肠源性内毒素在肝癌发生发展过程中的作用及机制研究
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摘要
肠源性内毒素在肝癌发生发展过程中的作用及机制研究
【研究背景及目的】
原发性肝癌是世界范围内发病率较高的恶性肿瘤之一,在我国是导致居民肿瘤死亡原因的第二位。原发性肝癌的发生被认为是一个多因素,多途径,和长期作用的结果,其病理学基础是各种致癌因素引起的肝脏慢性炎症与肝硬化。我国大多数的肝癌病人存在程度不同的肝硬化。
由于解剖学上的联系,肝脏处于防御肠源性细菌产物的第一线,并且是它们主要的过滤器官。当肝脏的功能受损时,肠源性细菌产物就可能通过门静脉或其侧支循环进入血液形成内毒素血症。已有文献报道,在多种肝脏疾病,如病毒性肝炎,肝硬化,肝癌和酒精性肝病中的病人中大部分存在肠道菌群的移位和肠源性内毒素血症,在动物实验中也证实肠源性内毒素在肝纤维化和酒精性肝病的发生发展中起重要作用。内毒素是强有力的致炎因子,可以引起肝内多种炎性因子的分泌,如TNFα, IL-6, TGFβ, IL-1α等的释放,而这些炎症因子导致了肝脏病变的发生发展。但现在不清楚肠道来源的LPS是如何促进肝脏肿瘤的发生发展。
内毒素(LPS)通过其受体Toll样受体4(TLR4)起作用。TLR4与LPS结合后,通过MyD88通路和TRIF通路向下游传递信号,前者可引起多种炎性介质的释放,后者则可引起Ⅰ型和Ⅱ型干扰素的释放。在肝细胞,枯否氏细胞(KC)、星状细胞、胆管上皮细胞、内皮细胞和树突状细胞都表达TLR4,这都提示TLR4可能在肝脏疾病的发生中起重要作用。研究也证实,在酒精性肝损伤,肝纤维化,缺血再灌注损伤,肝部分切除后的肝再生以及肝的自身免疫性疾病中,TLR4信号通路的参与必不可少。到目前为止,TLR4在肝癌发生中的作用还未见报道,但可以推测TLR4在肝癌的发生中可能有重要作用。
本项目拟应用大鼠的DEN模型研究肠源性内毒素在肝炎—肝硬化—肝癌这一过程中所起的作用,同时建立TLR4敲除的小鼠DEN模型,采用分子生物学和细胞学的方法探讨LPS发挥作用的机制,为肝癌的防治提供有潜在临床价值的实验数据。【实验方法】
1.建立DEN诱导的大鼠肝癌模型,利用抗生素清除肠源性内毒素,比较抗生素处理组和未处理组DEN引起的肝癌负荷。
2.建立小鼠DEN诱导的肝癌模型。比较LPS受体Toll样受体4(TLR4)敲除小鼠和对照小鼠的DEN引起的肿瘤负荷。
3.建立DEN引起的肝脏急性损伤模型,比较TLR4-/-小鼠和野生型小鼠DEN引起的肝脏损伤、凋亡以及代偿性增殖情况。利用Real-time PCR方法检测TLR4-/-小鼠和野生型小鼠肝脏中细胞因子TNFa和IL-6的表达水平,以及DEN代谢酶、p53相关基因的表达变化。
4.利用骨髓移植实验研究表达在实质细胞和非实质细胞上的TLR4在DEN诱导的肝损伤以及肝细胞代偿性增殖中的作用。
5.用免疫组化方法检测DEN在TLR4-/-小鼠和野生型小鼠肝脏中引起的NF-κB的活化情况；利用Real-time PCR方法检测NF-κB下游基因的表达情况；检测DEN引起的肝脏内ROS的含量。
6.用LPS预处理小鼠,研究LPS对DEN引起肝脏损伤的作用；
7.利用TNF/GalN以及Jo-2引起的暴发性肝炎模型研究LPS在肝细胞凋亡中的保护作用。
8.体外分离小鼠的原代肝细胞,用TNF/CHX诱导细胞凋亡,研究LPS保护肝细胞凋亡的机制。
【实验结果】
1.在DEN诱导的大鼠肝癌模型中存在血浆LPS水平的升高。在大鼠DEN模型中利用抗生素清除LPS可明显减少肝脏肿瘤的发生发展。
2.小鼠中TLR4缺失明显减少DEN诱导的肝脏肿瘤的发生,肿瘤中浸润的巨噬细胞明显减少,TNFa和IL-6的含量也明显减少。
3.TLR4缺失加重DEN诱导的肝损伤,但减轻DEN诱导的肝细胞的代偿性增殖。
4.TLR4-/-小鼠DEN引起的TNFα和IL-6表达低于野生型小鼠。骨髓来源细胞上TLR4的活化可引起TNFa和IL-6表达,从而促进肝细胞的代偿性增殖。
5.TLR4缺失可减少肝细胞内NFκB活化,使NF-κB下游抗凋亡基因Bcl-xl和A20的表达减少,清除活性氧族(ROS)的酶MnSOD的表达减少,肝内GSH减少,MDA增加,故TLR4-/-小鼠肝损伤加重。
6.DEN可引起小鼠血液中LPS水平的升高。LPS处理可减少DEN诱导的细胞凋亡。
7.LPS处理野生型小鼠可抵抗死亡受体配体引起的急性肝损伤,但对TLR4-/-小鼠无保护作用。
8.LPS预处理肝细胞产生的抗凋亡效应是NF-κB介导的。
【结论】
本研究从细胞和动物学水平证明肠源性LPS在炎症性肝细胞癌的发生发展中起重要作用。LPS通过与其受体TLR4结合,在炎症细胞中可引起多种炎症因子的分泌,促进细胞的增殖,在实质细胞中可通过活化NF-κB引起多种抗凋亡蛋白的表达从而抑制细胞凋亡。抑制肠道细菌的异常转位以及清除LPS可能会有效改善肝硬化病人的肝功能,从而减少肿瘤的发生发展。
Hepatocellular carcinoma (HCC) is a prevalent form of liver cancer that occurs two to four times more frequently in males than in females. The most prominent factors associated with HCC include chronic hepatitis B and C viral infection and other chronic necroinflammatory liver diseases, such as those caused by alcohol consumption or hepatic metabolic disorders. Chronic liver disease leads to continual injury and a wound-healing response that causes a torrent of problems, including advanced hepatic fibrosis or cirrhosis. A high level of plasmatic endotoxin or lipopolysaccharide (LPS), a cell-wall component of Gram-negative bacteria, is a common finding in the portal and systemic circulation of cirrhotic patients. This accumulation is likely due to changes in the intestinal mucosal permeability and increased bacterial translocation, coupled with a deficient clarification activity of the hepatic reticuloendothelial system. High levels of endotoxin may be responsible for the pathogenesis of the chronic inflammatory alterations that characterize cirrhosis and, hence, the major complications that arise in this disease.
Toll-like receptor 4 (TLR4) is a pattern recognition receptor that recognizes endotoxin and signals through adaptor molecules myeloid differentiation factor 88 (MyD88) and Toll/IL-1 receptor domain-containing adaptor-inducing interferon-β(TRIF) to activate transcription factors nuclear factor NF-κB, activator protein 1 (AP-1), and interferon regulatory factors (IRFs), that initiate innate immunity. The liver is well equipped to respond to endotoxin because TLR4 is present on both parenchymal cells (hepatocytes) and nonparenchymal cells, which include Kupffer cells, sinusoidal endothelial cells, stellate cells, and hepatic dendritic cells. Both cell populations possess intact TLR4 signaling pathways. Kupffer cells are the best-characterized target of endotoxin in the liver, where they have a crucial role in causing hepatocellular damage by producing pro-inflammatory cytokines (e.g., TNF-a and IL-6) and affect hepatic sinusoids to increase vascular permeability. Although hepatocytes also express low levels of the TLR4 receptor, they are only weakly responsive to LPS and may serve to uptake and remove endotoxin from the portal and systemic circulation. However, the effects of endotoxin in vivo on hepatic function and tumorigenesis are not well defined.
A causal link between inflammation and cancer is widely accepted. Robust clinical and epidemiologic data support the role of inflammation, induced by chronic hepatitis B or C viral infections and alcohol abuse, as a key player in HCC development. However, the exact molecular mechanisms and gatekeepers accounting for cellular transformation remain elusive. Given the important role of NF-κB signaling in mediating inflammatory signals, attention has been focused on its role in mediating the link between inflammation and the development of liver tumors. Inhibiting NF-κB obstructs later stages of tumor progression in Mdr2-deficient mice, which develop HCC in the context of chronic bile duct inflammation. By contrast, mice lacking the NF-κB upstream activator IκB kinaseβ(IKKβ) specifically in hepatocytes exhibit a marked increase in chemically induced hepatocarcinogenesis, suggesting that NF-κB has a protective function against HCC development. Interestingly, compared with the deletion of IKKβonly in hepatocytes, the additional deletion in Kupffer cells results in a remarkable decrease in tumor load. These apparently contradictory conclusions may reflect the distinct roles for inflammatory signals in epithelial cells and inflammatory cells during HCC formation.
Here we found that the circulating levels of LPS were elevated in experimental models of carcinogen-induced hepatocarcinogenesis. Reduction of LPS using antibiotics regimen in rats or genetic ablation of its receptor TLR4 in mice prevented excessive tumor growth and multiplicity. Additional investigation revealed that TLR4 ablation sensitizes the liver to carcinogen-induced toxicity via blocking NF-κB activation and sensitizing the liver to reactive oxygen species (ROS)-induced liver injury, but lessens inflammation-mediated compensatory proliferation. Reconstitution of TLR4-expressing myeloid cells in TLR4-deficient mice restored DEN-induced hepatic inflammation and proliferation, indicating a paracrine mechanism of LPS in tumor promotion. By contrast, disruption of the mucosal barrier allowing microbial translocation or in vivo LPS pre-challenge protects hepatocytes against carcinogen or death-receptor-induced liver injury. The survival effects of LPS on normal or malignant hepatocytes are largely mediated by the transcription factor NF-κB, whose inactivation reversed the LPS-mediated hepatic protection. Thus, sustained LPS accumulation represents a pathological mediator of inflammation-associated hepatocellular carcinoma (HCC) and manipulation of the gut flora to prevent pathogenic bacterial translocation and endotoxin absorption may favorably influence liver function in cirrhotic patients who are at risk of developing HCC.
【研究背景及目的】
原发性肝癌是世界范围内发病率较高的恶性肿瘤之一,在我国是导致居民肿瘤死亡原因的第二位。原发性肝癌的发生被认为是一个多因素,多途径,和长期作用的结果,其病理学基础是各种致癌因素引起的肝脏慢性炎症与肝硬化。我国大多数的肝癌病人存在程度不同的肝硬化。
由于解剖学上的联系,肝脏处于防御肠源性细菌产物的第一线,并且是它们主要的过滤器官。当肝脏的功能受损时,肠源性细菌产物就可能通过门静脉或其侧支循环进入血液形成内毒素血症。已有文献报道,在多种肝脏疾病,如病毒性肝炎,肝硬化,肝癌和酒精性肝病中的病人中大部分存在肠道菌群的移位和肠源性内毒素血症,在动物实验中也证实肠源性内毒素在肝纤维化和酒精性肝病的发生发展中起重要作用。内毒素是强有力的致炎因子,可以引起肝内多种炎性因子的分泌,如TNFα, IL-6, TGFβ, IL-1α等的释放,而这些炎症因子导致了肝脏病变的发生发展。但现在不清楚肠道来源的LPS是如何促进肝脏肿瘤的发生发展。
内毒素(LPS)通过其受体Toll样受体4(TLR4)起作用。TLR4与LPS结合后,通过MyD88通路和TRIF通路向下游传递信号,前者可引起多种炎性介质的释放,后者则可引起Ⅰ型和Ⅱ型干扰素的释放。在肝细胞,枯否氏细胞(KC)、星状细胞、胆管上皮细胞、内皮细胞和树突状细胞都表达TLR4,这都提示TLR4可能在肝脏疾病的发生中起重要作用。研究也证实,在酒精性肝损伤,肝纤维化,缺血再灌注损伤,肝部分切除后的肝再生以及肝的自身免疫性疾病中,TLR4信号通路的参与必不可少。到目前为止,TLR4在肝癌发生中的作用还未见报道,但可以推测TLR4在肝癌的发生中可能有重要作用。
本项目拟应用大鼠的DEN模型研究肠源性内毒素在肝炎—肝硬化—肝癌这一过程中所起的作用,同时建立TLR4敲除的小鼠DEN模型,采用分子生物学和细胞学的方法探讨LPS发挥作用的机制,为肝癌的防治提供有潜在临床价值的实验数据。【实验方法】
1.建立DEN诱导的大鼠肝癌模型,利用抗生素清除肠源性内毒素,比较抗生素处理组和未处理组DEN引起的肝癌负荷。
2.建立小鼠DEN诱导的肝癌模型。比较LPS受体Toll样受体4(TLR4)敲除小鼠和对照小鼠的DEN引起的肿瘤负荷。
3.建立DEN引起的肝脏急性损伤模型,比较TLR4-/-小鼠和野生型小鼠DEN引起的肝脏损伤、凋亡以及代偿性增殖情况。利用Real-time PCR方法检测TLR4-/-小鼠和野生型小鼠肝脏中细胞因子TNFa和IL-6的表达水平,以及DEN代谢酶、p53相关基因的表达变化。
4.利用骨髓移植实验研究表达在实质细胞和非实质细胞上的TLR4在DEN诱导的肝损伤以及肝细胞代偿性增殖中的作用。
5.用免疫组化方法检测DEN在TLR4-/-小鼠和野生型小鼠肝脏中引起的NF-κB的活化情况；利用Real-time PCR方法检测NF-κB下游基因的表达情况；检测DEN引起的肝脏内ROS的含量。
6.用LPS预处理小鼠,研究LPS对DEN引起肝脏损伤的作用；
7.利用TNF/GalN以及Jo-2引起的暴发性肝炎模型研究LPS在肝细胞凋亡中的保护作用。
8.体外分离小鼠的原代肝细胞,用TNF/CHX诱导细胞凋亡,研究LPS保护肝细胞凋亡的机制。
【实验结果】
1.在DEN诱导的大鼠肝癌模型中存在血浆LPS水平的升高。在大鼠DEN模型中利用抗生素清除LPS可明显减少肝脏肿瘤的发生发展。
2.小鼠中TLR4缺失明显减少DEN诱导的肝脏肿瘤的发生,肿瘤中浸润的巨噬细胞明显减少,TNFa和IL-6的含量也明显减少。
3.TLR4缺失加重DEN诱导的肝损伤,但减轻DEN诱导的肝细胞的代偿性增殖。
4.TLR4-/-小鼠DEN引起的TNFα和IL-6表达低于野生型小鼠。骨髓来源细胞上TLR4的活化可引起TNFa和IL-6表达,从而促进肝细胞的代偿性增殖。
5.TLR4缺失可减少肝细胞内NFκB活化,使NF-κB下游抗凋亡基因Bcl-xl和A20的表达减少,清除活性氧族(ROS)的酶MnSOD的表达减少,肝内GSH减少,MDA增加,故TLR4-/-小鼠肝损伤加重。
6.DEN可引起小鼠血液中LPS水平的升高。LPS处理可减少DEN诱导的细胞凋亡。
7.LPS处理野生型小鼠可抵抗死亡受体配体引起的急性肝损伤,但对TLR4-/-小鼠无保护作用。
8.LPS预处理肝细胞产生的抗凋亡效应是NF-κB介导的。
【结论】
本研究从细胞和动物学水平证明肠源性LPS在炎症性肝细胞癌的发生发展中起重要作用。LPS通过与其受体TLR4结合,在炎症细胞中可引起多种炎症因子的分泌,促进细胞的增殖,在实质细胞中可通过活化NF-κB引起多种抗凋亡蛋白的表达从而抑制细胞凋亡。抑制肠道细菌的异常转位以及清除LPS可能会有效改善肝硬化病人的肝功能,从而减少肿瘤的发生发展。
Hepatocellular carcinoma (HCC) is a prevalent form of liver cancer that occurs two to four times more frequently in males than in females. The most prominent factors associated with HCC include chronic hepatitis B and C viral infection and other chronic necroinflammatory liver diseases, such as those caused by alcohol consumption or hepatic metabolic disorders. Chronic liver disease leads to continual injury and a wound-healing response that causes a torrent of problems, including advanced hepatic fibrosis or cirrhosis. A high level of plasmatic endotoxin or lipopolysaccharide (LPS), a cell-wall component of Gram-negative bacteria, is a common finding in the portal and systemic circulation of cirrhotic patients. This accumulation is likely due to changes in the intestinal mucosal permeability and increased bacterial translocation, coupled with a deficient clarification activity of the hepatic reticuloendothelial system. High levels of endotoxin may be responsible for the pathogenesis of the chronic inflammatory alterations that characterize cirrhosis and, hence, the major complications that arise in this disease.
Toll-like receptor 4 (TLR4) is a pattern recognition receptor that recognizes endotoxin and signals through adaptor molecules myeloid differentiation factor 88 (MyD88) and Toll/IL-1 receptor domain-containing adaptor-inducing interferon-β(TRIF) to activate transcription factors nuclear factor NF-κB, activator protein 1 (AP-1), and interferon regulatory factors (IRFs), that initiate innate immunity. The liver is well equipped to respond to endotoxin because TLR4 is present on both parenchymal cells (hepatocytes) and nonparenchymal cells, which include Kupffer cells, sinusoidal endothelial cells, stellate cells, and hepatic dendritic cells. Both cell populations possess intact TLR4 signaling pathways. Kupffer cells are the best-characterized target of endotoxin in the liver, where they have a crucial role in causing hepatocellular damage by producing pro-inflammatory cytokines (e.g., TNF-a and IL-6) and affect hepatic sinusoids to increase vascular permeability. Although hepatocytes also express low levels of the TLR4 receptor, they are only weakly responsive to LPS and may serve to uptake and remove endotoxin from the portal and systemic circulation. However, the effects of endotoxin in vivo on hepatic function and tumorigenesis are not well defined.
A causal link between inflammation and cancer is widely accepted. Robust clinical and epidemiologic data support the role of inflammation, induced by chronic hepatitis B or C viral infections and alcohol abuse, as a key player in HCC development. However, the exact molecular mechanisms and gatekeepers accounting for cellular transformation remain elusive. Given the important role of NF-κB signaling in mediating inflammatory signals, attention has been focused on its role in mediating the link between inflammation and the development of liver tumors. Inhibiting NF-κB obstructs later stages of tumor progression in Mdr2-deficient mice, which develop HCC in the context of chronic bile duct inflammation. By contrast, mice lacking the NF-κB upstream activator IκB kinaseβ(IKKβ) specifically in hepatocytes exhibit a marked increase in chemically induced hepatocarcinogenesis, suggesting that NF-κB has a protective function against HCC development. Interestingly, compared with the deletion of IKKβonly in hepatocytes, the additional deletion in Kupffer cells results in a remarkable decrease in tumor load. These apparently contradictory conclusions may reflect the distinct roles for inflammatory signals in epithelial cells and inflammatory cells during HCC formation.
Here we found that the circulating levels of LPS were elevated in experimental models of carcinogen-induced hepatocarcinogenesis. Reduction of LPS using antibiotics regimen in rats or genetic ablation of its receptor TLR4 in mice prevented excessive tumor growth and multiplicity. Additional investigation revealed that TLR4 ablation sensitizes the liver to carcinogen-induced toxicity via blocking NF-κB activation and sensitizing the liver to reactive oxygen species (ROS)-induced liver injury, but lessens inflammation-mediated compensatory proliferation. Reconstitution of TLR4-expressing myeloid cells in TLR4-deficient mice restored DEN-induced hepatic inflammation and proliferation, indicating a paracrine mechanism of LPS in tumor promotion. By contrast, disruption of the mucosal barrier allowing microbial translocation or in vivo LPS pre-challenge protects hepatocytes against carcinogen or death-receptor-induced liver injury. The survival effects of LPS on normal or malignant hepatocytes are largely mediated by the transcription factor NF-κB, whose inactivation reversed the LPS-mediated hepatic protection. Thus, sustained LPS accumulation represents a pathological mediator of inflammation-associated hepatocellular carcinoma (HCC) and manipulation of the gut flora to prevent pathogenic bacterial translocation and endotoxin absorption may favorably influence liver function in cirrhotic patients who are at risk of developing HCC.
引文
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