进展中的机制。重组EDIL 3治疗应用于确认结果。结果与正常肝和硬化肝相比，EDIL 3在HCC中升高。EDIL 3蛋白高表达多见于肿瘤较大或门静脉癌栓形成的患者，预后差。EDIL 3在肝癌细胞中大量表达并由癌细胞分泌，体外和体内研究表明，EDIL 3可能以自分泌方式抑制肝癌细胞的失巢凋亡，促进肝癌细胞的非锚定依赖性生长。进一步的机制研究表明整联蛋白通过EDIL 3连接，因此FAK-Src-AKT信号的持续激活是抗失巢凋亡和锚定独立性的原因。Cilengitide和整合素αV的沉默均能阻断EDIL 3诱导的失巢凋亡抵抗。结论高水平的EDIL 3自分泌可能为肝癌细胞的存活提供了一个接受性的微环境，并可能参与了癌细胞的扩散。我们还强调了EDIL 3和整合素αV之间相互作用的重要性，并建议在选定的患者中通过RGD阻断来破坏EDIL 3与整合素的连接可能具有潜在的治疗价值。
BackgroundA remolded microenvironment in hepatocellular carcinoma (HCC) caused by abnormally expressed matricellular proteins could promote HCC progression. The cell-matrix interactions mediated by integrins play an important role in tumor microenvironment. Epidermal Growth Factor-like repeats and Discoidin I-Like Domains 3 (EDIL3), an extracellular matrix (ECM) protein with angiogenic and anti-inflammatory effects, is abnormally highly expressed in HCC. Here we aim to analyze its expression in liver and HCC tissues, investigate the underlined mechanisms accounted for HCC progression.MethodsEDIL3 expression level is examined in normal liver, cirrhotic liver and HCC at both mRNA and protein level. The association between EDIL3 and clinical outcomes is analyzed. The pattern of EDIL3 expression and location is examined using Immunofluorescence and ELISA. Overexpression or knock-down of EDIL3 in a panel of cell lines are subjected to assays related to proliferation, invasion, and anoikis to investigate the mechanisms of this matrix protein in HCC progression. Recombinant EDIL3 treatment is applied to confirm the results.ResultsCompared with normal liver and cirrhotic liver, EDIL3 is elevated in HCC. High level of EDIL3 protein is much more commonly in patients with larger tumor or portal vein tumor thrombus (PVTT) formation, associated with poor prognosis. EDIL3 is abundantly expressed in HCC cells and secreted by cancer cells.In vitroandin vivostudies indicate that EDIL3, probably in an autocrine manner, inhibits anoikis and promotes anchorage-independent growth of HCC cells. Further mechanistic studies suggest integrin ligation by EDIL3 and thus that the sustained activation of the FAK-Src-AKT signal is responsible for the anoikis resistance and anchorage independence. Both the administration of cilengitide, a RGD-containing integrin antagonist, and silencing of integrin αV, an important RGD-binding integrin, results in the blockade of anoikis-resistance induced by EDIL3.ConclusionOur study suggests that high levels of autocrine EDIL3 may contribute to a receptive microenvironment for the survival of detached HCC cells and may involve in cancer cell spreading. We also highlight the importance of interaction between EDIL3 and integrin αV and suggest disrupting the ligation of EDIL3 to integrins via RGD-blocking in selected patients may bear potential therapeutic value.
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影响因子：
30.5
作者：
通讯作者：
--
影响因子：
8
作者：
McCabe, N. P.;De, S.;Byzova, T. V.
通讯作者：
Byzova, T. V.
影响因子：
6.6
作者：
Beckham, Carla J.;Olsen, Jayme;Lee, Yi-Fen
通讯作者：
Lee, Yi-Fen
DOI：
10.1016/j.bbrc.2005.06.009
发表时间：
2005-08-05
影响因子：
3.1
作者：
Aoki, M;Kanamori, M;Kimura, T
通讯作者：
Kimura, T
影响因子：
7.2
作者：
Beausejour, Marco;Noel, Dominique;Thibodeau, Sonya;Bouchard, Veronique;Harnois, Charlene;Beaulieu, Jean-Francois;Demers, Marie-Josee;Vachon, Pierre H.
通讯作者：
Vachon, Pierre H.