Ablation of EIF5A2 induces tumor vasculature remodeling and improves tumor response to chemotherapy via regulation of matrix metalloproteinase 2 expression.
Ablation of EIF5A2 induces tumor vasculature remodeling and improves tumor response to chemotherapy via regulation of matrix metalloproteinase 2 expression.
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EIF5A2 的消除可诱导肿瘤脉管系统重塑，并通过调节基质金属蛋白酶 2 的表达来改善肿瘤对化疗的反应。
DOI：
10.18632/oncotarget.2236
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发表时间：
2014-08-30
期刊：
影响因子：
--
通讯作者：
Xie D
中科院分区：
文献类型：
--
作者：
Wang FW;Cai MY;Mai SJ;Chen JW;Bai HY;Li Y;Liao YJ;Li CP;Tian XP;Kung HF;Guan XY;Xie D
肝细胞癌（HCC）是一种高度血管化的肿瘤，临床预后差。我们的前期工作表明，真核细胞起始因子5A 2（EIF 5A 2）的过表达增强肝癌细胞的转移。在这项研究中，EIF 5A 2被确定为HCC患者疾病特异性生存率差的独立危险因素。体外和体内试验均表明，内源性EIF 5A 2的消融通过降低基质金属蛋白酶2（MMP-2）的表达来抑制肿瘤血管生成。鉴于MMP-2降解IV型胶原蛋白（血管基底膜（BM）的主要成分），我们随后研究了EIF 5A 2对肿瘤血管重塑的影响，使用互补的方法，包括荧光免疫染色，透射电子显微镜，肿瘤灌注测定和肿瘤缺氧测定。总之，我们的结果表明EIF 5A 2沉默增加了肿瘤血管壁的连续性，增加了血液灌注并改善了肿瘤氧合。此外，我们发现EIF 5A 2的消融增强了HCC细胞对5-氟尿嘧啶（5-FU）的化疗敏感性。最后，我们证明EIF 5A 2可能通过激活p38 MAPK和JNK/c-Jun途径增强MMP-2活性来发挥这些功能。结论：这项研究强调了EIF 5A 2在HCC肿瘤血管重塑中的重要作用，并表明EIF 5A 2代表了HCC治疗的潜在治疗靶点。
Hepatocellular carcinoma (HCC) is a highly vascularized tumor with poor clinical outcome. Our previous work has shown that eukaryotic initiation factor 5A2 (EIF5A2) over-expression enhances HCC cell metastasis. In this study, EIF5A2 was identified to be an independent risk factor for poor disease-specific survival among HCC patients. Both in vitro and in vivo assays indicated that ablation of endogenous EIF5A2 inhibited tumor angiogenesis by reducing matrix metalloproteinase 2 (MMP-2) expression. Given that MMP-2 degrades collagen IV, a main component of the vascular basement membrane (BM), we subsequently investigated the effect of EIF5A2 on tumor vasculature remodeling using complementary approaches, including fluorescent immunostaining, transmission electron microscopy, tumor perfusion assays and tumor hypoxia assays. Taken together, our results indicate that EIF5A2 silencing increases tumor vessel wall continuity, increases blood perfusion and improves tumor oxygenation. Additionally, we found that ablation of EIF5A2 enhanced the chemosensitivity of HCC cells to 5-Fluorouracil (5-FU). Finally, we demonstrated that EIF5A2 might exert these functions by enhancing MMP-2 activity via activation of p38 MAPK and JNK/c-Jun pathways. Conclusion: This study highlights an important role of EIF5A2 in HCC tumor vessel remodeling and indicates that EIF5A2 represents a potential therapeutic target in the treatment of HCC.
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影响因子：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
通讯作者：
Bruix, Jordi
影响因子：
15.9
作者：
Jiang, Lili;Lin, Chuyong;Li, Mengfeng
通讯作者：
Li, Mengfeng
分子机制和血管生成的临床应用。
影响因子：
64.8
作者：
Carmeliet, Peter;Jain, Rakesh K.
通讯作者：
Jain, Rakesh K.
DOI：
10.1038/nrc2442
发表时间：
2008-08
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
8.8
作者：
Khosravi, S.;Wong, R. P. C.;Ardekani, G. S.;Zhang, G.;Martinka, M.;Ong, C. J.;Li, G.
通讯作者：
Li, G.