兰州大学机构库 >生命科学学院
Slit-Robo信号在口腔癌形成中的功能研究
Alternative TitleThe role of Slit-Robo signaling in oral carcinogenesis
王丽京
Thesis Advisor王锐
2008-05-14
Degree Grantor兰州大学
Place of Conferral兰州
Degree Name博士
KeywordSlit-Robo信号 地鼠颊囊癌 新生血管形成 口腔癌 凋亡 肿瘤转移 抗体
Abstract结 论: 1、本研究表明Slit-Robo信号在口腔癌形成过程中由癌前向癌的恶性转化中发挥了重要的“开关”作用,是肿瘤发生发展中的一个早期分子事件;它的激活与浸润癌进展和深层侵袭密切相关。其机制可能是Slit2蛋白的分泌具有重要的吸引新生血管形成、促进肿瘤组织恶性增殖和深层侵袭的作用。Slit2蛋白可作为一个早期生物标记物的监测对口腔癌的早期诊断和新的治疗靶点具有重要意义。 2、表明应用针对Robo1的阻断性抗体R5后能够明显抑制地鼠颊囊癌的新生血管形成进而抑制肿瘤的生长。R5抗体抑制新生血管形成的作用是不依赖于VEGF而独立发挥作用的。肿瘤时Slit2在体内并没有直接参与白细胞的迁移。 3、舌鳞状上皮癌细胞系和脑转移亚系TB细胞均表达Slit2和Robo1蛋白,表明为Slit-Robo信号介导肿瘤细胞之间的“对话”,具有“自分泌”功能;并提示R5抗体阻断Slit-Robo信号后抑制了TB细胞的增殖能力和诱导凋亡发生;这种作用是通过下调TB细胞的PCNA和Ki-67蛋白表达水平和上调Fas/FasL信号途径而实现的。表明Slit-Robo信号可正向调控肿瘤的发生发展。 4、表明Slit-Robo信号的激活与肿瘤的侵袭、转移性能有关,该信号的激活能够促进舌癌细胞的黏附、迁移和侵袭力,这种作用是通过提高基质金属蛋白酶MMP2的活性以及降低E-cadherin分子信号而实现的。 本研究结果首次表明,在口腔癌成癌过程中特别是由癌前阶段向癌转化时Slit-Robo信号对新生血管形成的重要“开关”作用,因此该信号有望成为肿瘤早期诊断的分子标志。R5抗体在体内能抑制地鼠颊囊癌的新生血管形成,在体外能促进舌癌细胞增殖、迁移能力和诱导凋亡,这证明Slit-Robo信号在肿瘤生长和转移中的正向调控作用,也表明在临床口腔癌治疗中R5抗体有望成为靶向Slit-Robo信号的有效药物。
Other AbstractConclusions 1. Slit-Robo signaling can be significantly activitated in the stage of hamster cheek pouch and oral carcinoma in situ, plays an important role in neovascularization in the process of carcinoma progression, and has any synergistic effects on the angiogenic activities of VEGF. 2. Tumor angiogenesis and growth can be inhibited in chemical-induced hamster squamous carcinogenesis by specific neutralization of the Slit2-Robo1 interaction with R5, the function-blocking monoclonal antibody for Robo1. Furthermore, the effectiveness of Robo blockade is independent of VEGF signaling. Teatment with R5 has no significant effect on leukocytes levels in vivo model. 3. TB and Tca8113 cells express both Slit2 and Robo1 indicating that Slit-Robo signaling mediates the crosstalk between tumor cells and tumor cells and has the autocrine function. Furthermore, block of the expression of Slit2 and Robo1 on TB and Tca8113 cells by R5 mAb inhibites TB cell proliferation and induces apoptosis through down-regulating PCNA expression level of TB cell and up-regulating Fas/FasL signal pathway. These results have indicated that Slit-Robo signaling promotes tumor growth. 4. Activation of Slit-Robo signaling is in relation to tumor metastasis and can promote adhesion, migration, chemotaxis, invasive ability and angiogenesis through increasing the activity of MMP-2 and MMP-9 and decreasing E-cadherin signal pathway. Results from our current studies have firstly demonstrated that Slit-Robo signaling playes a critical role in the angiogenic switch in the stages of oral carcinogenesis, especially when pre-carcinoma translates to carcinoma. Furthermore, Slit-Robo signaling can be used as a reliable marker for the diagnosis of early carcinoma. R5 mAb can inhibit neovascularization of hamster cheek pouch in vivo, promotes cell proliferation and migratory ability of tongue cancer in vitro, and induces cell apoptosis of tongue cancer in vitro. These results have indicated that Slit-Robo signaling has an effect on tumor growth and metastasis and R5 can be expected to be an effective drug for patients with oral carcinoma through preventing Slit-Robo signaling.
URL查看原文
Language中文
Document Type学位论文
Identifierhttps://ir.lzu.edu.cn/handle/262010/221856
Collection生命科学学院
Recommended Citation
GB/T 7714
王丽京. Slit-Robo信号在口腔癌形成中的功能研究[D]. 兰州. 兰州大学,2008.
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