本文選題：食管鱗癌　切入點：CPT1A　出處：《昆明理工大學(xué)》2017年碩士論文　論文類型：學(xué)位論文

【摘要】：食管癌進展快、預(yù)后差,其死亡率居我國惡性腫瘤第四位。盡管手術(shù)及放化療技術(shù)取得了巨大的進步,但是食管癌患者的5年生存率仍然較低。因此鑒定食管癌變過程中的關(guān)鍵調(diào)控分子并揭示其調(diào)控機制,對于改善食管癌的診斷和治療具有重要意義。我們前期研究發(fā)現(xiàn),CPT1A的拷貝數(shù)增加與食管癌患者不良預(yù)后正相關(guān)。免疫組化的結(jié)果表明CPT1A高表達與食管癌患者的不良預(yù)后正相關(guān),且是獨立預(yù)后判斷因素。體外實驗發(fā)現(xiàn),敲降CPT1A可以顯著抑制KYSE450和KYSE510細胞的侵襲和轉(zhuǎn)移能力。為此我們根據(jù)基因表達譜芯片結(jié)果,進一步鑒定調(diào)控食管癌細胞轉(zhuǎn)移和侵襲的關(guān)鍵基因。在本研究中,我們通過RT-PCR和蛋白免疫沉淀法發(fā)現(xiàn)敲降CPT1A可以下調(diào)uPA的mRNA和蛋白表達水平。深入研究發(fā)現(xiàn),敲降CPT1A可以下調(diào)NF-κB p65的磷酸化水平,并且發(fā)現(xiàn)敲降NF-κB p65顯著抑制uPA的轉(zhuǎn)錄和腫瘤細胞的侵襲和遷移能力。PKCiota和P62是NF-κB信號通路的上游調(diào)控基因。我們研究進一步發(fā)現(xiàn)敲降CPT1A可以下調(diào)PKCiota和P62的表達水平,并且PKCiota與p62之間存在反饋調(diào)節(jié)作用。在KYSE450細胞中,敲降PKCiota可以下調(diào)P62和uPA的表達水平,以及NF-κB p65的磷酸化水平。而加入泛素-蛋白酶體途徑抑制劑MG132可以顯著回復(fù)敲降PKCiota和CPT1A所引起的P62表達水平下調(diào)。有趣的是,我們發(fā)現(xiàn)敲降NF-κB p65也可以下調(diào)CPT1A的表達水平。綜上所述,我們得出結(jié)論CPT1A通過調(diào)控PKCiota/p62/NF-KB/uPA信號軸促進食管癌細胞的侵襲和轉(zhuǎn)移能力。本論文進一步闡明了 CPT1A促進食管細胞轉(zhuǎn)移和侵襲的分子機制,并有望成為食管鱗癌治療的新的分子靶點。
[Abstract]:Esophageal cancer is developing rapidly and its prognosis is poor. Its mortality rate is the fourth highest in China. Despite the great progress made in surgery and radiotherapy and chemotherapy, But the 5-year survival rate of esophageal cancer patients is still low. It is important to improve the diagnosis and treatment of esophageal cancer. Our previous study found that the increased copy number of CPT1A was positively related to the poor prognosis of esophageal cancer patients. The immunohistochemical results showed that the high expression of CPT1A was positively correlated with the poor prognosis of esophageal cancer patients. In vitro, knock down CPT1A could significantly inhibit the invasion and metastasis of KYSE450 and KYSE510 cells. In this study, we found that knockout CPT1A could down-regulate the expression of mRNA and protein in uPA by RT-PCR and protein immunoprecipitation. Knockdown of CPT1A can down-regulate phosphorylation level of NF- 魏 B p65. It was also found that knockout NF- 魏 B p65 significantly inhibited uPA transcription and invasion and migration of tumor cells. PKCiota and P62 were upstream regulatory genes of NF- 魏 B signaling pathway. We further found that knockdown CPT1A could down-regulate the expression of PKCiota and P62. There is feedback regulation between PKCiota and p62. Knockout PKCiota can down-regulate the expression of P62 and uPA in KYSE450 cells. And the phosphorylation level of NF- 魏 B p65. The down-regulation of P62 expression induced by knockout PKCiota and CPT1A was significantly reversed by the addition of ubiquitin proteasome pathway inhibitor MG132. We found that knocking down NF- 魏 B p65 could also down-regulate the expression of CPT1A. We conclude that CPT1A can promote the invasion and metastasis of esophageal cancer cells by regulating PKCiota/p62/NF-KB/uPA signal axis. In this paper, we further elucidate the molecular mechanism of CPT1A promoting esophageal cell metastasis and invasion. It is expected to be a new molecular target for the treatment of esophageal squamous cell carcinoma.
【學(xué)位授予單位】：昆明理工大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R735.1

【參考文獻】

相關(guān)期刊論文 前1條

1 Sheng Yan;Xue-Feng Yang;Hao-Lei Liu;Nian Fu;Yan Ouyang;Kai Qing;;Long-chain acyl-CoA synthetase in fatty acid metabolism involved in liver and other diseases:An update[J];World Journal of Gastroenterology;2015年12期

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本文編號：1650734