本文選題：CXCL6 + 肝細胞癌　； 參考：《山東大學》2016年博士論文

【摘要】：研究背景原發(fā)性肝癌中約90%為肝細胞癌(簡稱肝癌),居全世界惡性腫瘤發(fā)病率第5位,其病死率在各種癌癥中居第2位。2014年世界衛(wèi)生組織WHO的統(tǒng)計資料顯示：全世界肝癌的發(fā)病率還存在上升趨勢。中國作為HBV(乙型肝炎病毒)高感染地區(qū),肝癌的發(fā)病率占全世界的50%以上。肝癌在中國于危害人們生命健康方面屬于前三大惡性腫瘤之一,給社會帶來沉重負擔。HCC(原發(fā)性肝細胞肝癌)的的特點是生長速度快,易于轉(zhuǎn)移和生存率低。目前為止,早期診斷和及時手術(shù)治療是肝癌患者最有效的治療措施。然而,術(shù)后復發(fā)和轉(zhuǎn)移是導致肝癌術(shù)后患者較差預(yù)后的關(guān)鍵問題。原發(fā)性肝癌的復發(fā)和轉(zhuǎn)移的臨床診斷目前主要依靠血清學檢測和影像學方法,包括B超的定期復查,術(shù)前血清甲胎蛋白(AFP)和術(shù)后AFP的對比檢測,并觀察其變化等。Nobuoka等研究發(fā)現(xiàn),與術(shù)前相比,AFP水平?jīng)]有顯著降低的肝癌患者較術(shù)后甲胎蛋白顯著降低的患者的復發(fā)率是明顯增高的。AFP檢測持續(xù)陽性提示殘余腫瘤活性增強的可能。一般來講,AFP對復發(fā)性肝癌的早期診斷的檢測率比B超低,B超的早期診斷檢出率比CT低。這三種方法的組合運用將是提高早期診斷率的有效方法。另外肝癌切除術(shù)后常規(guī)檢查中包括胸部正側(cè)位X線片及全身骨顯像ECT。目前尚無明確證據(jù)顯示正電子發(fā)射計算機斷層顯像(PET-CT)對于肝癌復發(fā)轉(zhuǎn)移有早期診斷價值。AFP以外,近年來發(fā)現(xiàn)DKK1對診斷原發(fā)性肝細胞肝癌有重要價值,DKK1有望成為新的肝癌腫瘤標志物。但上述檢測HCC轉(zhuǎn)移復發(fā)的方法顯然難以滿足目前理想的早診早治的臨床需要。因此,對肝癌轉(zhuǎn)移復發(fā)機腫瘤復發(fā)相關(guān)的分子標志物及積極有效的抗復發(fā)治療是當前肝癌診療中的重點。迫切需要找到新的治療靶點來應(yīng)對HCC的腫瘤的進展轉(zhuǎn)移。炎癥作為腫瘤的一大特征近年來已為大家所公認。在過去的研究中,人們發(fā)現(xiàn)炎癥與腫瘤的發(fā)生、發(fā)展密切相關(guān),深刻影響了腫瘤的生長,侵襲和轉(zhuǎn)移過程。趨化因子及其受體是炎癥微環(huán)境的重要組成部分。已有大量文獻研究證實,在促進腫瘤的發(fā)生、進展和侵襲的過程中,趨化因子及其受體起到了顯著的作用。在腫瘤侵襲過程中,癌癥細胞由腫瘤起源趨化因子誘導的趨化作用是至關(guān)重要的一步。趨化因子在促進肝癌進展中所發(fā)揮的作用也得到了越來越多的關(guān)注。趨化因子為可溶性小蛋白,是細胞因子超家族中的一類,是結(jié)構(gòu)相似、由多類細胞產(chǎn)生、具有趨化細胞遷移作用的一類因子,其相對分子質(zhì)量較小,多為8～10kD。其三級結(jié)構(gòu)是由半胱氨酸(cys)殘基組合而成。殘基包含4個,位置比較保守。根據(jù)位于其分子N端的半胱氨酸(cys)數(shù)目,另外再結(jié)合其前兩個半胱氨酸的三維排序方式不同,趨化因子家族可以分為CC(CCL1～CCL28)、 CXC(CXCL1～CXCL17)、C(XCL1～XCL2)和CX3C(CX3L1)4類不同的亞家族。目前為止,相關(guān)文獻對趨化因子的報道總計有50余種。趨化因子受體是一些G蛋白耦聯(lián)的七跨膜域受體,表達于一些特定的細胞表面。它們?yōu)橐环N糖蛋白,只含一條肽鏈,由大約330個氨基酸組成。7個跨膜區(qū)域,將分子劃分為4個部分,包含游離的細胞外N-端、3個細胞外環(huán)、3個細胞內(nèi)環(huán)及C-端。趨化因子可以在多種細胞活動過程中產(chǎn)生,并且與相應(yīng)的受體相結(jié)合,進而調(diào)節(jié)機體的各種功能。二者的相互作用,可以調(diào)控生物組織及器官之間的各類免疫細胞的定向遷移過程。因此,趨化因子和受體的相互作用在免疫細胞分化,發(fā)育和定向遷移的調(diào)節(jié)中有著重要作用。既往研究顯示,在某些腫瘤細胞中趨化因子及其受體高表達和腫瘤轉(zhuǎn)移具有高度相關(guān)性。腫瘤相關(guān)的趨化因子不僅可以促進腫瘤細胞增殖,抑制腫瘤細胞凋亡,還在腫瘤細胞的遷移過程發(fā)揮重要作用,同時可以趨化淋巴細胞浸潤腫瘤組織,參與腫瘤血管生成和腫瘤細胞器官選擇性轉(zhuǎn)移。CXCL6也稱為粒細胞趨化蛋白2(GCP-2),屬于ELR+趨化因子。類似于其他ELR+趨化因子,CXCL6促進腫瘤的生長作用在動物實驗中得到驗證。此外,CXCL6已經(jīng)被證明是在幾個實體腫瘤進展中的重要媒介。很多研究表明,CXCL6的高表達與腫瘤的發(fā)生、發(fā)展及其侵襲轉(zhuǎn)移有關(guān)。CXCL6被發(fā)現(xiàn)在實體腫瘤上調(diào),包括小細胞肺癌,黑色素瘤和結(jié)直腸癌。在常見的肝癌細胞株中,MHCC97H或HCCLM3細胞具有較高的轉(zhuǎn)移能力,而HepG2或SMMC7721具有較低的轉(zhuǎn)移能力。在MHCC97H或HCCLM3細胞中,CXCL6水平顯著高于其在HepG2或SMMC7721細胞中的水平。此結(jié)果表明CXCL6可能促進肝癌細胞侵襲轉(zhuǎn)移。然而,對CXCL6在肝癌侵襲轉(zhuǎn)移中所起作用的進一步的研究尚不充分。此外,CXCL6對預(yù)測肝癌患者的預(yù)后的意義尚不完全清楚。目的：通過本研究通過相關(guān)實驗旨在進一步探索與驗證CXCL6對肝癌細胞的增殖與侵襲的作用。分析CXCL6在臨床肝癌標本中的表達與腫瘤大小及血管侵犯、總體生存率(OS)以及無復發(fā)生存率(RFS)等預(yù)后相關(guān)指標的聯(lián)系。研究比較CXCL6在MHCC97L、MHCC97H、HCCLM3、HepG2和SMMC7721經(jīng)典肝癌細胞株中表達的差異。并通過靶向沉默CXCL6的MHCC97H和HCCLM3細胞系進行了體外細胞增殖和侵襲實驗,同時以CXCL6質(zhì)粒慢病毒轉(zhuǎn)染的SMMC-7721細胞來比較CXCL6表達水平的高低對HCC細胞侵襲能力的影響。并進一步研究MMP9被敲除后,CXCL6對HCC增殖及侵襲能力影響的改變。期待能為HCC復發(fā)及轉(zhuǎn)移的早期診斷和治療提供預(yù)測因子及治療靶點。材料與方法：1.我們收集了從2005年到2011年196份肝癌樣本,隨訪至2013年12月。采用免疫組化法檢測了CXCL6在肝癌組織芯片的表達,其中包括212例HCC樣本。完整的隨訪數(shù)據(jù)包括患者的年齡、性別、腫瘤大小、肝硬化程度、局部侵襲情況,TNM分期,年齡,腫瘤衛(wèi)星灶,血管侵犯,血栓形成。我們使用SPSS16.0軟件分析CXCL6表達與肝細胞癌患者的臨床病理特征參數(shù)之間的相關(guān)性。此外,應(yīng)用SPSS軟件通過乘積極限法(Kaplan-Meier法)來分析CXCL6和肝細胞癌患者的總體生存期和無復發(fā)生存期的相關(guān)性。2.應(yīng)用實時定量聚合酶鏈反應(yīng)(PCR)和Western blot(免疫印跡)方法比較了CXCL6在HCC及配對癌旁的正常肝組織的表達水平差異。3.通過應(yīng)用Lipofectamine2000試劑轉(zhuǎn)染小干擾RNA(siRNA)到MHCC97H和HCCLM3細胞評估CXCL6的作用。應(yīng)用qPCR和免疫印跡法檢測的siRNA在肝癌細胞中的敲除效果。同時我們設(shè)計了體外侵襲實驗以驗證沉默CXCL6后MHCC97H和HCCLM3細胞的侵襲能力。4.以siRNA靶向沉默CXCL6的MHCC97H和HCCLM3細胞系進行了體外細胞增殖實驗。5.通過慢病毒轉(zhuǎn)染法進行表達檢測進一步探討CXCL6在HCC細胞中作用。6.MMP9在被過表達CXCL6質(zhì)粒或者過表達對照質(zhì)粒轉(zhuǎn)染的肝癌細胞中被用RNA干擾的方法敲除,以檢測MMP9敲除后,CXCL6在SMMC-7721細胞的促侵襲作用的變化情況。實驗結(jié)果：1.我們采用免疫組化法檢測了CXCL6在肝癌組織芯片的表達,其中包括212例HCC樣本。通過分析178可配對組織中,我們發(fā)現(xiàn),在71.91%(128/178)HCC患者中CXCL6水平升高,但是在14.04%肝癌患者(25/178)表達下調(diào)。2.統(tǒng)計分析發(fā)現(xiàn)CXCL6的表達與腫瘤大小及血管侵犯(其是肝癌侵襲的重要臨床病理學指標)密切相關(guān)。此外,我們發(fā)現(xiàn),較高的CXCL6表達與較差的總體生存率(OS)以及無復發(fā)生存率(RFS)相關(guān)。肝癌患者低CXCL6表達患者比高表達患者預(yù)后較好。3.在HCC組織中CXCL6 mRNA和蛋白表達水平顯著高于其在配對的正常肝臟組織的表達水平。研究結(jié)果表明CXCL6在肝癌組織中與相應(yīng)的正常肝臟組織相比是上調(diào)的。4. CXCL6在MHCC97L,MHCC97H和HCCLM3細胞株中高表達,但在HepG2和SMMC7721細胞株中低表達。此外,在肝癌細胞系中CXCL6 mRNA表達水平通常與蛋白表達狀態(tài)一致。5.體外侵襲實驗表明CXCL6沉默顯著下調(diào)了MHCC97H和HCCLM3細胞的侵襲能力。6.以siRNA靶向沉默CXCL6的MHCC97H和HCCLM3細胞系進行了體外細胞增殖實驗結(jié)果表明,沉默CXCL6在體外顯著抑制肝癌細胞增殖。7.與對照組相比,被CXCL6質(zhì)粒慢病毒轉(zhuǎn)染的SMMC-7721細胞具有更高的侵襲和轉(zhuǎn)移能力。8. CXCL6在SMMC-7721細胞的促侵襲作用在MMP9被敲除后受抑制。結(jié)論：1.CXCL6在肝癌組織的陽性表達率顯著高于非腫瘤肝臟組織,在具有高轉(zhuǎn)移能力的肝癌細胞中高表達；CXCL6的表達呈與肝癌的惡性潛能正相關(guān)；CXCL6可能在促進肝癌細胞的運動中發(fā)揮作用。2.CXCL6高表達促進了HCC細胞的增殖和侵襲。3.CXCL6在肝癌細胞中促侵襲效應(yīng)可能使通過激活或作用MMP9起作用。4.CXCL6將來可能作為HCC一個潛在的獨立預(yù)后因子及治療靶標。
[Abstract]:About 90% of the primary hepatocellular carcinoma (HCC) in the background of primary liver cancer (HCC) is the fifth most malignant tumor in the world. The fatality rate of the second.2014 year WHO WHO in various cancers shows that the incidence of liver cancer in the world is still rising. China is a high infection area of HBV (hepatitis B virus). The incidence of liver cancer accounts for more than 50% of the world's world. Liver cancer is one of the top three malignant tumors in China, which endangers people's life and health. The heavy burden of.HCC (primary hepatocellular carcinoma) is characterized by rapid growth, easy transfer and low survival rate. Early diagnosis and timely surgical treatment are liver cancer. The most effective treatment for patients. However, postoperative recurrence and metastasis is a key problem in the poor prognosis of patients with liver cancer. The clinical diagnosis of the recurrence and metastasis of primary liver cancer is mainly based on serological and imaging methods, including regular reexamination of B-ultrasound, preoperative AFP and postoperative AFP. .Nobuoka and other studies found that the recurrence rate of patients with significant decrease in AFP levels compared with pre operation compared with preoperatively, the recurrence rate of patients with significantly lower alpha fetoprotein after operation is a significant increase in the possibility of enhanced residual tumor activity by.AFP detection. Generally speaking, the detection rate of early diagnosis of recurrent liver cancer by AFP The early diagnosis rate of B-ultrasound is lower than that of CT. The combination of these three methods will be an effective method to improve the early diagnosis rate. In addition, there is no clear evidence that positron emission computed tomography (PET-CT) has no clear evidence for the recovery of liver cancer in the routine examination of liver cancer after resection of liver cancer. In addition to the early diagnostic value of.AFP, DKK1 has been found to be of great value in the diagnosis of primary hepatocellular carcinoma in recent years. DKK1 is expected to be a new tumor marker for hepatocellular carcinoma. However, the method of detecting the recurrence of HCC metastasis is obviously difficult to meet the clinical requirements of the ideal early diagnosis and early treatment. Molecular markers and active and effective anti relapse therapy are the focus of current diagnosis and treatment of liver cancer. New therapeutic targets are urgently needed to cope with the progression of HCC tumor. In recent years, inflammation is recognized as a major feature of cancer. In the past, people found that inflammation and tumor development are closely related. It has a profound influence on the growth, invasion and metastasis of tumor. Chemokines and their receptors are important components of the inflammatory microenvironment. A large number of literature studies have shown that chemokines and their receptors play a significant role in promoting the occurrence, progression and invasion of tumors. Chemokine induced chemotaxis of tumor origin chemokine is a crucial step. Chemokine plays an increasingly important role in promoting the progression of liver cancer. Chemokine is a soluble small protein, a kind of cytokine superfamily, which is similar in structure, produced by multiple types of cells, and has chemotactic cell migration. One class of factors, whose relative molecular weight is smaller, is 8 to 10kD., and the tertiary structure is composed of cysteine (Cys) residues. The residue contains 4, and the position is conservative. According to the number of cysteine (Cys) located at the N end of its molecule, the chemokine family can be divided into C, which is in addition to the three dimensional ordering method of the former 2.5 cystine. 4 subfamilies of C (CCL1 to CCL28), CXC (CXCL1 to CXCL17), C (XCL1 to XCL2) and CX3C (CX3L1). So far, there are more than 50 reports on chemokines. Chemokine receptor is a seven transmembrane domain receptor coupled with some G protein, expressed on a specific cell surface. They are a glycoprotein containing only one polypeptide chain. Approximately 330 amino acids are composed of.7 transmembrane regions that divide molecules into 4 parts, including free extracellular N-, 3 extracellular rings, 3 cell rings and C- ends. Chemokines can be produced during a variety of cell activities and are combined with corresponding receptors to regulate the various functions of the body. The interaction of the two is possible. The interaction between chemokines and receptors plays an important role in the regulation of immune cell differentiation, development and directional migration. Previous studies have shown high expression of chemokines and their receptors and tumor metastasis in some tumor cells. Correlation. Tumor related chemokine can not only promote tumor cell proliferation, inhibit tumor cell apoptosis, but also play an important role in tumor cell migration, but also chemotactic lymphocyte infiltrating tumor tissue, and participate in tumor angiogenesis and tumor cell organ selective transfer.CXCL6, also known as granulocyte chemoattractant protein 2 (G CP-2) belongs to ELR+ chemokine. Similar to other ELR+ chemokines, CXCL6 promotes tumor growth in animal experiments. In addition, CXCL6 has been proved to be an important medium in the progress of several solid tumors. Many studies have shown that the high expression of CXCL6 is associated with the occurrence, development and invasion of the tumor in relation to the occurrence of.CXCL6 being transmitted. Now solid tumors are up-regulated, including small cell lung cancer, melanoma and colorectal cancer. In common hepatocellular carcinoma cell lines, MHCC97H or HCCLM3 cells have higher metastatic ability, while HepG2 or SMMC7721 has a lower metastatic ability. In MHCC97H or HCCLM3 cells, the level of CXCL6 is significantly higher than that in HepG2 or SMMC7721 cells. The results suggest that CXCL6 may promote the invasion and metastasis of hepatoma cells. However, further research on the role of CXCL6 in the invasion and metastasis of liver cancer is not sufficient. Furthermore, the significance of CXCL6 for predicting the prognosis of liver cancer patients is not completely clear. Objective: through this study, the purpose of this study was to further explore and verify the CXCL6's effect on liver cancer The effect of cell proliferation and invasion. Analysis of the relationship between CXCL6 expression in clinical liver cancer specimens and tumor size and vascular invasion, total survival rate (OS) and non relapse rate (RFS). Comparison of the differences in the expression of CXCL6 in MHCC97L, MHCC97H, HCCLM3, HepG2 and SMMC7721 classical hepatocellular carcinoma cell lines. The cell proliferation and invasion experiments of the MHCC97H and HCCLM3 cell lines of CXCL6 were carried out in vitro, and the effect of CXCL6 expression level on the invasion ability of HCC cells was compared with the SMMC-7721 cells transfected with CXCL6 plasmid lentivirus. The effect of CXCL6 on the proliferation and invasion of HCC was further studied. The early diagnosis and treatment of HCC recurrence and metastasis provide predictive factors and therapeutic targets. Materials and methods: 1. we collected 196 liver cancer samples from 2005 to 2011 and followed up to December 2013. The expression of CXCL6 in the tissue microarray of liver cancer was detected by immunohistochemistry, including 212 cases of HCC. Complete follow-up data included patients. Age, sex, tumor size, degree of liver cirrhosis, local invasion, TNM staging, age, tumor satellite, vascular invasion, thrombosis. We use SPSS16.0 software to analyze the correlation between CXCL6 expression and the clinicopathological parameters of patients with hepatocellular carcinoma. In addition, the SPSS software is used by the product limit method (Kaplan-Meier method). Analysis of the correlation between the overall survival time and the non recurrent survival period of CXCL6 and hepatocellular carcinoma patients.2. application real time quantitative polymerase chain reaction (PCR) and Western blot (immunoblotting) method compared CXCL6 expression levels in normal liver tissues near HCC and paired cancerous carcinoma by using Lipofectamine2000 reagent to transfect small interference RNA (siRNA). MHCC97H and HCCLM3 cells were used to evaluate the role of CXCL6. The effects of qPCR and Western blot on the knockout effect of siRNA in liver cancer cells were used. Meanwhile, we designed an in vitro invasion experiment to verify the invasion ability of MHCC97H and HCCLM3 cells after the silence CXCL6. The proliferation experiment.5. was detected by the expression of lentivirus transfection. The effect of CXCL6 in HCC cells was knocked out by RNA interference in the hepatoma cells transfected by overexpressed CXCL6 plasmids or over expressed control plasmids to detect the change of CXCL6 in SMMC-7721 cells after MMP9 knockout. Results: 1. we used immunohistochemical method to detect the expression of CXCL6 in the tissue microarray of liver cancer, including 212 cases of HCC. Through the analysis of 178 paired tissues, we found that the level of CXCL6 increased in 71.91% (128/178) HCC patients, but the expression of CXCL6 in 14.04% liver cancer patients (25/178) expression and analysis of.2. found the expression of CXCL6 and the tumor The size and vascular invasion are closely related to the important clinicopathological indicators of the invasion of liver cancer. In addition, we have found that higher CXCL6 expression is associated with poor overall survival (OS) and no relapse rate (RFS). The prognosis of low CXCL6 expression in patients with liver cancer is better than that of high expression patients.3. in HCC tissues, CXCL6 mRNA and protein expression water The results showed that CXCL6 was up to up.4. CXCL6 in MHCC97L, MHCC97H and HCCLM3 cell lines, but was low in the HepG2 and SMMC7721 cell lines, and the CXCL6 mRNA expression in the liver cancer cell lines. .5. in vitro invasiveness test showed that CXCL6 silencing significantly lowered the invasiveness of MHCC97H and HCCLM3 cells.6. with siRNA targeting the MHCC97H and HCCLM3 cell lines silenced CXCL6 in vitro. The results showed that silent CXCL6 significantly inhibited the proliferation of hepatoma cells in vitro and the control group. SMMC-7721 cells transfected by CXCL6 plasmid lentivirus had higher invasiveness and metastasis ability,.8. CXCL6 was inhibited after MMP9 knockout in SMMC-7721 cells. Conclusion: the positive expression rate of 1.CXCL6 in liver cancer tissues is significantly higher than that of non tumor liver tissues, and high expression in hepatoma cells with high metastasis ability; C The expression of XCL6 is positively related to the malignant potential of liver cancer; CXCL6 may play a role in promoting the movement of hepatoma cells,.2.CXCL6 high expression promotes the proliferation of HCC cells and invade the invasion effect of.3.CXCL6 in the liver cancer cells, which may cause.4.CXCL6 to act as a potential independent preconditioning of HCC in the future by activating or acting on MMP9. Post factor and therapeutic target.
【學位授予單位】：山東大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R735.7

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