Gelsolin在小鼠肝癌淋巴道转移中的作用及其机制的研究
摘要
背景：原发性肝细胞癌是常见的恶性肿瘤之一,在我国具有较高的发病率。目前手术治疗是肝癌治疗的首选方案,但术后5年生存率很低。大量的尸检报告证实近1／3的肝癌患者发生淋巴道转移,并且是早期转移致死的主要方式。尽管进行了大量的研究和探讨,但是肝癌淋巴道转移的分子机制尚不清楚。此前我们通过基因干扰技术成功构建了gelsolin表达显著下调的小鼠肝癌腹水细胞Hca-F(FG下调细胞)和转染GSN无关序列的Hca-F细胞(FG无关序列细胞)。GSN是细胞骨架蛋白的重要组成成份之一,以钙依赖的方式调节肌动蛋白的装配,对细胞运动性、细胞骨架结构动力学重排过程中的信号转导、细胞凋亡的调控都发挥着重要作用。
目的：1.研究动物体内模型中GSN下调表达对肝癌细胞在增殖、转移等方面的影响,由此确定GSN表达水平与小鼠肝癌淋巴道转移潜能的关系。2.探索与GSN在肝癌淋巴道转移中发挥作用相关的基因和分子通路,并依此做出有效干预,对肝癌的的研究提供新思路。
方法：1.建立动物体内模型,比较FG下调细胞组、FG无关序列细胞组肿瘤淋巴结转移率、肿瘤淋巴结转移面积比率和肿瘤体积的差异。2.采用免疫组织化学方法,检测FG下调细胞和FG无关序列细胞的GSN定位和表达强度差异。3.采用免疫印迹方法,比较体内外肿瘤细胞中GSN、E-cadherin.N-cadherin.PKC-α和CLIC1的表达情况。
结果：1.动物体内模型中,第5、10、15、20、28天五个时间点上,FG下调细胞组原发灶肿瘤体积大于FG无关序列细胞组,P<0.05。2.FG无关序列细胞组的肿瘤淋巴结转移率为80%,高于FG下调细胞组的50%,P=0.047;FG无关序列细胞组的胭窝、腹股沟淋巴结转移灶面积比率高于FG下调细胞组,P值分别为0.002、0.004。3.免疫组化结果显示,GSN主要定位在肿瘤细胞胞浆,FG下调细胞组肿瘤原发灶中的GSN表达均低于FG无关序列细胞组,P值为0.028；FG下调细胞组肿瘤淋巴结转移灶中GSN表达低于FG无关序列细胞组,P值为0.031；FG下调细胞组肿瘤淋巴结转移灶中的GSN表达高于原发灶,P值为0.001；而FG无关序列细胞组GSN在肿瘤淋巴结转移灶与肿瘤原发灶中的表达差异不显著,P值为0.279。4.Western Blot结果显示,体内外FG下调细胞中PKC-α、CLIC1表达高于FG无关序列细胞,P<0.05；FG下调细胞中GSN.N-cadherin的表达低于FG无关序列细胞,P<0.05;未检测到E-cadherin的表达。
结论：1.建立了GSN下调表达的动物模型,下调Hca-F细胞中GSN的表达,虽可促进原发灶肿瘤增殖,但可降低Hca-F细胞的体内淋巴结转移率和肿瘤淋巴结转移面积比率。2.GSN主要定位在肿瘤细胞的细胞浆,在FG下调细胞组肿瘤原发灶及肿瘤淋巴结转移灶中的表达均低于FG无关序列细胞组,FG下调细胞组肿瘤淋巴结转移灶中的GSN表达高于原发灶,FG无关序列细胞组GSN在肿瘤淋巴结转移灶与肿瘤原发灶中的表达差异不显著3.GSN下调表达的体外肿瘤细胞和体内肿瘤组织中,PKC-α、CLIC1的表达上调,N-cadherin的表达下调,E-cadherin呈现缺失表达,说明抑制GSN表达后通过与以上相关基因的作用促进了细胞增殖,抑制了肿瘤淋巴道转移。
Background:Hepatocarcinoma (HCC) is one of the common malignant tumors with high incidence in China. Currently surgery is the preferred treatment for liver cancer,but 5-years survival rate is still very low. The autopsy report confirmed that nearly 1/3 of patiendces with lymph node metastasis of liver cancer which is the main reason of early metastasis and leading to death. Despite a great number of researchers, the molecular mechanism of liver cancer lymphatic metastasis is not clear yet. Using the genetic interference technology,we successfully constructed hepato-carcinoma ascites cells Hca-F,FGdown cells in which expression of gelsolin (GSN) was significantly reduced and Fcontrol cells which are transfected with unrelated sequence of GSN.GSN is an important constitument of cytoskeletal proteins which play an important role in regulating the assembly of actin in calcium-dependent manner, cell motility,cell apoptosis and the signal transduction of cytoskeletal dynamic structural rearrangement process.
Objective:1.Study on the influence of downregulation of GSN to the proliferation and metastasis of hepatoma cells in animal model in order to determine the relation of expression levels of GSN to the potential of lymphatic metastatic of mouse liver cancer; 2. Exploring the related genes and molecular pathways of GSN involving in lymphatic metastasis of Hepatocarcinoma, accordingly to make effective interventions, providing new ideas for the research of Hepatocarcinoma.
Method:1.By establishing animal model,we want to compare the difference of the rate of tumor cells lymph node metastasis, the area ratio of lymph node metastasis and tumor volume of the two cell groups.2. The method of Immunohistochemisitry is used to detect the difference of localization and expression of GSN between FGdown cells and Fcontrol cells.3. Western blot was used to compare the different expression of GSN、E-cadherin、N-cadherin、PKC-α、PKC-β、and CLIC1 of tumor cells in vivo and in vitro.
Result:1.In animal model, the tumor volume of FGdown cells group was greater than Fcontrol cells group on the five time points days of 5,10,15,20,28,P＜0.05.2. The 80%lymph node metastasis rates in Fcontrol cells group was higher than the 50%lymph node metastasis rate in FGdown cells group,P=0.047; the fossa poplitea and groin lymph node metastasis aera ratio of Fcontrol cells group was higher than the FGdown cells group,P=0.002, 0.004.3. Immunohistochemistry showed that GSN mainly localized in cytoplasm of the tumor cells. The expression of GSN in primary tumor cells of FGdown cells group was significantly lower than it in Fcontrol cells group, P=0.028; the expression of GSN in lymphatic metastasis tumor of FGdown cells group was significantly lower than it in Fcontrol cells group, P=0.031; the expression of GSN in lymph node metastasis tumor cells was higher than primary tumor in FGdown cells group,P=0.001;but the different expression of GSN in lymph node metastases tumor cells and primary tumor is quiet in Fcontrol cells group,P=0.279.4. Western-Blot experiments in vivo and in vitro showed that the expression of PKC-αand CLIC1 was higher in FGdown cells than it in Fcontrol cells, P＜0.05; the expression of GSN and N-cadherin in FGdown cells was lower than it in Fcontrol cells, P＜0.05; no expression of E-cadherin was detected.
Conclusion:1.The animal model of GSN down-regulated expression was established,downregulation of GSN in Hca-F cells can promote the proliferation of primary tumors,but reduce lymph node metastasis rate and lymph node metastasis area ratio.2. GSN mainly located in the cytoplasm of tumor cells. The expression of GSN in primary tumors and lymphatic metastasis tumors of FGdown cells group was significantly lower than it in Fcontroi cells group,the expression of GSN in lymph node metastases tumor cells was higher than primary tumor in FGdown cells group,but the difference expression of GSN in lymph node metastasis tumor cells and primary tumor is quiet in Fcontrol cells group.3. After the inhibition of GSN in hepato- cellular carcinoma cells in vitro and in vivo, PKC-a and CLIC1 was upregulated, N-cadherin was reduced, E-cadherin was absent,this demonstrates that inhibiting the expression of GSN can promote cell proliferation and inhibite tumor cells lymphatic metastasis via interactions of GSN and related gene.
目的：1.研究动物体内模型中GSN下调表达对肝癌细胞在增殖、转移等方面的影响,由此确定GSN表达水平与小鼠肝癌淋巴道转移潜能的关系。2.探索与GSN在肝癌淋巴道转移中发挥作用相关的基因和分子通路,并依此做出有效干预,对肝癌的的研究提供新思路。
方法：1.建立动物体内模型,比较FG下调细胞组、FG无关序列细胞组肿瘤淋巴结转移率、肿瘤淋巴结转移面积比率和肿瘤体积的差异。2.采用免疫组织化学方法,检测FG下调细胞和FG无关序列细胞的GSN定位和表达强度差异。3.采用免疫印迹方法,比较体内外肿瘤细胞中GSN、E-cadherin.N-cadherin.PKC-α和CLIC1的表达情况。
结果：1.动物体内模型中,第5、10、15、20、28天五个时间点上,FG下调细胞组原发灶肿瘤体积大于FG无关序列细胞组,P<0.05。2.FG无关序列细胞组的肿瘤淋巴结转移率为80%,高于FG下调细胞组的50%,P=0.047;FG无关序列细胞组的胭窝、腹股沟淋巴结转移灶面积比率高于FG下调细胞组,P值分别为0.002、0.004。3.免疫组化结果显示,GSN主要定位在肿瘤细胞胞浆,FG下调细胞组肿瘤原发灶中的GSN表达均低于FG无关序列细胞组,P值为0.028；FG下调细胞组肿瘤淋巴结转移灶中GSN表达低于FG无关序列细胞组,P值为0.031；FG下调细胞组肿瘤淋巴结转移灶中的GSN表达高于原发灶,P值为0.001；而FG无关序列细胞组GSN在肿瘤淋巴结转移灶与肿瘤原发灶中的表达差异不显著,P值为0.279。4.Western Blot结果显示,体内外FG下调细胞中PKC-α、CLIC1表达高于FG无关序列细胞,P<0.05；FG下调细胞中GSN.N-cadherin的表达低于FG无关序列细胞,P<0.05;未检测到E-cadherin的表达。
结论：1.建立了GSN下调表达的动物模型,下调Hca-F细胞中GSN的表达,虽可促进原发灶肿瘤增殖,但可降低Hca-F细胞的体内淋巴结转移率和肿瘤淋巴结转移面积比率。2.GSN主要定位在肿瘤细胞的细胞浆,在FG下调细胞组肿瘤原发灶及肿瘤淋巴结转移灶中的表达均低于FG无关序列细胞组,FG下调细胞组肿瘤淋巴结转移灶中的GSN表达高于原发灶,FG无关序列细胞组GSN在肿瘤淋巴结转移灶与肿瘤原发灶中的表达差异不显著3.GSN下调表达的体外肿瘤细胞和体内肿瘤组织中,PKC-α、CLIC1的表达上调,N-cadherin的表达下调,E-cadherin呈现缺失表达,说明抑制GSN表达后通过与以上相关基因的作用促进了细胞增殖,抑制了肿瘤淋巴道转移。
Background:Hepatocarcinoma (HCC) is one of the common malignant tumors with high incidence in China. Currently surgery is the preferred treatment for liver cancer,but 5-years survival rate is still very low. The autopsy report confirmed that nearly 1/3 of patiendces with lymph node metastasis of liver cancer which is the main reason of early metastasis and leading to death. Despite a great number of researchers, the molecular mechanism of liver cancer lymphatic metastasis is not clear yet. Using the genetic interference technology,we successfully constructed hepato-carcinoma ascites cells Hca-F,FGdown cells in which expression of gelsolin (GSN) was significantly reduced and Fcontrol cells which are transfected with unrelated sequence of GSN.GSN is an important constitument of cytoskeletal proteins which play an important role in regulating the assembly of actin in calcium-dependent manner, cell motility,cell apoptosis and the signal transduction of cytoskeletal dynamic structural rearrangement process.
Objective:1.Study on the influence of downregulation of GSN to the proliferation and metastasis of hepatoma cells in animal model in order to determine the relation of expression levels of GSN to the potential of lymphatic metastatic of mouse liver cancer; 2. Exploring the related genes and molecular pathways of GSN involving in lymphatic metastasis of Hepatocarcinoma, accordingly to make effective interventions, providing new ideas for the research of Hepatocarcinoma.
Method:1.By establishing animal model,we want to compare the difference of the rate of tumor cells lymph node metastasis, the area ratio of lymph node metastasis and tumor volume of the two cell groups.2. The method of Immunohistochemisitry is used to detect the difference of localization and expression of GSN between FGdown cells and Fcontrol cells.3. Western blot was used to compare the different expression of GSN、E-cadherin、N-cadherin、PKC-α、PKC-β、and CLIC1 of tumor cells in vivo and in vitro.
Result:1.In animal model, the tumor volume of FGdown cells group was greater than Fcontrol cells group on the five time points days of 5,10,15,20,28,P＜0.05.2. The 80%lymph node metastasis rates in Fcontrol cells group was higher than the 50%lymph node metastasis rate in FGdown cells group,P=0.047; the fossa poplitea and groin lymph node metastasis aera ratio of Fcontrol cells group was higher than the FGdown cells group,P=0.002, 0.004.3. Immunohistochemistry showed that GSN mainly localized in cytoplasm of the tumor cells. The expression of GSN in primary tumor cells of FGdown cells group was significantly lower than it in Fcontrol cells group, P=0.028; the expression of GSN in lymphatic metastasis tumor of FGdown cells group was significantly lower than it in Fcontrol cells group, P=0.031; the expression of GSN in lymph node metastasis tumor cells was higher than primary tumor in FGdown cells group,P=0.001;but the different expression of GSN in lymph node metastases tumor cells and primary tumor is quiet in Fcontrol cells group,P=0.279.4. Western-Blot experiments in vivo and in vitro showed that the expression of PKC-αand CLIC1 was higher in FGdown cells than it in Fcontrol cells, P＜0.05; the expression of GSN and N-cadherin in FGdown cells was lower than it in Fcontrol cells, P＜0.05; no expression of E-cadherin was detected.
Conclusion:1.The animal model of GSN down-regulated expression was established,downregulation of GSN in Hca-F cells can promote the proliferation of primary tumors,but reduce lymph node metastasis rate and lymph node metastasis area ratio.2. GSN mainly located in the cytoplasm of tumor cells. The expression of GSN in primary tumors and lymphatic metastasis tumors of FGdown cells group was significantly lower than it in Fcontroi cells group,the expression of GSN in lymph node metastases tumor cells was higher than primary tumor in FGdown cells group,but the difference expression of GSN in lymph node metastasis tumor cells and primary tumor is quiet in Fcontrol cells group.3. After the inhibition of GSN in hepato- cellular carcinoma cells in vitro and in vivo, PKC-a and CLIC1 was upregulated, N-cadherin was reduced, E-cadherin was absent,this demonstrates that inhibiting the expression of GSN can promote cell proliferation and inhibite tumor cells lymphatic metastasis via interactions of GSN and related gene.
引文
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