趋化作用的细胞因子受体在肝癌细胞中的表达及其作用机制
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摘要
背景与目的：原发性肝癌是世界上第六位致死性肿瘤,在中国居第二位。在中国,肝细胞癌的发生与乙肝病毒感染等密切相关。由于肝癌临床症状的非特异性,多数患者发现时已失去了最佳的手术机会。非外科治疗如经动脉化疗栓塞(TACE)、射频消融(RFA)、经皮酒精注射(PEI)等治疗作用仍然有限。许多患者最终死于
术后复发和转移。生物治疗(包括基因治疗)为肝癌转移治疗提供了新的方向。然而,肝癌侵袭和转移是个多步骤多基因的过程,涉及肝癌细胞的生物学特性,肿瘤局部微环境如基质金属蛋白酶,整合素,基质细胞和血管等,以及局部和系统免疫。趋化作用的细胞因子和趋化作用的细胞因子受体是免疫细胞归巢和定向趋化的关键分子。目前为止,功能明确的有50多个趋化作用的细胞因子和18个趋化作用的细胞因子受体。还有一些趋化作用的细胞因子及受体在功能上不是很明确。2001年,Mullar首次报道趋化作用的细胞因子受体在乳腺癌细胞表达并与肿瘤细胞转移相关,尤其是CXCR4与肺转移,CCR7与淋巴结转移密切相关。现在,越来越多.的研究表明趋化作用的细胞因子受体可以在肿瘤细胞上功能表达,尤其是具有高转移性的肿瘤细胞。
本文致力于发现与肝癌的侵袭转移与趋化作用的细胞因子受体的关系。了解趋化作用的细胞因子的受体(CCR1 CCR7 CXCR3 CXCR4)在人肝癌细胞系(Hep3BHepG2HLE和HLF)的表达情况,并探讨其作用机制。
方法：采用逆转录-聚合酶链反应(RT-PCR)细胞免疫组化流式细胞仪,Western blot测定趋化作用的细胞因子的受体在肝癌细胞表面的表达情况,通过肝癌细胞Hep3B体外侵袭实验即重组大鼠巨噬细胞激动蛋白-1 (CCL3)对Hep3B细胞穿透人工重组基底膜能力的影响来检测趋化作用的细胞因子的受体在肝癌侵袭转移时所起的作用,并通过激光共聚焦显微镜观察趋化作用的细胞因子的受体在肝癌细胞侵袭转移过程中的作用机制。
结果：通过RT-PCR,流式细胞术可检测到CCR1mRNA及蛋白因子在肝癌细胞中表达,免疫组化显示CCRl在肝癌细胞包膜和胞浆内都有表达。细胞侵袭实验提不Hep3B在CCL3的刺激下,Hep-3B细胞侵入基底膜的数量随着CCL3浓度的增加而增加,对照组细胞侵入基底膜的数量随着CCL3浓度的增加没有发生变化,差异有显著性(P<0.01),差异有显著性(P<0.01)。运用激光共聚焦检测到实验组胞内钙离子的浓度增加。
结论：
1,肝癌细胞系(Hep3B HepG2HLE和HLF)的表面的表达CCR1。
2,且CCR1在肝癌细胞侵袭转移中发挥重要的作用,其作用机制与细胞内钙离子浓度有很大关系。
Objective:Hepatocellular carcinoma (HCC) is the fifth deadly tumor in the world, Development of HCC is associated with hepatic B virus. HCC patients do not have specifity of symptom, so many patients lost opportunity to operate. Non-surgery therapies such as transaterial chemotherapy embolization (TACE), radiofrequency ablation (RFA), percutaneous ethanol injection (TEI) has limited effects. Many patients succumb to the recurrence and metastasis at last. Biotherapy and gene therapysuppose the new direction for therapy of metastasis of HCC. However, invasion and metastasis of HCC is a process of multi-step and multi-gene, which is concerned to biological characteristics oftumor cells, the local microenviroments in tumor such as matrix metalloprotease (MMP), integrin, stroma-cell and blood vessel, and local and systematic immunology. Chemokines and chemokine receptors are the critical molecular in homing and directionalchemotaxis of immunocells. To date, about 45 chemokines and 18 chemokine receptors have thedefinite functions. Another chemokine and chemokine receptors have not clear in function. In2001, Muller first reported the expressions of chemokine receptors in breast cancer were related tothe metastasis of tumor cells, particularly CXCR4 in lung metastasis, and CCR7 in lymph nodemetastasis. By now, more and more researchers have shown that chemokine receptors can befunctionally expressed in tumor cells, particularly in tumor cells with high metastasis potentials.
Therefore, we establlish the relationship between HCC and chemokoine receptor. To investigate the expression and mechanism of chemokine receptor (CCR1 CCR7 CXCR3 CXCR4) in hepatoma carcinoma cell (Hep3B HepG2 HLE and HLF)
Methods:RT-PCR immunohistochemistry and Flow Cytometric were used to determine the expression and mechanism of CCRl chemokine receptor in hepatoma carcinoma cell. invasion of Hep3B was analyzed with basal membrane by CCL3 and mechanism of chemokine receptor was analyzed in hepatoma carcinoma cell by confocal microscopy,
Result:CCR1 mRNA and protein could be detected in hepatoma carcinoma cell. Immunohistochemistry revealed that CCR1 protein was located on membrane and intracytoplasm of hepatoma carcinoma cell. The number of hepatoma carcinoma cells that go through basal membrane were significantly more in experiment group(213±12) than the number of hepatoma carcinoma cells were in control group (102±11) (P<0.01). and the density of the calciumion increases in hepatoma carcinoma cells in experiment group.
Conclusions:hepatoma carcinoma cell expresses CCR1 chemokine recepter, and CCR1 plays an important role in course of metastasis and invasion of hepatoma carcinoma cell. and the density of the calciumion have a great relationship with the mechanism of chemokine receptor in hepatoma carcinoma.
术后复发和转移。生物治疗(包括基因治疗)为肝癌转移治疗提供了新的方向。然而,肝癌侵袭和转移是个多步骤多基因的过程,涉及肝癌细胞的生物学特性,肿瘤局部微环境如基质金属蛋白酶,整合素,基质细胞和血管等,以及局部和系统免疫。趋化作用的细胞因子和趋化作用的细胞因子受体是免疫细胞归巢和定向趋化的关键分子。目前为止,功能明确的有50多个趋化作用的细胞因子和18个趋化作用的细胞因子受体。还有一些趋化作用的细胞因子及受体在功能上不是很明确。2001年,Mullar首次报道趋化作用的细胞因子受体在乳腺癌细胞表达并与肿瘤细胞转移相关,尤其是CXCR4与肺转移,CCR7与淋巴结转移密切相关。现在,越来越多.的研究表明趋化作用的细胞因子受体可以在肿瘤细胞上功能表达,尤其是具有高转移性的肿瘤细胞。
本文致力于发现与肝癌的侵袭转移与趋化作用的细胞因子受体的关系。了解趋化作用的细胞因子的受体(CCR1 CCR7 CXCR3 CXCR4)在人肝癌细胞系(Hep3BHepG2HLE和HLF)的表达情况,并探讨其作用机制。
方法：采用逆转录-聚合酶链反应(RT-PCR)细胞免疫组化流式细胞仪,Western blot测定趋化作用的细胞因子的受体在肝癌细胞表面的表达情况,通过肝癌细胞Hep3B体外侵袭实验即重组大鼠巨噬细胞激动蛋白-1 (CCL3)对Hep3B细胞穿透人工重组基底膜能力的影响来检测趋化作用的细胞因子的受体在肝癌侵袭转移时所起的作用,并通过激光共聚焦显微镜观察趋化作用的细胞因子的受体在肝癌细胞侵袭转移过程中的作用机制。
结果：通过RT-PCR,流式细胞术可检测到CCR1mRNA及蛋白因子在肝癌细胞中表达,免疫组化显示CCRl在肝癌细胞包膜和胞浆内都有表达。细胞侵袭实验提不Hep3B在CCL3的刺激下,Hep-3B细胞侵入基底膜的数量随着CCL3浓度的增加而增加,对照组细胞侵入基底膜的数量随着CCL3浓度的增加没有发生变化,差异有显著性(P<0.01),差异有显著性(P<0.01)。运用激光共聚焦检测到实验组胞内钙离子的浓度增加。
结论：
1,肝癌细胞系(Hep3B HepG2HLE和HLF)的表面的表达CCR1。
2,且CCR1在肝癌细胞侵袭转移中发挥重要的作用,其作用机制与细胞内钙离子浓度有很大关系。
Objective:Hepatocellular carcinoma (HCC) is the fifth deadly tumor in the world, Development of HCC is associated with hepatic B virus. HCC patients do not have specifity of symptom, so many patients lost opportunity to operate. Non-surgery therapies such as transaterial chemotherapy embolization (TACE), radiofrequency ablation (RFA), percutaneous ethanol injection (TEI) has limited effects. Many patients succumb to the recurrence and metastasis at last. Biotherapy and gene therapysuppose the new direction for therapy of metastasis of HCC. However, invasion and metastasis of HCC is a process of multi-step and multi-gene, which is concerned to biological characteristics oftumor cells, the local microenviroments in tumor such as matrix metalloprotease (MMP), integrin, stroma-cell and blood vessel, and local and systematic immunology. Chemokines and chemokine receptors are the critical molecular in homing and directionalchemotaxis of immunocells. To date, about 45 chemokines and 18 chemokine receptors have thedefinite functions. Another chemokine and chemokine receptors have not clear in function. In2001, Muller first reported the expressions of chemokine receptors in breast cancer were related tothe metastasis of tumor cells, particularly CXCR4 in lung metastasis, and CCR7 in lymph nodemetastasis. By now, more and more researchers have shown that chemokine receptors can befunctionally expressed in tumor cells, particularly in tumor cells with high metastasis potentials.
Therefore, we establlish the relationship between HCC and chemokoine receptor. To investigate the expression and mechanism of chemokine receptor (CCR1 CCR7 CXCR3 CXCR4) in hepatoma carcinoma cell (Hep3B HepG2 HLE and HLF)
Methods:RT-PCR immunohistochemistry and Flow Cytometric were used to determine the expression and mechanism of CCRl chemokine receptor in hepatoma carcinoma cell. invasion of Hep3B was analyzed with basal membrane by CCL3 and mechanism of chemokine receptor was analyzed in hepatoma carcinoma cell by confocal microscopy,
Result:CCR1 mRNA and protein could be detected in hepatoma carcinoma cell. Immunohistochemistry revealed that CCR1 protein was located on membrane and intracytoplasm of hepatoma carcinoma cell. The number of hepatoma carcinoma cells that go through basal membrane were significantly more in experiment group(213±12) than the number of hepatoma carcinoma cells were in control group (102±11) (P<0.01). and the density of the calciumion increases in hepatoma carcinoma cells in experiment group.
Conclusions:hepatoma carcinoma cell expresses CCR1 chemokine recepter, and CCR1 plays an important role in course of metastasis and invasion of hepatoma carcinoma cell. and the density of the calciumion have a great relationship with the mechanism of chemokine receptor in hepatoma carcinoma.
引文
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