【摘要】：第一章GATA6通過上調(diào)LOXL2促進(jìn)膽管癌侵襲轉(zhuǎn)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(shí)由于侵襲轉(zhuǎn)移嚴(yán)重影響了手術(shù)治療的效果以及患者的預(yù)后情況。侵襲轉(zhuǎn)移是包括CCA在內(nèi)的多種惡性腫瘤重要的生物學(xué)特征,受多層次多因素的調(diào)控,具體過程和機(jī)理至今尚不明確。上皮間質(zhì)轉(zhuǎn)化(Epithelial-mesenchymal transition, EMT)是來源于上皮細(xì)胞的惡性腫瘤細(xì)胞獲得遷移能力和侵襲能力的重要的過程。因此,研究EMT關(guān)鍵分子的調(diào)控機(jī)制、探CCA侵襲轉(zhuǎn)移機(jī)理,探索有效的治療措施、研發(fā)潛在治療靶點(diǎn)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(gè)在維持細(xì)胞外基質(zhì)穩(wěn)態(tài)、細(xì)胞運(yùn)動(dòng)等生物學(xué)方面起著重要作用的修飾酶。GATA結(jié)合蛋白6(GATA binding protein 6, GATA6)是在胚胎發(fā)育中調(diào)控細(xì)胞增殖和分化的重要轉(zhuǎn)錄分子。近年研究表明LOXL2和GATA6在多種腫瘤中表達(dá)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(rèn)為是腫瘤抑制因子,而在另一些腫瘤中則促進(jìn)腫瘤進(jìn)程,是潛在的癌基因。因此,研究LOXL2和GATA6在CCA中的表達(dá)情況、探討二者在CCA中所扮演的角色、明確它們究竟是促進(jìn)還是抑制CCA進(jìn)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(xì)胞中的表達(dá)與侵襲轉(zhuǎn)移相關(guān),并且LOXL2和GATA6在表達(dá)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(guān)聯(lián)性。生物信息學(xué)分析發(fā)現(xiàn)在LOXL2基因啟動(dòng)子區(qū)存在GATA6的可能結(jié)合位點(diǎn),提示GATA6可能是LOXL2的上游調(diào)控分子。另外有文獻(xiàn)提示,LOXL2在腫瘤中表現(xiàn)為促癌分子參與腫瘤侵襲轉(zhuǎn)移進(jìn)程時(shí),可通過介導(dǎo)上皮標(biāo)志物E-cadherin的表達(dá)下調(diào),從而促進(jìn)EMT的發(fā)生和腫瘤的侵襲轉(zhuǎn)移。因此,我們推測(cè)CCA中GATA6能調(diào)控LOXL2的表達(dá),促進(jìn)EMT發(fā)生從而增強(qiáng)CCA細(xì)胞的侵襲遷移能力。材料方法與研究結(jié)果1、CCA腫瘤組織和細(xì)胞中LOXL2和GATA6的表達(dá)呈顯著相關(guān)性收集西南醫(yī)院肝膽外科2005至2012年,手術(shù)切除的90例CCA患者的組織及24例相應(yīng)癌旁組織的石蠟標(biāo)本。采用免疫組化方法檢測(cè)發(fā)現(xiàn)CCA腫瘤組織中的LOXL2和GATA6的表達(dá)水平較癌旁組織中異常增高,經(jīng)統(tǒng)計(jì)學(xué)分析顯示二者在腫瘤組織中的表達(dá)具有顯著相關(guān)性。同時(shí)在CCA細(xì)胞中(QBC939和RBE)通過RT-qPCR和Western blot實(shí)驗(yàn)檢測(cè)QBC939細(xì)胞的LOXL2的表達(dá)情況,發(fā)現(xiàn)LOXL2在mRNA水平與蛋白水平的表達(dá)均高于RBE細(xì)胞,進(jìn)一步檢測(cè)發(fā)現(xiàn)GATA6的表達(dá)趨勢(shì)與LOXL2一致。以上結(jié)果表明LOXL2和GATA6在CCA中的表達(dá)具有相關(guān)性。2、CCA腫瘤組織和細(xì)胞中LOXL2與GATA6的高表達(dá)都與侵襲轉(zhuǎn)移有關(guān)收集上述90例患者的病例資料(包括隨訪資料),通過統(tǒng)計(jì)學(xué)方法分析LOXL2和GATA6在CCA腫瘤組織中的高表達(dá)與臨床病例特征的相關(guān)性,發(fā)現(xiàn)LOXL2和GATA6的表達(dá)水平均與患者的淋巴結(jié)轉(zhuǎn)移情況顯著相關(guān)。進(jìn)一步運(yùn)用Kaplan-Meier模型分析發(fā)現(xiàn)LOXL2和GATA6的高表達(dá)均導(dǎo)致不良預(yù)后。采用Transwell侵襲實(shí)驗(yàn)和損傷修復(fù)實(shí)驗(yàn)檢測(cè)發(fā)現(xiàn)高表達(dá)LOXL2和GATA6的QBC939細(xì)胞的侵襲能力和遷移能力均明顯強(qiáng)于RBE細(xì)胞。以上結(jié)果表明LOXL2和GATA6在CCA中功能具有相似性。3、CCA細(xì)胞中GATA6對(duì)LOXL2存在正向調(diào)控作用生物信息學(xué)分析發(fā)現(xiàn)LOXL2基因啟動(dòng)子區(qū)域可能存在GATA6的結(jié)合位點(diǎn),提示GATA6可能是LOXL2的上游調(diào)控分子。進(jìn)而通過RNA干擾和過表達(dá)策略,從正反兩方面檢測(cè)GATA6對(duì)LOXL2表達(dá)的影響。在QBC939細(xì)胞中干擾GATA6的表達(dá),LOXL2的mRNA水平和蛋白水平隨之降低；在RBE細(xì)胞中過表達(dá)GATA6, LOXL2的mRNA水平和蛋白水平隨之升高。以上結(jié)果表明GATA6對(duì)LOXL2的表達(dá)具有正向調(diào)控作用。4、GATA6通過調(diào)控LOXL2表達(dá)影響CCA細(xì)胞的侵襲遷移采用“恢復(fù)實(shí)驗(yàn)”,即通過干預(yù)GATA6表達(dá)后再反向干預(yù)LOXL2的表達(dá),通過Transwell侵襲實(shí)驗(yàn)和損傷修復(fù)實(shí)驗(yàn)檢測(cè)CCA細(xì)胞侵襲遷移能力的改變。干擾GATA6表達(dá)能明顯減弱QBC939細(xì)胞侵襲遷移的能力,反向恢復(fù)LOXL2表達(dá)后能夠在一定程度上逆轉(zhuǎn)干擾GATA6表達(dá)所導(dǎo)致的侵襲遷移受抑制的現(xiàn)象。在RBE細(xì)胞中過表達(dá)GATA6能明顯增強(qiáng)細(xì)胞侵襲遷移的能力,而這種抑制作用能被反向干擾LOXL2表達(dá)部分削弱。以上結(jié)果表明GATA6可通過調(diào)控LOXL2的表達(dá)影響CCA細(xì)胞的侵襲遷移。5、GATA6-LOXL2通路通過促進(jìn)EMT增強(qiáng)CCA細(xì)胞的侵襲遷移采用免疫組化方法檢測(cè)發(fā)現(xiàn)高表達(dá)GATA6和LOXL2的CCA腫瘤組織中,上皮標(biāo)志物E-cadherin低表達(dá),而間質(zhì)標(biāo)志物Vimentin高表達(dá),且經(jīng)統(tǒng)計(jì)學(xué)分析顯示E-cadherin和Vimentin的表達(dá)水平分別與GATA6和LOXL2的表達(dá)水平顯著相關(guān)。進(jìn)一步在CCA細(xì)胞中通過“恢復(fù)實(shí)驗(yàn)”,即干預(yù)GATA6表達(dá)后再反向干預(yù)LOXL2的表達(dá),檢測(cè)EMT標(biāo)志物E-cadherin表達(dá)水平的變化,結(jié)果顯示QBC939細(xì)胞中GATA6介導(dǎo)的LOXL2上調(diào)抑制CCA細(xì)胞中E-cadherin的表達(dá),而RBE細(xì)胞中GATA6介導(dǎo)的LOXL2下調(diào)促進(jìn)CCA細(xì)胞中E-cadherin的表達(dá)。以上結(jié)果表明GATA6通過調(diào)控LOXL2表達(dá)影響EMT,進(jìn)而促進(jìn)EMT發(fā)生和侵襲轉(zhuǎn)移。研究結(jié)論本研究明確了GATA6和LOXL2表達(dá)水平具有正向相關(guān)性。通過統(tǒng)計(jì)學(xué)分析發(fā)現(xiàn)二者在CCA中的高表達(dá)均與患者的淋巴結(jié)轉(zhuǎn)移情況、不良預(yù)后密切相關(guān)。進(jìn)一步在CCA細(xì)胞模型上,通過RNA干擾和過表達(dá)策略,從正反兩方面證實(shí)了GATA6對(duì)LOXL2表達(dá)具有正向調(diào)控作用,并通過“恢復(fù)實(shí)驗(yàn)”進(jìn)一步證實(shí)了GATA6通過上調(diào)LOXL2表達(dá)促進(jìn)EMT,從而促進(jìn)CCA細(xì)胞的侵襲遷移。以上實(shí)驗(yàn)結(jié)果不僅可能發(fā)現(xiàn)LOXL2在CCA侵襲轉(zhuǎn)移中的自身表達(dá)調(diào)控機(jī)制,更重要的是可能為將來基于GATA6-LOXL2為靶標(biāo)的CCA臨床治療提供理論及實(shí)驗(yàn)依據(jù)。第二章核受體FXR通過上調(diào)SOCS3抑制肝細(xì)胞癌增殖的研究研究背景肝細(xì)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(zhuǎn)錄因子STAT3信號(hào)通路在其發(fā)生發(fā)展中發(fā)揮著重要促進(jìn)作用。細(xì)胞信號(hào)轉(zhuǎn)導(dǎo)抑制蛋白3(Suppressors of cytokine signaling 3, SOCS3),作為STAT3通路重要的內(nèi)源性負(fù)反饋調(diào)節(jié)分子,在多種癌癥中低表達(dá),導(dǎo)致STAT3的異常活化。而越來越多的證據(jù)也顯示SOCS3的恢復(fù)表達(dá)(即功能回復(fù))在HCC、炎癥性結(jié)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(rèn)為是一個(gè)重要的內(nèi)源性抗腫瘤分子,上調(diào)其表達(dá)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(zhì)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(hù)作用,但總體來說具體機(jī)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(diào)控SOCS3表達(dá)而發(fā)揮抗癌作用呢?因此我們以HCC細(xì)胞為模型,通過解析FXR在SOCS3基因啟動(dòng)子區(qū)的具體結(jié)合位點(diǎn),闡明FXR通過上調(diào)SOCS3抑制HCC的新機(jī)制,從而為探索以FXR-SOCS3為靶標(biāo)的HCC治療提供新的實(shí)驗(yàn)依據(jù)和理論基礎(chǔ)。材料方法與研究結(jié)果一、FXR通過上調(diào)SOCS3抑制肝細(xì)胞癌增殖生長(zhǎng)通過MTS細(xì)胞增殖實(shí)驗(yàn)、流式細(xì)胞技術(shù)、RT-qPCR和Western blot等實(shí)驗(yàn)證實(shí)了FXR激動(dòng)劑GW4064可以抑制人HCC細(xì)胞(HepG2和Huh7)的增殖,誘導(dǎo)細(xì)胞周期阻滯在G1期,誘導(dǎo)細(xì)胞周期關(guān)鍵分子p21的表達(dá)、抑制STAT3的磷酸化活化。并通過RNA干擾策略證實(shí)GW4064的上述抑增殖效應(yīng)是通過上調(diào)SOCS3表達(dá)實(shí)現(xiàn)的。進(jìn)一步進(jìn)行在體實(shí)驗(yàn)證實(shí)GW4064能抑制裸鼠HCC移植瘤的生長(zhǎng)。二、闡明GW4064上調(diào)SOCS3表達(dá)的具體分子機(jī)制采用針對(duì)FXR的siRNA證實(shí)GW4064上調(diào)SOCS3是通過活化FXR實(shí)現(xiàn)的。生物信息學(xué)分析SOCS3基因啟動(dòng)子區(qū)可能存在FXR反應(yīng)元件。進(jìn)而通過報(bào)告基因檢測(cè)驗(yàn)(結(jié)合點(diǎn)突變策略)、EMSA實(shí)驗(yàn)、ChIP實(shí)驗(yàn)證實(shí)FXR通過與人SOCS3基因啟動(dòng)子區(qū)-1878～-1858區(qū)域的FXR反應(yīng)元件(IR9)結(jié)合,促進(jìn)SOCS3的轉(zhuǎn)錄活性,從而上調(diào)其表達(dá)。三、肝細(xì)胞癌組織中FXR與SOCS3表達(dá)明顯降低,而STAT3異�；罨占髂厢t(yī)院肝膽外科2013至2014年間手術(shù)切除的66例HCC臨床標(biāo)本,采用免疫組化方法檢測(cè)發(fā)現(xiàn),與相應(yīng)癌旁組織相比,HCC腫瘤組織中的FXR和SOCS3的表達(dá)水平顯著降低(統(tǒng)計(jì)學(xué)分析表明二者的表達(dá)水平具有顯著相關(guān)性),同時(shí)STAT3的活化水平(即p-STAT3的表達(dá)水平)在HCC腫瘤組織中明顯增高。臨床標(biāo)本上的結(jié)果與細(xì)胞水平實(shí)驗(yàn)的結(jié)果相符。研究結(jié)論我們以肝細(xì)胞癌(HCC)細(xì)胞為模型,詳細(xì)解析了FXR在SOCS3基因啟動(dòng)子區(qū)的具體結(jié)合位點(diǎn),闡明了FXR上調(diào)SOCS3的分子機(jī)制。通過RNA干擾策略證實(shí)了FXR通過上調(diào)SOCS3表達(dá)抑制HCC細(xì)胞的增殖、誘導(dǎo)細(xì)胞周期阻滯、上調(diào)細(xì)胞周期關(guān)鍵分子p21的表達(dá),抑制STAT3的磷酸化活化；在裸鼠HCC移植瘤模型上驗(yàn)證了FXR的抑癌效應(yīng)。并進(jìn)一步在HCC患者的腫瘤組織中明確了FXR和SOCS3G表達(dá)水平的正向相關(guān)性。以上研究結(jié)果闡明FXR通過上調(diào)SOCS3抑制HCC的新機(jī)制,從而為探索以FXR-SOCS3為靶標(biāo)的HCC治療提供新的實(shí)驗(yàn)依據(jù)和理論基礎(chǔ)。
[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(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R735

【相似文獻(xiàn)】

相關(guān)期刊論文 前10條

1 邢長(zhǎng)英;歸綏琪;;SOCS3作用機(jī)制與婦產(chǎn)科研究進(jìn)展[J];生殖與避孕;2007年04期

2 ;Expression of SOCS-1 in the liver tissues of chronic hepatitis B and its clinical significance[J];World Journal of Gastroenterology;2008年04期

3 ;Dendritic Cells Transduced with SOCS1 Gene Exhibit Regulatory DC Properties and Prolong Allograft Survival[J];Cellular & Molecular Immunology;2009年02期

4 許文頻;李衛(wèi)東;;SOCS3分子——治療人類多種疾病的潛在靶標(biāo)[J];藥學(xué)學(xué)報(bào);2011年07期

5 李詠;韓梅芳;李維娜;師愛超;張?jiān)獊?王宏艷;王發(fā)席;李蘭;吳婷;丁琳;陳韜;嚴(yán)偉明;羅小平;寧琴;;SOCS3 Expression Correlates with Severity of Inflammation in Mouse Hepatitis Virus Strain 3-induced Acute Liver Failure and HBV-ACLF[J];Journal of Huazhong University of Science and Technology(Medical Sciences);2014年03期

6 毛一雷,Ling P Bistrian BR,Smith RJ Joslin;新發(fā)現(xiàn)的SOCS蛋白家族:揭示了創(chuàng)傷和營(yíng)養(yǎng)不良時(shí)代謝異常的機(jī)理[J];中國(guó)臨床營(yíng)養(yǎng)雜志;2000年01期

7 ;Gene Delivery of SOCS3 Protects Mice from Lethal Endotoxic Shock[J];Cellular & Molecular Immunology;2005年05期

8 周運(yùn)恒;榮光華;楊再興;仲人前;;SOCS及其免疫學(xué)作用研究進(jìn)展[J];現(xiàn)代免疫學(xué);2007年06期

9 張奇;吳健;于波;;SOCS1與免疫調(diào)節(jié)的研究進(jìn)展[J];免疫學(xué)雜志;2010年11期

10 丁浩;孫國(guó)芳;李菊香;洪葵;程曉曙;;SOCS1對(duì)氧化低密度脂蛋白促進(jìn)人血管平滑肌細(xì)胞增殖作用的影響[J];嶺南心血管病雜志;2011年S1期

相關(guān)會(huì)議論文 前10條

1 Zhiyao Bao;Quirui Zhang;Huanying Wan;Min Zhou;Ping He;;Expression of SOCS-1 in the peripheral blood from patients with idiopathic pulmonary fibrosis[A];中華醫(yī)學(xué)會(huì)呼吸病學(xué)年會(huì)——2013第十四次全國(guó)呼吸病學(xué)學(xué)術(shù)會(huì)議論文匯編[C];2013年

2 徐雪;李娟;王亞軍;;家雞細(xì)胞因子信號(hào)傳導(dǎo)抑制因子(SOCS1)基因的克隆及其組織表達(dá)[A];四川省動(dòng)物學(xué)會(huì)第九次會(huì)員代表大會(huì)暨第十屆學(xué)術(shù)研討會(huì)論文集[C];2011年

3 王國(guó)兵;李成榮;楊軍;溫鵬強(qiáng);賈實(shí)磊;;SOCS1/SOCS3甲基化改變?cè)趦和毙訧TP Th17/Treg細(xì)胞失衡中的作用初探[A];中華醫(yī)學(xué)會(huì)第十七次全國(guó)兒科學(xué)術(shù)大會(huì)論文匯編（上冊(cè)）[C];2012年

4 許衍碩;陳志斌;梁艷冰;唐皓;馬中富;;外周血單個(gè)核細(xì)胞SOCS-1表達(dá)與MODS患者預(yù)后關(guān)系的研究[A];全國(guó)危重病急救醫(yī)學(xué)學(xué)術(shù)會(huì)議論文匯編[C];2007年

5 許衍碩;陳志斌;梁艷冰;唐皓;馬中富;;外周血單個(gè)核細(xì)胞SOCS-1表達(dá)與MODS患者預(yù)后關(guān)系的研究[A];2008年廣東省中醫(yī)熱病、急癥、中西醫(yī)結(jié)合急救、危重病、災(zāi)害醫(yī)學(xué)學(xué)術(shù)會(huì)議學(xué)術(shù)論文集[C];2008年

6 譚峰;方美鳳;梁艷桂;劉曉林;陳文霖;;急性腦梗塞患者血清SOCS-3的動(dòng)態(tài)變化及其意義[A];國(guó)家中醫(yī)藥管理局腦病重點(diǎn)研究室建設(shè)研討會(huì)暨中風(fēng)病科研成果推廣交流會(huì)論文匯編[C];2010年

7 夏杰;步宏;石毓君;孫懷強(qiáng);包驥;;部分肝切除后肝再生過程中SOCS3基因啟動(dòng)子甲基化檢測(cè)[A];中華醫(yī)學(xué)會(huì)病理學(xué)分會(huì)2010年學(xué)術(shù)年會(huì)日程及論文匯編[C];2010年

8 陳志斌;梁艷冰;唐皓;林賢壽;何東華;馬中富;;外周血單個(gè)核細(xì)胞SOCS-1與SOCS-3表達(dá)與MODS患者預(yù)后關(guān)系的研究[A];2008年廣東省中醫(yī)熱病、急癥、中西醫(yī)結(jié)合急救、危重病、災(zāi)害醫(yī)學(xué)學(xué)術(shù)會(huì)議學(xué)術(shù)論文集[C];2008年

9 劉霞;張永亮;安華章;徐紅梅;于益芝;楊曉;曹雪濤;;SOCS3反饋抑制巨噬細(xì)胞內(nèi)源性TGF-β1負(fù)向調(diào)節(jié)TLR4反應(yīng)的作用和機(jī)制研究[A];中國(guó)免疫學(xué)會(huì)第五屆全國(guó)代表大會(huì)暨學(xué)術(shù)會(huì)議論文摘要[C];2006年

10 李菊香;萬磊;夏子榮;蘇海;顏素娟;程曉曙;吳清華;;細(xì)胞因子信號(hào)抑制物SOCS1/JAB介導(dǎo)CT-1對(duì)心肌胞急性缺氧復(fù)氧損傷的保護(hù)作用[A];江西省第四次中西醫(yī)結(jié)合心血管學(xué)術(shù)交流會(huì)論文集[C];2008年

相關(guān)重要報(bào)紙文章 前1條

1 本報(bào)特約撰稿人 陸志城;SOCS3：抗過敏反應(yīng)藥物的新靶標(biāo)[N];醫(yī)藥經(jīng)濟(jì)報(bào);2003年

相關(guān)博士學(xué)位論文 前10條

1 劉冰;USP18/SOCS1在丙肝病毒耐受Ⅰ型和Ⅲ型干擾素中的作用及其分子機(jī)制研究[D];北京協(xié)和醫(yī)學(xué)院;2015年

2 戴梓茹;敲除SOCS1a引起斑馬魚肝臟脂肪變性和胰島素抵抗[D];華中科技大學(xué);2015年

3 郭飛;GATA6上調(diào)LOXL2促進(jìn)膽管癌侵襲轉(zhuǎn)移和FXR上調(diào)SOCS3抑制肝細(xì)胞癌增殖的研究[D];第三軍醫(yī)大學(xué);2015年

4 周運(yùn)恒;SOCS在原發(fā)性膽汁性肝硬化發(fā)病機(jī)制中的作用研究[D];第二軍醫(yī)大學(xué);2009年

5 邢長(zhǎng)英;補(bǔ)腎益氣方調(diào)控人早孕滋養(yǎng)細(xì)胞SOCS3表達(dá)改善其生物學(xué)功能的研究[D];復(fù)旦大學(xué);2006年

6 張沛;SOCS3在心臟移植慢性排斥反應(yīng)中的作用和機(jī)制研究[D];華中科技大學(xué);2014年

7 白莉;SOCS3基因?qū)θ毖醮笫蠓蝿?dòng)脈平滑肌細(xì)胞增殖及細(xì)胞癌基因表達(dá)的影響[D];第三軍醫(yī)大學(xué);2004年

8 王晨;JAK/STAT信號(hào)通路抑制因子SOCS-1/3對(duì)糖尿病腎病作用及其機(jī)制的研究[D];河北醫(yī)科大學(xué);2008年

9 豆玉鳳;負(fù)載全腫瘤抗原及SOCS1siRNA轉(zhuǎn)染的樹突狀細(xì)胞殺傷兒童惡性腫瘤細(xì)胞的研究[D];第四軍醫(yī)大學(xué);2010年

10 劉青娟;炎癥在糖尿病腎病發(fā)病中的作用及細(xì)胞因子信號(hào)轉(zhuǎn)導(dǎo)抑制因子SOCS-1、SOCS-3的影響[D];河北醫(yī)科大學(xué);2010年

相關(guān)碩士學(xué)位論文 前10條

1 劉鈺;Plko.1-SOCS3-siRNA慢病毒表達(dá)載體的構(gòu)建與鑒定[D];蘭州大學(xué);2015年

2 任倩;SOCS2和STAT5在喉癌中的表達(dá)及其臨床意義[D];山西醫(yī)科大學(xué);2015年

3 舒祿云;SOCS3基因?qū)ψ訉m內(nèi)膜癌細(xì)胞增殖和遷移作用的研究[D];南方醫(yī)科大學(xué);2015年

4 黃佳晏;SOCS3對(duì)IgA腎病患者IgA1刺激人腎小球系膜細(xì)胞增殖的影響及機(jī)制探討[D];南昌大學(xué)醫(yī)學(xué)院;2015年

5 徐旺;SOCS1介導(dǎo)AngⅡ促血管平滑肌細(xì)胞增殖的作用及機(jī)制[D];南昌大學(xué)醫(yī)學(xué)院;2015年

6 訾廣芹;過敏性紫癜兒童SOCS表達(dá)及與Th17/Treg細(xì)胞失衡關(guān)系研究[D];青島大學(xué);2015年

7 張慶群;SOCS低甲基化在過敏性紫癜兒童Th17/Treg細(xì)胞失衡中的作用研究[D];青島大學(xué);2015年

8 錢明;EGFR重組蛋白沖擊SOCS1沉默的DC對(duì)Hep-2細(xì)胞殺傷作用的研究[D];遼寧醫(yī)學(xué)院;2015年

9 桂博翔;SOCS3在H9N2禽流感病毒誘發(fā)急性肺損傷及繼發(fā)細(xì)菌性肺炎中的作用研究[D];華東師范大學(xué);2016年

10 杜寶文;豬SOCS-2 cDNA基因的克隆、序列分析及表達(dá)研究[D];西北農(nóng)林科技大學(xué);2007年

，

本文編號(hào)：2214926