TLR4与NF-κB在非小细胞肺癌组织中的表达及临床意义
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摘要
研究背景:
肺癌是目前人类最为常见的恶性肿瘤之一,进展迅速,预后差,已严重威胁到人类的健康。近半个世纪以来肺癌发病率和死亡率一直呈明显上升趋势,在工业发达的国家更为明显,且城市高于农村。在我国多数大城市中肺癌发病率和死亡率也居恶性肿瘤的第一位和第二位。目前,诸多学者对肺癌的生物学行为进行了广泛的研究,但其发病机制仍不十分清楚。近年来,炎症对肿瘤生长关系的影响受到了很多的关注,越来越多的证据表明,在促进肿瘤的发生和演进中,慢性感染和炎症被认为是最重要的后天性和环境因素,而其中Toll样受体(Toll-like receptors, TLRs)介导的信号传导通路可能起到重要作用,如TLRs表达的上调与胃癌、肠癌、乳腺癌等发生、发展有密切关系。肺癌是一种和环境暴露密切相关的疾病,肺部的异常炎性反应可能与肺癌的发生有一定的关联。
Toll样受体4(Toll-like receptor 4, TLR4)是发现最早的TLRs家族的重要成员之一,在天然免疫中发挥着重要作用。核因子-κB(nuclear factor-kappaB, NF-κB)是广泛存在于哺乳动物细胞中的一种重要转录调控因子,能与多种基因启动子中含有的κB序列结合,发挥转录因子作用,激活多种与细胞生长或凋亡相关的细胞因子转录。同TLRs家族的其它成员一样,TLR4活化的信号传导属于经典的Toll样信号通路,可以启动NF-κB途径和应激激酶途径(stress kinase pathway),最终导致炎症反应。TLR4是目前发现与肿瘤发病关系最密切的TLRs家族成员之一,而已有多项研究表明NF-κB可能参与肿瘤的发生、发展和转移,但二者在非小细胞肺癌(non-small cell lung cancer, NSCLC)组织中是否表达和具有相关性,及其在肺癌的发病中是否起作用尚有待研究。
研究目的:
从蛋白水平研究TLR4与NF-κB在NSCLC组织和正常肺组织中的表达情况,分析二者与肺癌病理分型、临床分期、淋巴结转移和肿瘤细胞分化程度等临床病理资料的相关性以及TLR4与NF-κB之间的相关性,探讨其与肺癌的发生、发展及临床特征之间的关系。
研究方法:
本研究采用免疫组化方法检测TLR4与NF-κB在49例非小细胞肺癌组织和20例癌旁正常肺组织(均为手术切除存档蜡块)中的表达情况。所有标本均经病理证实为肺癌或正常肺组织。
结果:
TLR4和NF-κB在NSCLC组织中的表达阳性率分别为57.1%(28/49)和69.4%(34/49),均显著高于正常肺组织中的15%(3/20)和10%(2/20)(P<0.05)。NSCLC组织中TLR4与NF-κB蛋白的表达与患者的年龄、性别、吸烟、TNM分期、淋巴结转移均无明显关系(P>0.05)。但其中TLR4的表达与肿瘤的分化程度有关(P<0.05),NF-κB在腺癌中的表达明显高于鳞癌(P<0.05),且TLR4和NF-κB之间的表达呈正相关(P<0.05)。
结论:
TLR4和NF-κB在NSCLC组织中的表达明显高于癌旁正常肺组织,且TLR4和NF-κB间的表达密切相关,TLR4的表达与肿瘤的分化程度有关,分化程度越低,TLR4表达就越高,NF-κB在腺癌中的表达明显高于鳞癌,提示二者可能参与NSCLC的发生、发展过程,通过TLR4激活NF-κB通路可能在NSCLC的发生发展过程中起到重要作用,且TLR4和NF-κB与肿瘤的恶性度有一定的关系,这将为肺癌发病机制的研究提供新的思路。
Background:
Lung cancer, the most common human malignancy with a rapid growth, has been a serious threat to human health. Nearly half a century of lung cancer incidence and mortality rates has clear ascendant trend in developed countries, and the city is more obvious than in rural areas. In most large cities the incidence and mortality rates of lung cancer occupies the first or second position in malignant tumors. At present, many scholars for lung cancer biology conduct extensive research, but its pathogenesis is still unclear. In recent years, the inflammation of the effect of tumor growth has gained a lot of attention, at present more and more evidence proves that, in promoting tumors development and evolution, chronic infection and inflammation is thought to be the most important posteriority and environmental factor, and toll-like receptors mediated signaling pathways may play an important role. For instance, the up-regulation expression of toll-like receptors have a close relationship with gastric carcinoma, breast carcinoma and bowel cancer’s growth and metastasis. Lung cancer is closely related to a kind of environmental exposure, and lung abnormal inflammatory has some relations with such disease.
Toll-like receptor4, one of the important TLRs family members, plays an important role in natural immune systems. Nuclear factor-kappaB, widely existing in mammalian cells, is a kind of important transcription regulation factor, performs function of transcription factor, and activates transcription of cytokines associated with cells growth or apoptosis. TLR4-activating signaling pathway, like other members of TLRs, belongs to typical TLRs signaling pathway, can start NF-κB pathway and stress kinase pathway, then ultimately leads to inflammatory response. TLR4 is now found most associated with cancer incidence in TLRs family members, and many studies also show that NF-κB may participate in tumors development and metastasis. But it is needed to be studied whether both are expressed in non-small cell lung cancer tissue, their relevance, and whether they have relationship in the pathogenesis of lung cancer.
Objective:
This study was designed to investigate the protein expression of Toll-like receptor 4(TLR4) and nuclear factor-kappaB (NF-κB) in human normal lung tissues and non-small cell lung cancer (NSCLC) tissues, and analyse the relationship of TLR4 and NF-κB with various clinicopathological such as tumor's histological type, TNM stage, lymph node metastasis and toumor's differentiation degree. To explore the relationship between expression of TLR4 and NF-κB and oncogenesis development and clinical characteristic of lung cancer.
Methods:
In this study, Immunohistochemical SP methods were used to investigate the expression of TLR4 and NF-κB in 49 cases of NSCLC and 20 cases of paracancerous normal lung tissues. All the cases were used for routine histopathological diagnosis.
Results:
The positive rates of TLR4 and NF-κB protein were found 57.1%(28/49) and 69.4%(34/49) in NSCLC tissues, significantly higher than 15%(3/20) and 10%(2/20) in 20 cases of paracancerous normal lung tissues (P<0.05). The expression of TLR4 and NF-κB in NSCLC tissues was no relationship with patient's age, gender, smoking, TNM stage and lymph node metastasis (P>0.05). But TLR4 expression had a close relationship with tumor's differentiation degree of NSCLC (P<0.05). The expression of NF-κB in adenocarcinoma was stronger than in Squamous cell carcinoma (P<0.05). The expression of TLR4 was positively correlated with the expression of NF-κB (P<0.05).
Conclusions:
Abnormality great expression of TLR4 and NF-κB in NSCLC tissues and the expression of TLR4 was positively correlated with the expression of NF-κB, the expression of TLR4 are associated with with tumor's differentiation degree, the more malignancy, and the more expression of TLR4, the expression of NF-κB in adenocarcinoma was stronger than in Squamous cell carcinoma. All these may hint that TLR4 and NF-κB may play an important role in the progression and development of NSCLC,which may provid a new pathway for research pathogenesy of lung cancer.
肺癌是目前人类最为常见的恶性肿瘤之一,进展迅速,预后差,已严重威胁到人类的健康。近半个世纪以来肺癌发病率和死亡率一直呈明显上升趋势,在工业发达的国家更为明显,且城市高于农村。在我国多数大城市中肺癌发病率和死亡率也居恶性肿瘤的第一位和第二位。目前,诸多学者对肺癌的生物学行为进行了广泛的研究,但其发病机制仍不十分清楚。近年来,炎症对肿瘤生长关系的影响受到了很多的关注,越来越多的证据表明,在促进肿瘤的发生和演进中,慢性感染和炎症被认为是最重要的后天性和环境因素,而其中Toll样受体(Toll-like receptors, TLRs)介导的信号传导通路可能起到重要作用,如TLRs表达的上调与胃癌、肠癌、乳腺癌等发生、发展有密切关系。肺癌是一种和环境暴露密切相关的疾病,肺部的异常炎性反应可能与肺癌的发生有一定的关联。
Toll样受体4(Toll-like receptor 4, TLR4)是发现最早的TLRs家族的重要成员之一,在天然免疫中发挥着重要作用。核因子-κB(nuclear factor-kappaB, NF-κB)是广泛存在于哺乳动物细胞中的一种重要转录调控因子,能与多种基因启动子中含有的κB序列结合,发挥转录因子作用,激活多种与细胞生长或凋亡相关的细胞因子转录。同TLRs家族的其它成员一样,TLR4活化的信号传导属于经典的Toll样信号通路,可以启动NF-κB途径和应激激酶途径(stress kinase pathway),最终导致炎症反应。TLR4是目前发现与肿瘤发病关系最密切的TLRs家族成员之一,而已有多项研究表明NF-κB可能参与肿瘤的发生、发展和转移,但二者在非小细胞肺癌(non-small cell lung cancer, NSCLC)组织中是否表达和具有相关性,及其在肺癌的发病中是否起作用尚有待研究。
研究目的:
从蛋白水平研究TLR4与NF-κB在NSCLC组织和正常肺组织中的表达情况,分析二者与肺癌病理分型、临床分期、淋巴结转移和肿瘤细胞分化程度等临床病理资料的相关性以及TLR4与NF-κB之间的相关性,探讨其与肺癌的发生、发展及临床特征之间的关系。
研究方法:
本研究采用免疫组化方法检测TLR4与NF-κB在49例非小细胞肺癌组织和20例癌旁正常肺组织(均为手术切除存档蜡块)中的表达情况。所有标本均经病理证实为肺癌或正常肺组织。
结果:
TLR4和NF-κB在NSCLC组织中的表达阳性率分别为57.1%(28/49)和69.4%(34/49),均显著高于正常肺组织中的15%(3/20)和10%(2/20)(P<0.05)。NSCLC组织中TLR4与NF-κB蛋白的表达与患者的年龄、性别、吸烟、TNM分期、淋巴结转移均无明显关系(P>0.05)。但其中TLR4的表达与肿瘤的分化程度有关(P<0.05),NF-κB在腺癌中的表达明显高于鳞癌(P<0.05),且TLR4和NF-κB之间的表达呈正相关(P<0.05)。
结论:
TLR4和NF-κB在NSCLC组织中的表达明显高于癌旁正常肺组织,且TLR4和NF-κB间的表达密切相关,TLR4的表达与肿瘤的分化程度有关,分化程度越低,TLR4表达就越高,NF-κB在腺癌中的表达明显高于鳞癌,提示二者可能参与NSCLC的发生、发展过程,通过TLR4激活NF-κB通路可能在NSCLC的发生发展过程中起到重要作用,且TLR4和NF-κB与肿瘤的恶性度有一定的关系,这将为肺癌发病机制的研究提供新的思路。
Background:
Lung cancer, the most common human malignancy with a rapid growth, has been a serious threat to human health. Nearly half a century of lung cancer incidence and mortality rates has clear ascendant trend in developed countries, and the city is more obvious than in rural areas. In most large cities the incidence and mortality rates of lung cancer occupies the first or second position in malignant tumors. At present, many scholars for lung cancer biology conduct extensive research, but its pathogenesis is still unclear. In recent years, the inflammation of the effect of tumor growth has gained a lot of attention, at present more and more evidence proves that, in promoting tumors development and evolution, chronic infection and inflammation is thought to be the most important posteriority and environmental factor, and toll-like receptors mediated signaling pathways may play an important role. For instance, the up-regulation expression of toll-like receptors have a close relationship with gastric carcinoma, breast carcinoma and bowel cancer’s growth and metastasis. Lung cancer is closely related to a kind of environmental exposure, and lung abnormal inflammatory has some relations with such disease.
Toll-like receptor4, one of the important TLRs family members, plays an important role in natural immune systems. Nuclear factor-kappaB, widely existing in mammalian cells, is a kind of important transcription regulation factor, performs function of transcription factor, and activates transcription of cytokines associated with cells growth or apoptosis. TLR4-activating signaling pathway, like other members of TLRs, belongs to typical TLRs signaling pathway, can start NF-κB pathway and stress kinase pathway, then ultimately leads to inflammatory response. TLR4 is now found most associated with cancer incidence in TLRs family members, and many studies also show that NF-κB may participate in tumors development and metastasis. But it is needed to be studied whether both are expressed in non-small cell lung cancer tissue, their relevance, and whether they have relationship in the pathogenesis of lung cancer.
Objective:
This study was designed to investigate the protein expression of Toll-like receptor 4(TLR4) and nuclear factor-kappaB (NF-κB) in human normal lung tissues and non-small cell lung cancer (NSCLC) tissues, and analyse the relationship of TLR4 and NF-κB with various clinicopathological such as tumor's histological type, TNM stage, lymph node metastasis and toumor's differentiation degree. To explore the relationship between expression of TLR4 and NF-κB and oncogenesis development and clinical characteristic of lung cancer.
Methods:
In this study, Immunohistochemical SP methods were used to investigate the expression of TLR4 and NF-κB in 49 cases of NSCLC and 20 cases of paracancerous normal lung tissues. All the cases were used for routine histopathological diagnosis.
Results:
The positive rates of TLR4 and NF-κB protein were found 57.1%(28/49) and 69.4%(34/49) in NSCLC tissues, significantly higher than 15%(3/20) and 10%(2/20) in 20 cases of paracancerous normal lung tissues (P<0.05). The expression of TLR4 and NF-κB in NSCLC tissues was no relationship with patient's age, gender, smoking, TNM stage and lymph node metastasis (P>0.05). But TLR4 expression had a close relationship with tumor's differentiation degree of NSCLC (P<0.05). The expression of NF-κB in adenocarcinoma was stronger than in Squamous cell carcinoma (P<0.05). The expression of TLR4 was positively correlated with the expression of NF-κB (P<0.05).
Conclusions:
Abnormality great expression of TLR4 and NF-κB in NSCLC tissues and the expression of TLR4 was positively correlated with the expression of NF-κB, the expression of TLR4 are associated with with tumor's differentiation degree, the more malignancy, and the more expression of TLR4, the expression of NF-κB in adenocarcinoma was stronger than in Squamous cell carcinoma. All these may hint that TLR4 and NF-κB may play an important role in the progression and development of NSCLC,which may provid a new pathway for research pathogenesy of lung cancer.
引文
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4 Schmausser B, Andrulis M, Endrich S, et al. Toll-like receptors TLR4, TLR5 and TLR9 on gastric carcinoma cells: an implication for interaction with Helicobacter pylori[J]. Int J Med Microbiol, 2005, 295(3): 179-185.
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28 Ren T, Wen ZK, Liu ZM, et a1. Functional expression of TLR9 is associated to the metastatic potential of human lung cancer cell: functional active role of TLR9 on tumor metastasis [J]. Cancer Biol Ther, 2007, 6(11): 1704-9.
29 Merrell MA, Ilvesaro JM, Lehtonen N, et al. Toll-like receptor 9 agonists promote cellular invasion by increasing matrix metalloproteinase activity [J]. Mol Cancer Res, 2006, 4(7): 437-447.
30 Ilvesaro J M, Merrell M A, Swain T M, et a1. Toll like receptor-9 agonists stimulate prostate cancer invasion in vitro [J]. Prostate, 2007, 67(7): 774-781.
31 Ren T, Xu L, Jiao S, et a1. TLR9 Signaling Promotes Tumor Progression of Human Lung Cancer Cell In Vivo [J]. Pathol Oncol Res, 2009, Mar 25.
32 Kelly MG, Alvero AB, Chen R, et al. TLR-4 signaling promotes tumor growth and paclitaxel chemoresistance in ovarian cancer[J]. Cancer Res, 2006, 66(7): 3859-3868.
33 Beachy PA, Karhadkar SS, Berman DM. Mending and malignancy[J]. Nature, 2004, 431(7007): 402.
34 Balkwill F, Coussens LM. Cancer: an inflammatory link[J]. Nature, 2004, 431(7007): 405–406.
35 Baniyssh M. TCR chain downregulation: curtaining excessive inflammatory immune response[J]. Nat Rev lmmunol, 2004, 4(9): 675-687.
36 Inoue J, Gohda J, Akiyama T, Semba K. NF-κB activation in development and progression of cancer[J]. Cancer Sci, 2007, 98 (3): 268–274.
37 Chen R, Alvero AB, Silasi DA, Mor G. Inflammation, cancer and chemoresistance: taking advantage of the toll-like receptor signaling pathway[J]. Am J Reprod Immunol, 2007, 57(2): 93-107.
38 Huang B, Zhao J, Shen S, et a1. Listeria monocytogenes promotes tumor growth via tumor cell toll-like receptor 2 signaling[J]. Cancer Res, 2007, 67(9):4346-4352.
39 Pikarsky E, Porat RM, Stein I, et al. NF-kappaB functions as a tumour promoter in inflammation-associated cancer[J]. Nature, 2004, 23, 431(7007): 461-466.
40 Chang YJ, Wu MS, Lin JT, et al. Induction of cyclooxygenase-2 overexpression in human gastric epithelial cells by Helicobacter pylori involves TLR2/TLR9 and c-Src-dependent nuclear factor-kappaB activation [J]. Mol Pharmacol, 2004, 66(6): 1465-77.
41 Ikebe M, Kitaura Y, Nakamura M, et al. Lipopolysaccharide (LPS) increases the invasive ability of pancreatic cancer cells through the TLR4/MyD88 signaling pathway[J]. J Surg Oncol, 2009 , 100(8): 725-731.
42 Killeen SD, Wang JH, Andrews EJ, et al. Bacterial endotoxin enhances colorectal cancer cell adhesion and invasion through TLR4 and NF-kappaB-dependent activation of the urokinase plasminogen activator system[J]. Br J Cancer, 2009 , 100(10): 1589-602.
43 Luo JL, Maeda S, Hsu LC, et al. Inhibition of NF-κB in cancer cells converts inflammation- induced tumor growth mediated by TNFαto TRAIL-mediated tumor regression[J]. Cancer Cell, 2004, 6(3): 297-305.
44 Szajnik M, Szczepanski MJ, Czystowska M, et al. TLR4 signaling induced by lipopolysaccharide or paclitaxel regulates tumor survival and chemoresistance in ovarian cancer[J]. Oncogene, 2009, 28(49): 4353-4363.
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3 He W, Liu Q, Wang L, et al. TLR4 signaling promotes immune escape of human lung cancer cells by inducing immunosuppressive cytokines and apoptosis resistance[J]. Mol Immunol, 2007, 44 (11): 2850–2859.
4 Schmausser B, Andrulis M, Endrich S, et al. Toll-like receptors TLR4, TLR5 and TLR9 on gastric carcinoma cells: an implication for interaction with Helicobacter pylori[J]. Int J Med Microbiol, 2005, 295(3): 179-185.
5 Bohnhorst J, Rasmussen T, Moen SH, et al. Toll-like receptors mediate proliferation and survival of multiple myeloma cells[J]. Leukemia, 2006, 20(6): 1138-1144.
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27 Jego G, Bataille R, Geffroy-Luscau A, et a1. Pathogen-associated molecular patterns are growth and survival factors for human myeloma cells through Toll-like receptors [J]. Leukemia, 2006, 20(6): 1130.
28 Ren T, Wen ZK, Liu ZM, et a1. Functional expression of TLR9 is associated to the metastatic potential of human lung cancer cell: functional active role of TLR9 on tumor metastasis [J]. Cancer Biol Ther, 2007, 6(11): 1704-9.
29 Merrell MA, Ilvesaro JM, Lehtonen N, et al. Toll-like receptor 9 agonists promote cellular invasion by increasing matrix metalloproteinase activity [J]. Mol Cancer Res, 2006, 4(7): 437-447.
30 Ilvesaro J M, Merrell M A, Swain T M, et a1. Toll like receptor-9 agonists stimulate prostate cancer invasion in vitro [J]. Prostate, 2007, 67(7): 774-781.
31 Ren T, Xu L, Jiao S, et a1. TLR9 Signaling Promotes Tumor Progression of Human Lung Cancer Cell In Vivo [J]. Pathol Oncol Res, 2009, Mar 25.
32 Kelly MG, Alvero AB, Chen R, et al. TLR-4 signaling promotes tumor growth and paclitaxel chemoresistance in ovarian cancer[J]. Cancer Res, 2006, 66(7): 3859-3868.
33 Beachy PA, Karhadkar SS, Berman DM. Mending and malignancy[J]. Nature, 2004, 431(7007): 402.
34 Balkwill F, Coussens LM. Cancer: an inflammatory link[J]. Nature, 2004, 431(7007): 405–406.
35 Baniyssh M. TCR chain downregulation: curtaining excessive inflammatory immune response[J]. Nat Rev lmmunol, 2004, 4(9): 675-687.
36 Inoue J, Gohda J, Akiyama T, Semba K. NF-κB activation in development and progression of cancer[J]. Cancer Sci, 2007, 98 (3): 268–274.
37 Chen R, Alvero AB, Silasi DA, Mor G. Inflammation, cancer and chemoresistance: taking advantage of the toll-like receptor signaling pathway[J]. Am J Reprod Immunol, 2007, 57(2): 93-107.
38 Huang B, Zhao J, Shen S, et a1. Listeria monocytogenes promotes tumor growth via tumor cell toll-like receptor 2 signaling[J]. Cancer Res, 2007, 67(9):4346-4352.
39 Pikarsky E, Porat RM, Stein I, et al. NF-kappaB functions as a tumour promoter in inflammation-associated cancer[J]. Nature, 2004, 23, 431(7007): 461-466.
40 Chang YJ, Wu MS, Lin JT, et al. Induction of cyclooxygenase-2 overexpression in human gastric epithelial cells by Helicobacter pylori involves TLR2/TLR9 and c-Src-dependent nuclear factor-kappaB activation [J]. Mol Pharmacol, 2004, 66(6): 1465-77.
41 Ikebe M, Kitaura Y, Nakamura M, et al. Lipopolysaccharide (LPS) increases the invasive ability of pancreatic cancer cells through the TLR4/MyD88 signaling pathway[J]. J Surg Oncol, 2009 , 100(8): 725-731.
42 Killeen SD, Wang JH, Andrews EJ, et al. Bacterial endotoxin enhances colorectal cancer cell adhesion and invasion through TLR4 and NF-kappaB-dependent activation of the urokinase plasminogen activator system[J]. Br J Cancer, 2009 , 100(10): 1589-602.
43 Luo JL, Maeda S, Hsu LC, et al. Inhibition of NF-κB in cancer cells converts inflammation- induced tumor growth mediated by TNFαto TRAIL-mediated tumor regression[J]. Cancer Cell, 2004, 6(3): 297-305.
44 Szajnik M, Szczepanski MJ, Czystowska M, et al. TLR4 signaling induced by lipopolysaccharide or paclitaxel regulates tumor survival and chemoresistance in ovarian cancer[J]. Oncogene, 2009, 28(49): 4353-4363.