Hypoxia-induced up-regulation of angiogenin, besides VEGF, is related to progression of oral cancer
Hypoxia-induced up-regulation of angiogenin, besides VEGF, is related to progression of oral cancer
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DOI：
10.1016/j.oraloncology.2012.05.009
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发表时间：
2012-11-01
期刊：
影响因子：
4.8
通讯作者：
Sasaki, Akira
中科院分区：
文献类型：
--
作者：
Kishimoto, Koji;Yoshida, Shoko;Sasaki, Akira
目的：血管生成素(Angigenin，Ang)是一种重要的血管生成因子，通过刺激内皮细胞和癌细胞的核糖体RNA转录，诱导血管生成和癌细胞增殖，对肿瘤的发展具有双重作用。本研究旨在探讨血管紧张素转换酶(Ang)和血管内皮生长因子(VEGF)在口腔癌组织中的表达及其与缺氧的关系，探讨Ang作为口腔癌治疗靶点的可能价值。材料和方法：采用免疫组织化学(IHC)、实时定量RT-PCR和Western blotting方法检测Ang、VEGF和缺氧诱导因子1α(HIF-1α)在口腔鳞状细胞癌(OSCC)标本和口腔鳞状细胞癌细胞系中的表达。结果：50例口腔鳞癌组织中Ang和HIF-1α的表达呈显著正相关(P=0.031)。而血管内皮生长因子与缺氧诱导因子-1α的表达无明显相关性(P=0.243)。所有10株口腔鳞癌细胞系在低氧条件下血管紧张素转换酶分泌均增加，其中6株显著增加。相比之下，在低氧条件下，这些细胞系中的任何一种细胞的血管内皮生长因子分泌都没有明显增加。在HSC-2和SAS OSCC细胞中，Ang mRNA表达的增加与HIF-1α蛋白的表达具有很好的相关性。但缺氧12h后，血管内皮生长因子的表达仍未见明显增加。Ang在高表达和分泌VEGF的HSC-2细胞中的表达下调，抑制了裸鼠核糖体的生物合成、细胞增殖、肿瘤血管生成和异种移植瘤的生长。结论：Ang在口腔癌低氧环境中表达上调，其抑制作用具有一定的治疗意义。(C)2012爱思唯尔有限公司。保留所有权利。
Objectives: Angiogenin (ANG) is a prominent angiogenic factor that has been shown to have a dual effect on tumor progression by inducing both angiogenesis and cancer cell proliferation through stimulating ribosomal RNA transcription in both endothelial cells and cancer cells. In the present study, we investigated the expression profiles of ANG and vascular endothelial growth factor (VEGF) in oral cancer and their correlation with hypoxia and evaluated the possible value of ANG as a therapeutic target for oral cancer.Materials and Methods: Immunohistochemistry (IHC), ELISA, real-time RT-PCR and Western blotting were used to examine the expression of ANG, VEGF, and hypoxia-inducible factor 1 alpha (HIF-1 alpha) in oral squamous cell carcinoma (OSCC) specimens and human OSCC cell lines. In order to examine the role of ANG, we knocked down ANG expression in HSC-2 cells by means of plasmid-mediated RNA interference.Results: IHC showed that the expression of ANG was significantly correlated with that of HIF-1 alpha in 50 OSCC specimens (P = 0.031). However, no significant correlation between VEGF and HIF-1 alpha expression was found (P = 0.243). Consistently, ANG secretion increased under hypoxia in all of the 10 OSCC cell lines tested; and a significant increase was observed in 6 of them. In contrast, there was no noticeable increase in VEGF secretion under hypoxia in any of these cell lines. In HSC-2 and SAS OSCC cells, the increase in ANG mRNA expression correlated very well with that of HIF-1 alpha protein expression after hypoxia onset. However, no noticeable increase in VEGF mRNA expression was observed even after 12 h of hypoxia. Down-regulation of ANG expression in HSC-2 cells highly expressing and secreting VEGF inhibited ribosome biogenesis, cell proliferation, tumor angiogenesis, and xenograft growth in athymic mice.Conclusion: These results suggest that ANG is up-regulated in the hypoxic environment of oral cancers and that its inhibition can have a therapeutic implication. (C) 2012 Elsevier Ltd. All rights reserved.