【摘要】：第一章GATA6通過上調LOXL2促進膽管癌侵襲轉移的研究研究背景膽管癌(Cholangiocarcinoma, CCA)是一種常見的肝膽系統(tǒng)惡性腫瘤,由于早期癥狀不明顯,晚期發(fā)現(xiàn)時由于侵襲轉移嚴重影響了手術治療的效果以及患者的預后情況。侵襲轉移是包括CCA在內的多種惡性腫瘤重要的生物學特征,受多層次多因素的調控,具體過程和機理至今尚不明確。上皮間質轉化(Epithelial-mesenchymal transition, EMT)是來源于上皮細胞的惡性腫瘤細胞獲得遷移能力和侵襲能力的重要的過程。因此,研究EMT關鍵分子的調控機制、探CCA侵襲轉移機理,探索有效的治療措施、研發(fā)潛在治療靶點具有重要意義。賴氨酰氧化酶樣蛋白2(Lysyl oxidase-like 2 protein, LOXL2)是一個在維持細胞外基質穩(wěn)態(tài)、細胞運動等生物學方面起著重要作用的修飾酶。GATA結合蛋白6(GATA binding protein 6, GATA6)是在胚胎發(fā)育中調控細胞增殖和分化的重要轉錄分子。近年研究表明LOXL2和GATA6在多種腫瘤中表達水平不一致,并且發(fā)揮的作用也不盡相同,在有的組織中被認為是腫瘤抑制因子,而在另一些腫瘤中則促進腫瘤進程,是潛在的癌基因。因此,研究LOXL2和GATA6在CCA中的表達情況、探討二者在CCA中所扮演的角色、明確它們究竟是促進還是抑制CCA進程顯得十分必要。我們前期研究發(fā)現(xiàn)LOXL2和GATA6在CCA組織和細胞中的表達與侵襲轉移相關,并且LOXL2和GATA6在表達模式和功能上存在很多一致性,提示LOXL2和GATA6可能存在某種關聯(lián)性。生物信息學分析發(fā)現(xiàn)在LOXL2基因啟動子區(qū)存在GATA6的可能結合位點,提示GATA6可能是LOXL2的上游調控分子。另外有文獻提示,LOXL2在腫瘤中表現(xiàn)為促癌分子參與腫瘤侵襲轉移進程時,可通過介導上皮標志物E-cadherin的表達下調,從而促進EMT的發(fā)生和腫瘤的侵襲轉移。因此,我們推測CCA中GATA6能調控LOXL2的表達,促進EMT發(fā)生從而增強CCA細胞的侵襲遷移能力。材料方法與研究結果1、CCA腫瘤組織和細胞中LOXL2和GATA6的表達呈顯著相關性收集西南醫(yī)院肝膽外科2005至2012年,手術切除的90例CCA患者的組織及24例相應癌旁組織的石蠟標本。采用免疫組化方法檢測發(fā)現(xiàn)CCA腫瘤組織中的LOXL2和GATA6的表達水平較癌旁組織中異常增高,經(jīng)統(tǒng)計學分析顯示二者在腫瘤組織中的表達具有顯著相關性。同時在CCA細胞中(QBC939和RBE)通過RT-qPCR和Western blot實驗檢測QBC939細胞的LOXL2的表達情況,發(fā)現(xiàn)LOXL2在mRNA水平與蛋白水平的表達均高于RBE細胞,進一步檢測發(fā)現(xiàn)GATA6的表達趨勢與LOXL2一致。以上結果表明LOXL2和GATA6在CCA中的表達具有相關性。2、CCA腫瘤組織和細胞中LOXL2與GATA6的高表達都與侵襲轉移有關收集上述90例患者的病例資料(包括隨訪資料),通過統(tǒng)計學方法分析LOXL2和GATA6在CCA腫瘤組織中的高表達與臨床病例特征的相關性,發(fā)現(xiàn)LOXL2和GATA6的表達水平均與患者的淋巴結轉移情況顯著相關。進一步運用Kaplan-Meier模型分析發(fā)現(xiàn)LOXL2和GATA6的高表達均導致不良預后。采用Transwell侵襲實驗和損傷修復實驗檢測發(fā)現(xiàn)高表達LOXL2和GATA6的QBC939細胞的侵襲能力和遷移能力均明顯強于RBE細胞。以上結果表明LOXL2和GATA6在CCA中功能具有相似性。3、CCA細胞中GATA6對LOXL2存在正向調控作用生物信息學分析發(fā)現(xiàn)LOXL2基因啟動子區(qū)域可能存在GATA6的結合位點,提示GATA6可能是LOXL2的上游調控分子。進而通過RNA干擾和過表達策略,從正反兩方面檢測GATA6對LOXL2表達的影響。在QBC939細胞中干擾GATA6的表達,LOXL2的mRNA水平和蛋白水平隨之降低；在RBE細胞中過表達GATA6, LOXL2的mRNA水平和蛋白水平隨之升高。以上結果表明GATA6對LOXL2的表達具有正向調控作用。4、GATA6通過調控LOXL2表達影響CCA細胞的侵襲遷移采用“恢復實驗”,即通過干預GATA6表達后再反向干預LOXL2的表達,通過Transwell侵襲實驗和損傷修復實驗檢測CCA細胞侵襲遷移能力的改變。干擾GATA6表達能明顯減弱QBC939細胞侵襲遷移的能力,反向恢復LOXL2表達后能夠在一定程度上逆轉干擾GATA6表達所導致的侵襲遷移受抑制的現(xiàn)象。在RBE細胞中過表達GATA6能明顯增強細胞侵襲遷移的能力,而這種抑制作用能被反向干擾LOXL2表達部分削弱。以上結果表明GATA6可通過調控LOXL2的表達影響CCA細胞的侵襲遷移。5、GATA6-LOXL2通路通過促進EMT增強CCA細胞的侵襲遷移采用免疫組化方法檢測發(fā)現(xiàn)高表達GATA6和LOXL2的CCA腫瘤組織中,上皮標志物E-cadherin低表達,而間質標志物Vimentin高表達,且經(jīng)統(tǒng)計學分析顯示E-cadherin和Vimentin的表達水平分別與GATA6和LOXL2的表達水平顯著相關。進一步在CCA細胞中通過“恢復實驗”,即干預GATA6表達后再反向干預LOXL2的表達,檢測EMT標志物E-cadherin表達水平的變化,結果顯示QBC939細胞中GATA6介導的LOXL2上調抑制CCA細胞中E-cadherin的表達,而RBE細胞中GATA6介導的LOXL2下調促進CCA細胞中E-cadherin的表達。以上結果表明GATA6通過調控LOXL2表達影響EMT,進而促進EMT發(fā)生和侵襲轉移。研究結論本研究明確了GATA6和LOXL2表達水平具有正向相關性。通過統(tǒng)計學分析發(fā)現(xiàn)二者在CCA中的高表達均與患者的淋巴結轉移情況、不良預后密切相關。進一步在CCA細胞模型上,通過RNA干擾和過表達策略,從正反兩方面證實了GATA6對LOXL2表達具有正向調控作用,并通過“恢復實驗”進一步證實了GATA6通過上調LOXL2表達促進EMT,從而促進CCA細胞的侵襲遷移。以上實驗結果不僅可能發(fā)現(xiàn)LOXL2在CCA侵襲轉移中的自身表達調控機制,更重要的是可能為將來基于GATA6-LOXL2為靶標的CCA臨床治療提供理論及實驗依據(jù)。第二章核受體FXR通過上調SOCS3抑制肝細胞癌增殖的研究研究背景肝細胞癌(Hepatocellular carcinoma, HCC)是一種全世界范圍高發(fā)的惡性腫瘤,死亡率極高。致癌轉錄因子STAT3信號通路在其發(fā)生發(fā)展中發(fā)揮著重要促進作用。細胞信號轉導抑制蛋白3(Suppressors of cytokine signaling 3, SOCS3),作為STAT3通路重要的內源性負反饋調節(jié)分子,在多種癌癥中低表達,導致STAT3的異�；罨６絹碓蕉嗟淖C據(jù)也顯示SOCS3的恢復表達(即功能回復)在HCC、炎癥性結腸癌、惡性間皮胸膜瘤等腫瘤中具有顯著的抑癌活性。SOCS3目前被認為是一個重要的內源性抗腫瘤分子,上調其表達無疑將有助于HCC等多種腫瘤的防治。核受體法尼酯X受體(Farnesoid X receptor, FXR)除了密切參與物質代謝與抗炎外,在HCC等多種惡性腫瘤中能發(fā)揮顯著的抑癌保護作用,但總體來說具體機制還有待深入探討。鑒于FXR和SOCS3在HCC中的重要作用,那么FXR能否通過調控SOCS3表達而發(fā)揮抗癌作用呢?因此我們以HCC細胞為模型,通過解析FXR在SOCS3基因啟動子區(qū)的具體結合位點,闡明FXR通過上調SOCS3抑制HCC的新機制,從而為探索以FXR-SOCS3為靶標的HCC治療提供新的實驗依據(jù)和理論基礎。材料方法與研究結果一、FXR通過上調SOCS3抑制肝細胞癌增殖生長通過MTS細胞增殖實驗、流式細胞技術、RT-qPCR和Western blot等實驗證實了FXR激動劑GW4064可以抑制人HCC細胞(HepG2和Huh7)的增殖,誘導細胞周期阻滯在G1期,誘導細胞周期關鍵分子p21的表達、抑制STAT3的磷酸化活化。并通過RNA干擾策略證實GW4064的上述抑增殖效應是通過上調SOCS3表達實現(xiàn)的。進一步進行在體實驗證實GW4064能抑制裸鼠HCC移植瘤的生長。二、闡明GW4064上調SOCS3表達的具體分子機制采用針對FXR的siRNA證實GW4064上調SOCS3是通過活化FXR實現(xiàn)的。生物信息學分析SOCS3基因啟動子區(qū)可能存在FXR反應元件。進而通過報告基因檢測驗(結合點突變策略)、EMSA實驗、ChIP實驗證實FXR通過與人SOCS3基因啟動子區(qū)-1878～-1858區(qū)域的FXR反應元件(IR9)結合,促進SOCS3的轉錄活性,從而上調其表達。三、肝細胞癌組織中FXR與SOCS3表達明顯降低,而STAT3異常活化收集西南醫(yī)院肝膽外科2013至2014年間手術切除的66例HCC臨床標本,采用免疫組化方法檢測發(fā)現(xiàn),與相應癌旁組織相比,HCC腫瘤組織中的FXR和SOCS3的表達水平顯著降低(統(tǒng)計學分析表明二者的表達水平具有顯著相關性),同時STAT3的活化水平(即p-STAT3的表達水平)在HCC腫瘤組織中明顯增高。臨床標本上的結果與細胞水平實驗的結果相符。研究結論我們以肝細胞癌(HCC)細胞為模型,詳細解析了FXR在SOCS3基因啟動子區(qū)的具體結合位點,闡明了FXR上調SOCS3的分子機制。通過RNA干擾策略證實了FXR通過上調SOCS3表達抑制HCC細胞的增殖、誘導細胞周期阻滯、上調細胞周期關鍵分子p21的表達,抑制STAT3的磷酸化活化；在裸鼠HCC移植瘤模型上驗證了FXR的抑癌效應。并進一步在HCC患者的腫瘤組織中明確了FXR和SOCS3G表達水平的正向相關性。以上研究結果闡明FXR通過上調SOCS3抑制HCC的新機制,從而為探索以FXR-SOCS3為靶標的HCC治療提供新的實驗依據(jù)和理論基礎。
[Abstract]:Chapter 1 GATA6 promotes the invasion and metastasis of cholangiocarcinoma (CCA) by up-regulating LOXL2. Background Cholangiocarcinoma (CCA) is a common malignant tumor of the hepatobiliary system. Epithelial-mesenchymal transition (EMT) is an important process for cancer cells derived from epithelial cells to acquire the ability of migration and invasion. Lysyl oxidase-like 2 protein (LOXL2) is a modified enzyme that plays an important role in maintaining the homeostasis of extracellular matrix and cell movement. GATA binding protein 6 (GATA6) is an important transcriptional molecule that regulates cell proliferation and differentiation during embryonic development. Recent studies have shown that LOXL2 and GATA6 are not uniformly expressed in various tumors and play different roles. They are considered as tumor suppressor in some tissues and promote in other tumors. Therefore, it is necessary to study the expression of LOXL2 and GATA6 in CCA and their roles in CCA and to determine whether they promote or inhibit CCA progression. Bioinformatics analysis revealed that there was a possible binding site of GATA6 in the promoter region of LOXL2 gene, suggesting that GATA6 may be an upstream regulator of LOXL2. In addition, literature suggests that LOXL2 may be a tumor-promoting molecule. Therefore, we speculate that GATA 6 in CCA can regulate the expression of LOXL2, promote the occurrence of EMT and enhance the invasion and migration of CCA cells by mediating the down-regulation of the expression of E-cadherin.Material methods and research results 1, CCA tumor tissue and metastasis. The expression of LOXL2 and GATA6 was significantly correlated. Paraffin specimens of 90 CCA patients and 24 corresponding adjacent tissues were collected from the Department of Hepatobiliary Surgery of Southwest Hospital from 2005 to 2012. The expression of LOXL2 and GATA6 in CCA tumor tissues was significantly higher than that in adjacent tissues by immunohistochemistry. The expression of LOXL2 was detected by RT-q PCR and Western blot in CCA cells (QBC939 and RBE). It was found that the expression of LOXL2 in mRNA and protein levels was higher than that in RBE cells. The above results showed that the expression of LOXL2 and GATA6 in CCA was correlated. 2. The high expression of LOXL2 and GATA6 in CCA tumor tissues and cells was related to invasion and metastasis. The data of 90 cases (including follow-up data) were collected. The high expression of LOXL2 and GATA6 in CCA tumor tissues and clinical cases were statistically analyzed. The expression levels of LOXL2 and GATA6 were significantly correlated with lymph node metastasis. Further analysis of Kaplan-Meier model showed that the high expression of LOXL2 and GATA6 resulted in poor prognosis. The invasion of QBC939 cells with high expression of LOXL2 and GATA6 was detected by Transwell invasion test and damage repair test. The above results showed that the functions of LOXL2 and GATA6 were similar in CCA. 3. Bioinformatics analysis showed that GATA6 might have a binding site in the promoter region of LOXL2 gene, suggesting that GATA6 might be an upstream regulator of LOXL2. By RNA interference and overexpression strategy, the effects of GATA6 on LOXL2 expression were detected in both positive and negative ways. After interfering with GATA6 expression in QBC939 cells, the mRNA and protein levels of LOXL2 decreased, and the mRNA and protein levels of LOXL2 increased when GATA6 was overexpressed in RBE cells. GATA6 can affect the invasion and migration of CCA cells by regulating the expression of LOXL2. GATA6 can interfere with the expression of LOXL2 in CCA cells by "recovery test", that is, by interfering with the expression of GATA6 and then interfering with the expression of LOXL2 in reverse direction. The ability of invasion and migration of CCA cells was detected by Transwell invasion test and damage repair test. Overexpression of GATA6 in RBE cells can significantly enhance the ability of invasion and migration, and this inhibition can be partially weakened by reverse interference with LOXL2 expression. GATA6-LOXL2 pathway enhanced the invasion and migration of CCA cells by stimulating EMT. Immunohistochemical staining showed that E-cadherin, an epithelial marker, was low in CCA tumor tissues with high expression of GATA6 and LOXL2, but Vimentin, an interstitial marker, was high in CCA cells. The expression levels of E-cadherin and Vimentin were significantly correlated with the expression levels of GATA6 and LOXL2, respectively. Further, the expression of LOXL2 in CCA cells was detected by "recovery test" after GATA6 expression was interfered, and the expression level of E-cadherin, an EMT marker, was detected. The results showed that GATA6-mediated up-regulation of LOXL2 in QBC939 cells was inhibited. In CCA cells, E-cadherin expression was increased by GATA6-mediated LOXL2 down-regulation, while in RBE cells, LOXL2 down-regulation promoted E-cadherin expression. These results suggest that GATA6 affects EMT by regulating LOXL2 expression, thereby promoting EMT occurrence and invasion and metastasis. It was found that the high expression of GATA6 in CCA was closely related to lymph node metastasis and poor prognosis. Furthermore, in CCA cell model, the positive and negative effects of GATA6 on LOXL2 expression were confirmed by RNA interference and overexpression strategy, and GATA6 up-regulated LOX by "recovery test". L2 expression promotes EMT and thus promotes invasion and migration of CCA cells. These results may not only reveal the mechanism of LOXL2 expression in CCA invasion and metastasis, but also provide theoretical and experimental evidence for future clinical treatment of CCA based on GATA6-LOXL2. Chapter 2 Nuclear receptor FXR inhibits liver fineness by up-regulating SOCS3. Background Hepatocellular carcinoma (HCC) is a worldwide malignant tumor with high mortality. The STAT3 signaling pathway plays an important role in the development of HCC. As an important endogenous negative feedback regulator of STAT3 pathway, low expression in many cancers leads to abnormal activation of STAT3. More and more evidences also show that the restored expression of SOCS3 (i.e. functional recovery) has significant antitumor activity in HCC, inflammatory colon cancer, malignant mesothelioma and other tumors. Farnesoid X receptor (FXR) plays an important role in the prevention and treatment of HCC and other malignant tumors. In addition to its close involvement in substance metabolism and anti-inflammation, FXR plays a significant inhibitory and protective role in HCC and other malignant tumors, but the specific mechanism remains to be further explored. In view of the important role of FXR and SOCS3 in HCC, can FXR play an anticancer role by regulating the expression of SOCS3? Therefore, by analyzing the specific binding sites of FXR in the promoter region of SOCS3 gene in HCC cells, we clarify the new mechanism of FXR inhibiting HCC by up-regulating SOCS3, so as to explore the HCC targeting FXR-SOCS3. Material methods and research results 1. FXR can inhibit the proliferation of hepatocellular carcinoma by up-regulating SOCS-3. FXR agonist GW4064 can inhibit the proliferation of human HCC cells (HepG2 and Huh7) and induce cell cycle by MTS cell proliferation, flow cytometry, RT-qPCR and Western blot. Blocking the expression of p21, the key molecule of cell cycle, and inhibiting the phosphorylation and activation of STAT3 in G1 phase, was demonstrated by RNA interference strategy. Further in vivo experiments showed that GW4064 could inhibit the growth of HCC xenograft tumor in nude mice. 2. To clarify the role of GW4064 in up-regulating the expression of SOCS3. Bioinformatics analysis showed that FXR reaction elements may exist in the promoter region of SOCS3 gene. Further, through reporter gene test (binding point mutation strategy), EMSA test and ChIP test, FXR was confirmed to be up-regulated by activating FXR in the promoter region of human SOCS3 gene. Three, the expression of FXR and SOCS3 in hepatocellular carcinoma tissues was significantly decreased, while STAT3 abnormal activation was detected in 66 HCC clinical specimens from the Department of Hepatobiliary Surgery, Southwest Hospital from 2013 to 2014. Immunohistochemical method was used to detect the expression of FXR and SOCS3 in the corresponding adjacent tissues. The expression levels of FXR and SOCS3 in HCC tumors were significantly lower than those in HCC tumors (statistical analysis showed that there was a significant correlation between the expression levels of FXR and SOCS3), and the activation level of STAT3 (i.e. the expression level of p-STAT3) was significantly higher in HCC tumors. Using hepatocellular carcinoma (HCC) cells as a model, the specific binding sites of FXR in the promoter region of SOCS 3 gene were analyzed in detail, and the molecular mechanism of up-regulation of SOCS 3 by FXR was elucidated. Phosphorylation activation of T3, inhibition of FXR on HCC xenograft in nude mice, and positive correlation between FXR and SOCS3G expression levels were further clarified in HCC patients. The above results clarify the new mechanism of FXR inhibiting HCC by up-regulating SOCS3, thus providing new insights into HCC therapy targeting FXR-SOCS3. The experimental basis and theoretical basis.
【學位授予單位】：第三軍醫(yī)大學
【學位級別】：博士
【學位授予年份】：2015
【分類號】：R735

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