本文選題：p-Smad3 + 凋亡�。� 參考：《浙江大學(xué)》2016年博士論文

【摘要】：背景和目的：肝細(xì)胞肝癌(HCC)是一種常見(jiàn)的腫瘤類型,預(yù)后較差。多激酶抑制劑索拉菲尼是臨床上唯一獲批用于肝癌系統(tǒng)性治療的藥物。然而,僅有少數(shù)病人對(duì)索拉菲尼敏感。低氧的微環(huán)境被認(rèn)為是索拉菲尼耐藥的原因之一。既往研究發(fā)現(xiàn),LB-100,一種絲氨酸/蘇氨酸蛋白酶磷酸酶2A (PP2A)抑制劑作用于肝細(xì)胞肝癌具有化療增敏作用。本研究中,我們檢測(cè)了LB-100是否具有增加肝癌細(xì)胞對(duì)索拉菲尼敏感性的作用。方法：使用Cell Counting Kit-8檢測(cè)細(xì)胞活力；使用Annexin V-FITC Detection Kit試劑盒檢測(cè)細(xì)胞凋亡；使用免疫印跡法檢測(cè)細(xì)胞蛋白表達(dá)水平相對(duì)變化；使用Ser/Thr phosphatase assay kit I檢測(cè)PP2A活性。在裸鼠模型上,比較索拉菲尼單用或與LB-100聯(lián)合使用對(duì)肝細(xì)胞肝癌皮下移植瘤生長(zhǎng)的影響。結(jié)果：僅在低氧環(huán)境中,LB-100能夠增加索拉菲尼對(duì)肝癌細(xì)胞的抑制效果。LB-100能夠顯著地上調(diào)肝癌細(xì)胞中p-Smad3蛋白水平,p-Smad3水平的上調(diào)介導(dǎo)了LB-100的化療增敏效應(yīng)。LB-100下調(diào)了抗凋亡蛋白Bcl-2表達(dá)水平,增加了索拉菲尼誘導(dǎo)的肝癌凋亡。進(jìn)一步地,我們證明LB-100誘導(dǎo)的p-Smad3過(guò)表達(dá)是通過(guò)抑制PP2A活性實(shí)現(xiàn)的。此外,在低氧環(huán)境下,LB-100誘導(dǎo)了p38 MAPK通路激活,這也增加了pSmad3依賴的Bcl-2下調(diào)及后續(xù)的凋亡。結(jié)論：低氧環(huán)境下,LB-100增加肝癌細(xì)胞對(duì)索拉菲尼的敏感性。這種化療增敏作用是通過(guò)抑制PP2A,引起p-Smad3水平的升高實(shí)現(xiàn)的。升高的p-Smad3下調(diào)了Bcl-2,導(dǎo)致了肝癌細(xì)胞的凋亡增加。
[Abstract]:Background and purpose: hepatocellular carcinoma (HCC) is a common tumor type and has a poor prognosis. Sola Feeney, a multi kinase inhibitor, is the only drug for systematic treatment of liver cancer. However, only a few patients are sensitive to sorafeni. Hypoxic microenvironment is considered to be one of the reasons for Sola Feeney resistance. Now, LB-100, a serine / threonine protease phosphatase 2A (PP2A) inhibitor acts on chemotherapeutic sensitization in hepatocellular carcinoma. In this study, we detected whether LB-100 had an increase in the effect of hepatoma cells on Sola Feeney Min sensibility. Methods: Cell Counting Kit-8 was used to detect cell viability; Annexin V-FITC Dete was used. Ction Kit kits were used to detect cell apoptosis; the relative changes in cell protein expression were detected by Western blot; PP2A activity was detected using Ser/Thr phosphatase assay kit I. In nude mice, the effects of Sola Feeney alone or combined with LB-100 on the growth of hepatocellular carcinoma skin graft growth were compared. In the environment, LB-100 can increase the inhibitory effect of Sola Feeney on hepatoma cells.LB-100 can significantly increase the level of p-Smad3 protein in liver cancer cells. The up regulation of p-Smad3 level mediates the chemosensitivity effect of LB-100, which reduces the expression of anti apoptotic protein Bcl-2 and increases the apoptosis of liver cancer induced by Sao Rafini. Further, we LB-100 induced p-Smad3 overexpression was realized by inhibiting PP2A activity. In addition, in hypoxia environment, LB-100 induced the activation of p38 MAPK pathway, which also increased the Bcl-2 down regulation of pSmad3 dependent and subsequent apoptosis. Conclusion: in low oxygen environment, LB-100 increases the sensitivity of hepatoma cells to Sola Feeney. This chemosensitization effect is By inhibiting PP2A, the level of p-Smad3 was increased. The increase of p-Smad3 reduced Bcl-2, resulting in an increase in apoptosis of hepatoma cells.

【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R735.7

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1 傅琦涵;LB-100增加低氧環(huán)境下肝細(xì)胞肝癌對(duì)索拉菲尼敏感性研究[D];浙江大學(xué);2016年

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本文編號(hào)：1863905