本文選題：肝細(xì)胞癌(HCC) + 甲苯磺酸索拉非尼　； 參考：《中國(guó)人民解放軍醫(yī)學(xué)院》2016年博士論文

【摘要】：目的：回顧性收集并研究于我院口服甲苯磺酸索拉非尼片的晚期原發(fā)性肝細(xì)胞肝癌患者的臨床及病理資料,統(tǒng)計(jì)分析與甲苯磺酸索拉非尼片臨床療效相關(guān)的預(yù)后因素：探索低氧環(huán)境誘發(fā)的甲苯磺酸索拉非尼耐藥機(jī)制。材料與方法：回顧性收集了2005年1月至2013年1月期間于我院口服甲苯磺酸索拉非尼片的晚期HCC患者的臨床病理資料,收集這些患者的肝癌組織蠟塊標(biāo)本并切片,應(yīng)用SPSS19.9統(tǒng)計(jì)軟件對(duì)生存預(yù)后進(jìn)行單因素分析及多因素分析;培養(yǎng)肝癌細(xì)胞系,進(jìn)行Western Blot、PCI、CCK8毒性檢測(cè)、HIF1SiRNA轉(zhuǎn)染、免疫熒光染色等。結(jié)果：(1)74例患者口服甲苯磺酸索拉非尼,中位隨訪時(shí)間為535天；其中64例為男性患者,10例為女性患者(6.4：1),中位年齡62歲,丙型肝炎既往史、較高的KPS評(píng)分、無(wú)腫瘤家族史的患者中位PFS相對(duì)較長(zhǎng);丙型肝炎既往史、AFP400, KPS評(píng)分≥90,高分化癌,不伴有吸煙史、飲酒史及腫瘤家族史的患者中位生存期較長(zhǎng);腫瘤家族史、乙型肝炎、KPS評(píng)分70-80、低分化癌是生存的不良預(yù)后因素;飲酒既往史、乙型肝炎、KPS評(píng)分70-80是與甲苯磺酸索拉非尼片療效相關(guān)的不良預(yù)后因素；(2)口服甲苯磺酸索拉非尼片療效較差的臨床晚期HCC患者,免疫熒光染色顯示組織標(biāo)本中HIF 1α及YAP在細(xì)胞核內(nèi)聚集,胞核陽(yáng)性率較高,而臨床獲益明顯的患者肝癌組織中,HIF 1α及YAP主要集中在細(xì)胞質(zhì);(3)在正常培養(yǎng)的肝癌細(xì)胞中,HIF1α及YAP均有少量表達(dá),但重合率較低且主要集中在細(xì)胞質(zhì),細(xì)胞核陽(yáng)性率低;(4)肝癌細(xì)胞在常氧環(huán)境下加用甲苯磺酸索拉非尼,HIF 1α及YAP主要集中在細(xì)胞質(zhì),細(xì)胞核陽(yáng)性率進(jìn)一步降低;(5)肝癌細(xì)胞在低氧環(huán)境下加用甲苯磺酸索拉非尼,HIF 1α及YAP共同向核內(nèi)遷移,細(xì)胞核陽(yáng)性率升高;(6)低氧環(huán)境下,YAP、HIF、1α表達(dá)升高且主要集中在細(xì)胞核,提示低氧環(huán)境可能促成肝癌細(xì)胞對(duì)甲苯磺酸索拉非尼產(chǎn)生抵抗力,促使產(chǎn)生耐藥；(7)當(dāng)YAP主要集中在肝癌細(xì)胞核時(shí),EMT相關(guān)指標(biāo)E-鈣粘附減少,N-鈣粘附素、波形蛋白表達(dá)水平相應(yīng)增多,預(yù)示著YAP向細(xì)胞核內(nèi)遷移現(xiàn)象與肝癌細(xì)胞的惡性程度及侵襲性密切相關(guān);(8)正常培養(yǎng)的肝癌細(xì)胞中,細(xì)胞毒性檢測(cè)提示低氧狀態(tài)可能抵抗甲苯磺酸索拉非尼抗腫瘤效應(yīng),逆向促進(jìn)腫瘤細(xì)胞增殖生長(zhǎng);(9) HIF1SiRNA轉(zhuǎn)染肝癌細(xì)胞,當(dāng)HIF la表達(dá)下調(diào)后,對(duì)其進(jìn)行低氧及甲苯磺酸索拉非尼的處理,YAP的表達(dá)水平及向細(xì)胞核的遷移現(xiàn)象同前無(wú)明顯變化,但是細(xì)胞毒性檢測(cè)實(shí)驗(yàn)顯示,肝癌細(xì)胞對(duì)索拉非尼的耐受性有所下降；(10) HIF 1α及YAP蛋白在低氧誘導(dǎo)的甲苯磺酸索拉非尼耐藥機(jī)制中起到了一定的協(xié)同作用。結(jié)論：(1)通過(guò)對(duì)口服甲苯磺酸索拉非尼片的晚期HCC患者的臨床病理資料及生存預(yù)后分析,我們發(fā)現(xiàn)肝炎病史、KPS評(píng)分、腫瘤家族史等臨床因素與患者的生存及甲苯磺酸索拉非尼片的療效存在密切關(guān)系,對(duì)該類臨床患者的治療及預(yù)后具有一定的指導(dǎo)意義;(2)低氧環(huán)境能夠抵抗甲苯磺酸索拉非尼部分抗腫瘤效應(yīng),誘導(dǎo)其耐藥的產(chǎn)生;(3)低氧環(huán)境下,YAP向細(xì)胞核內(nèi)遷移遷移現(xiàn)象與耐藥及預(yù)后有著重要關(guān)系;(4)HIF1SiRNA轉(zhuǎn)染的肝癌細(xì)胞對(duì)索拉菲尼的敏感性有所增加；(5) HIF la及YAP在低氧誘導(dǎo)的甲苯磺酸索拉非尼耐藥機(jī)制中可能起到了一定的協(xié)同作用。
[Abstract]:Objective: To retrospectively collect and study the clinical and pathological data of patients with advanced primary hepatocellular carcinoma (HCC) in our hospital, and to analyze the prognostic factors associated with the clinical efficacy of Sorafenib Tosylate Tablets: explore the mechanism of ssorafeni resistance induced by the hypoxic environment. Materials and methods: The clinicopathological data of late HCC patients in our hospital from January 2005 to January 2013 were collected, and the paraffin specimens of these patients were collected and sliced. A single factor analysis and multi factor analysis were used to analyze the survival prognosis with SPSS19.9 statistical software, and to develop the hepatoma cell line for West. Ern Blot, PCI, CCK8 toxicity test, HIF1SiRNA transfection, immunofluorescence staining and so on. Results: (1) 74 patients were taken orally with sorafenib toluene sulfonic acid, the median follow-up time was 535 days, of which 64 were male patients, 10 were female patients (6.4:1), middle age 62 years, hepatitis C history, higher KPS score, and no family history of tumor. The position of PFS was relatively long; the past history of hepatitis C, AFP400, KPS score was more than 90, high differentiated cancer, no history of smoking, drinking history and family history of cancer had a longer median survival period; the family history of cancer, hepatitis B, KPS score, and low differentiated carcinoma were the poor prognostic factors of survival; drinking past history, hepatitis B, and KPS score 70-80 were with toluene sulphur. The adverse prognostic factors associated with acid sorafenib (2) the late clinical HCC patients with poor therapeutic efficacy of oral Sorafenib Tosylate Tablets showed that HIF 1 alpha and YAP were aggregated in the nucleus and the positive rate of the nucleus was higher in the tissue specimens. The HIF 1 alpha and YAP were mainly concentrated in the liver cancer tissues of the patients with significant clinical benefits. Cytoplasm; (3) in normal cultured hepatoma cells, HIF1 A and YAP had a small amount of expression, but the recoincidence rate was low and mainly concentrated in the cytoplasm, and the positive rate of the nucleus was low; (4) the hepatoma cells were added with toluene sulfonic acid Sola Fini, HIF 1 A and YAP mainly in the cytoplasm, and the positive rate of the nucleus was further reduced; (5) hepatoma cells In the hypoxic environment, Sola Fini, HIF 1 alpha and YAP were migrated to the nucleus, and the positive rate of the nucleus increased; (6) the expression of YAP, HIF, 1 alpha was increased and mainly concentrated in the nucleus under the environment of hypoxia, suggesting that the hypoxia environment may contribute to the resistance of the hepatoma cells to toluene sulfonic acid and induce resistance; (7) when YAP main. To concentrate on the cell nucleus of liver cancer, the EMT related index E- calcium adherence decreases, N- calcin and vimentin expression increase correspondingly, indicating that the migration of YAP into the nucleus is closely related to the malignancy and invasiveness of the hepatoma cells. (8) the cytotoxicity test suggests that hypoxia may resist toluene in normal cultured hepatoma cells. The effect of sorafeni sulfonate on tumor cell proliferation and growth of tumor cells; (9) HIF1SiRNA transfected hepatoma cells, when the expression of HIF La was downregulated, it was treated with hypoxia and sorafenib toluene sulfonic acid. The expression level of YAP and the migration of the nucleus to the nucleus had no obvious change, but the cytotoxicity test showed that the liver cancer was fine. The tolerance to sorafenib decreased; (10) HIF 1 alpha and YAP protein had a synergistic effect in the mechanism of low oxygen induced sorafenib resistance in toluene sulfonic acid. Conclusion: (1) we found the history of hepatitis, KP, through the analysis of the clinicopathological materials and survival prognosis of the advanced HCC patients with oral Sorafenib Tosylate Tablets. S score, the family history of tumor and other clinical factors are closely related to the survival of the patients and the curative effect of Sorafenib Tosylate Tablets, and have certain guiding significance for the treatment and prognosis of this kind of clinical patients. (2) the hypoxia environment can resist the Sola Fini partial swelling tumor effect of toluene sulfonic acid and induce the production of its resistance; (3) Y in the hypoxia environment. The migration and migration of AP into the nucleus has an important relationship with drug resistance and prognosis. (4) the sensitivity of HIF1SiRNA transfected hepatoma cells to Sola Feeney is increased; (5) HIF La and YAP may play a certain synergistic effect in the mechanism of low oxygen induced sorafenib toluene sulfonic acid.

【學(xué)位授予單位】：中國(guó)人民解放軍醫(yī)學(xué)院
【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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