肝癌c-Met表达异常与索拉非尼耐药关系研究及肝癌动物模型建立
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摘要
第一部分肝细胞性肝癌患者HGF/c-Met表达特征评价
目的：检测原发性肝细胞性肝癌(hepatocellular carcinoma, HCC)患者血清肝细胞生长因子(hepatocyte growth factor, HGF)水平及HCC组织c-Met蛋白表达水平。
方法：通过双抗体夹心酶联免疫ELISA方法检测血清标本中HGF水平,通过免疫组织化学方法检测肝脏病理标本c-Met蛋白染色强度。对肝癌组与肝硬化组及健康人群组在HGF水平、c-Met染色强度等变量进行One-Way ANOVA统计分析和Friedman非非参数检验,评价肝癌组与其他两组间是否存在显著性差异。
结果：血清HGF浓度在肝癌组、肝硬化组和正常对照组分别为0.609±0.134ng/ml、0.378±0.116ng/ml、0.271±0.083ng/ml,肝癌组患者血清HGF水平明显高于肝硬化组和正常对照组,差异具有显著性(P<0.01)。不同体积的肿瘤之间血清HGF水平存在显著性差异(P<0.05),肿瘤体积越大则血清HGF水平越高。c-Met蛋白在HCC组织上呈阳性表达,c-Met阳性染色主要定位于肿瘤细胞的胞膜和胞质,而在癌旁组织及正常组织呈弱阳性和低表达,差异具有显著性意义,P<0.01。HCC组织c-Met阳性表达强度与肿瘤分化程度等密切相关,(P<0.05)。
结论：
1.HCC患者血清HGF水平较肝硬化及正常对照组明显升高,差异具有显著性。
2. HCC患者术前血清HGF水平与肿瘤大小有明显正相关性,肿瘤体积越大则血清HGF水平越高。
3.c-Met蛋白在HCC组织中表达强度明显高于癌旁组织及正常肝组织,差异具有显著性意义。
4. c-Met表达异常与HCC病理分化程度等密切相关。
第二部分c-Met过表达细胞株构建及索拉非尼耐药特征观察
目的：评价c-Met过表达导致的细胞信号传导异常对索拉非尼抑制肝癌细胞增殖的影响并寻找相应治疗对策。
方法：首先通过慢病毒载体将c-Met基因转染至HepG2细胞,并使HepG2细胞能够稳定表达c-Met蛋白,通过嘌呤霉素筛选获得稳定转染的细胞株HepG2-met。通过MTT比色法法及AnnexinV-FITC和PI双染法检测细胞周期及凋亡的方法,评价索拉非尼对HepG2细胞/HepG2-met细胞增殖影响是否存在差异,确定c-Met蛋白表达异常升高对索拉非尼抵抗作用。通过Western Blot方法检测(?) c-Met蛋白及其下游mTOR信号蛋白P70S6K、4E-BP1磷酸化水平在HepG2细胞(?)HepG2=met细胞之间的差异,寻找c-Met蛋白表达异常升高对索拉非尼抵抗作用的分子机制。在此基础上通过联合mTOR抑制药物雷帕霉素逆转索拉非尼耐药现象。
结果：通过RT-PCR检测慢病毒感染的HepG2细胞中c-Met mRNA确定慢病毒转染MOI=20为最佳MOI值,通过2.5ug/ml嘌呤霉素持续作用10天筛选出抗嘌呤霉素的稳定细胞株HepG2-met。 Westem blot方法分析c-Met的表达和磷酸化及mTOR信号途径中P70S6K、4E-BP1蛋白磷酸化改变,显示HepG2-met细胞在c-Met的表达和磷酸化及P70S6K、4E-BP1蛋白磷酸化水平上均明显超过HepG2细胞。通过细胞生长曲线检测发现HepG2-met具有较HepG2更为活跃的细胞增殖能力。MTT法检测HepG2/HepG2-met细胞对索拉非尼增殖抑制敏感性：索拉非尼对HepG2/HepG2-met细胞增殖抑制作用随着药物浓度的增加而逐渐增加,表现出剂量依赖性；HepG2-met具有一定的索拉非尼药物作用抵抗特征。通过流式细胞术检测可以看出HepG2-met细胞处于S期的比例为65.5%,较HepG2细胞的39.92%明显升高,提示HepG2-met增殖更为活跃,在应用相同剂量的索拉非尼作用后HepG2-met细胞S期比例降至41.07%,细胞凋亡率为35.48%；HepG2细胞的S期比例降至25.89%,细胞凋亡率为63.42%,两组间比较仍有显著性差异,提示索拉非尼对HepG2-met细胞增殖抑制作用有所下降,HepG2-met表现出对索拉非尼一定的耐药性。当HepG2-met组联合应用索拉非尼及小剂量的雷帕霉素后,S期比例降至32.03%,细胞凋亡率上升至65.01%,提示雷帕霉素可以部分逆转HepG2-met细胞高表达c-Met造成的对索拉非尼一定耐药性。
结论：
1.通过慢病毒转染方式成功构建出c-Met过表达的HepG2-met细胞株,c-Met表达水平较HepG2明显升高。
2. HepG2-met细胞株c-Met的表达和磷酸化水平升高,同时其下游信号如mTOR信号途径中P70S6K、4E-BP1蛋白磷酸化较HepG2明显升高。
3. HepG2-met细胞株具有较HepG2更为活跃的细胞增殖能力。
4. HepG2-met具有一定的索拉非尼药物作用抵抗特征。
5.雷帕霉素通过抑制1mTOR信号途径中P70S6K、4E-BP1蛋白磷酸化可以部分逆转HepG2-met对索拉非尼的耐药作用。
第三部分裸鼠荷人肝癌皮下模型的建立
目的：通过临床肝癌标本建立裸鼠异种肝癌模型并对肝癌中HBV状态作初步检测。
方法：采集肝移植患者肝癌病理组织,种植于裸鼠皮下,经过多次传代生长后,获得可以稳定生长与传代的肝癌裸鼠模型。通过HE染色比较原代肝癌病例组织结构与多次传代后的移植性肝癌模型的病理结果,评价异种肝癌模型是否具有与原代相似的病理组织学特征。同时通过PCR方法检测与HBV相关性肝癌的动物模型中HBV DNA存在状态,初步探讨HBV与HCC相关关系。
结果：成功建立4例肝癌动物模型。异种移植肿瘤标本和病人原发肿瘤标本的病理学形态相似,保留了原发肿瘤的部分组织形态学特性。4例肝癌异种移植物模型肿瘤标本分别进行HBV DNA的S区、C区和X区三个独立区域检测,结果一例标本S区、C区和X区均呈阳性,一例标本S区和X区呈阳性,一例标本S区和C区呈阳性。
结论：
1.通过裸鼠皮下种植肝癌组织成功建立4例肝癌动物模型。
2.异种移植肿瘤标本和病人原发肿瘤标本的病理学形态相似,保留了原发肿瘤的部分组织形态学特性。
3.部分肝癌模型标本中存在HBV DNA,可能是重要的致癌因素。
Part one HGF/c-Met expression characteristics evaluation for patients with HCC
Objective To detect the serum HGF concentration and c-Met protein expression in liver of HCC patients.
Methods The level of serum HGF was detected by ELISA method. Immunohisto-chemistry was used to detect c-Met protein staining intensity within liver pathology specimens.
Results The serum HGF concentration in HCC group, cirrhosis group and normal control group were0.609±0.134ng/ml,0.378±0.116ng/ml, and0.271±0.083ng/ml, respectively. HGF levels in patients with HCC group were significantly higher than that in other two groups (P<0.01). There was a significant difference of HGF levels between different tumor volume (P<0.05). HCC tissues showed positive expression of c-Met staining, but the expressions were weakly in the paracancerous tissues, cirrhotic liver tissue and normal liver tissue (P<0.01). The intensity of c-Met expression closely related to the tumor differentiation and showed a negative correlation (P<0.05).
Conclusions1. The serum HGF level of HCC patients was significantly higher than that of liver cirrhosis patients and normal control group.2. The serum HGF levels of HCC were significantly associated with tumor size.3. The c-Met protein staining intensity in HCC tissue was significantly higher than in paracancerous and normal liver tissues.4. The c-Met protein staining intensity was closely related to HCC histological differentiation.
Part two The c-Met over-expression cell lines building and sorafenib-resistant features observing
Objective To evaluate the effect of c-Met overexpression and subsequent cell signaling abnormalities for sorafenib-resistance of HCC and to find countermeasures.
Methods The c-Met gene was transfected to HepG2cells by lentiviral vector, and selected the stably transfected cell lines HepG2-met by puromycin. Evaluated the cell cycle and apoptosis rate for HepG2cells and HepG2-met cells with sorafenib. The c-Met protein and its downstream mTOR signaling protein such as P70S6K,4E-BP1 and their phosphorylation levels were detected by Western Blot, to find out if c-Met overexpression can subsequently lead to mTOR signaling abnormalities. Then observed if the resistance to sorafenib could be reversed by combination with mTOR inhibiting drug rapamycin.
Results c-Met mRNA was determined by RT-PCR. The stable transfected cell lines HepG2-met was selected by2.5ug/ml puromycin for about10days. Western blot analysis showed that the c-Met, P70S6K and4E-BP1protein phosphorylation level in HepG2-met cells were significantly higher than in HepG2cells. HepG2-met had more proliferative activity. Sorafenib inhibited the proliferation of HepG2/HepG2-met cells, and the effects enhanced with drug concentration increased. HepG2-met cells had a certain resistance to sorafenib. HepG2-met cells S phase decreased and apoptosis rate increased when cultured with sorafenib combining small doses of rapamycin, the results suggested that the resistance to sorafenib could be reversed by combination with mTOR inhibiting drug.
Conclusions1. HepG2-met cells with high level c-Met expression were constructed.2. c-Met expression and phosphorylation levels increased in HepG2-met cells, while its downstream mTOR signaling protein phosphorylation of P70S6K and4E-BP1were as higher than in HepG2cells.3. HepG2-met cells were more proliferatively active.4. HepG2-met cells showed a certain degree of drug resistance to sorafenib.5. Rapamycin inhibited mTOR signaling pathway protein phosphorylation of P70S6K and4E-BP1partially reversing sorafenib resistance of HepG2-met.
Part three Establishment of nude mice bearing human liver tumor models
Objective Xenograft tumor models established by transplantation of human tumor into immunodifficient mice, and made the initial detection of HBV status in tumor.
Methods The fresh human liver tumor samples were selected from clinic patients, and implanted in nude mices. Compared the histopathological characteristics between the original liver cancer and the stabilized tumor model by HE staining. And then detected the HBV DNA existing status in tumor model by PCR methods.
Results We successfully established four cases of liver cancer animal models. The pathological characteristics of xenograft tumor samples and primary patient tumor specimens were similar. HBV S, C, and X sequences were respectively detected from three cases of liver cancer xenograft model tumor samples by PCR methods.
Conclusions1.Four cases of liver cancer xenograft models were established by subcutaneously implanting in the nude mices.2. Xenograft tumor samples and patients' primary tumor specimens had the similar histomorphometric characteristics.3. HBV DNA can be detected in the HCC model specimens, and it may be important carcinogenic factors.
目的：检测原发性肝细胞性肝癌(hepatocellular carcinoma, HCC)患者血清肝细胞生长因子(hepatocyte growth factor, HGF)水平及HCC组织c-Met蛋白表达水平。
方法：通过双抗体夹心酶联免疫ELISA方法检测血清标本中HGF水平,通过免疫组织化学方法检测肝脏病理标本c-Met蛋白染色强度。对肝癌组与肝硬化组及健康人群组在HGF水平、c-Met染色强度等变量进行One-Way ANOVA统计分析和Friedman非非参数检验,评价肝癌组与其他两组间是否存在显著性差异。
结果：血清HGF浓度在肝癌组、肝硬化组和正常对照组分别为0.609±0.134ng/ml、0.378±0.116ng/ml、0.271±0.083ng/ml,肝癌组患者血清HGF水平明显高于肝硬化组和正常对照组,差异具有显著性(P<0.01)。不同体积的肿瘤之间血清HGF水平存在显著性差异(P<0.05),肿瘤体积越大则血清HGF水平越高。c-Met蛋白在HCC组织上呈阳性表达,c-Met阳性染色主要定位于肿瘤细胞的胞膜和胞质,而在癌旁组织及正常组织呈弱阳性和低表达,差异具有显著性意义,P<0.01。HCC组织c-Met阳性表达强度与肿瘤分化程度等密切相关,(P<0.05)。
结论：
1.HCC患者血清HGF水平较肝硬化及正常对照组明显升高,差异具有显著性。
2. HCC患者术前血清HGF水平与肿瘤大小有明显正相关性,肿瘤体积越大则血清HGF水平越高。
3.c-Met蛋白在HCC组织中表达强度明显高于癌旁组织及正常肝组织,差异具有显著性意义。
4. c-Met表达异常与HCC病理分化程度等密切相关。
第二部分c-Met过表达细胞株构建及索拉非尼耐药特征观察
目的：评价c-Met过表达导致的细胞信号传导异常对索拉非尼抑制肝癌细胞增殖的影响并寻找相应治疗对策。
方法：首先通过慢病毒载体将c-Met基因转染至HepG2细胞,并使HepG2细胞能够稳定表达c-Met蛋白,通过嘌呤霉素筛选获得稳定转染的细胞株HepG2-met。通过MTT比色法法及AnnexinV-FITC和PI双染法检测细胞周期及凋亡的方法,评价索拉非尼对HepG2细胞/HepG2-met细胞增殖影响是否存在差异,确定c-Met蛋白表达异常升高对索拉非尼抵抗作用。通过Western Blot方法检测(?) c-Met蛋白及其下游mTOR信号蛋白P70S6K、4E-BP1磷酸化水平在HepG2细胞(?)HepG2=met细胞之间的差异,寻找c-Met蛋白表达异常升高对索拉非尼抵抗作用的分子机制。在此基础上通过联合mTOR抑制药物雷帕霉素逆转索拉非尼耐药现象。
结果：通过RT-PCR检测慢病毒感染的HepG2细胞中c-Met mRNA确定慢病毒转染MOI=20为最佳MOI值,通过2.5ug/ml嘌呤霉素持续作用10天筛选出抗嘌呤霉素的稳定细胞株HepG2-met。 Westem blot方法分析c-Met的表达和磷酸化及mTOR信号途径中P70S6K、4E-BP1蛋白磷酸化改变,显示HepG2-met细胞在c-Met的表达和磷酸化及P70S6K、4E-BP1蛋白磷酸化水平上均明显超过HepG2细胞。通过细胞生长曲线检测发现HepG2-met具有较HepG2更为活跃的细胞增殖能力。MTT法检测HepG2/HepG2-met细胞对索拉非尼增殖抑制敏感性：索拉非尼对HepG2/HepG2-met细胞增殖抑制作用随着药物浓度的增加而逐渐增加,表现出剂量依赖性；HepG2-met具有一定的索拉非尼药物作用抵抗特征。通过流式细胞术检测可以看出HepG2-met细胞处于S期的比例为65.5%,较HepG2细胞的39.92%明显升高,提示HepG2-met增殖更为活跃,在应用相同剂量的索拉非尼作用后HepG2-met细胞S期比例降至41.07%,细胞凋亡率为35.48%；HepG2细胞的S期比例降至25.89%,细胞凋亡率为63.42%,两组间比较仍有显著性差异,提示索拉非尼对HepG2-met细胞增殖抑制作用有所下降,HepG2-met表现出对索拉非尼一定的耐药性。当HepG2-met组联合应用索拉非尼及小剂量的雷帕霉素后,S期比例降至32.03%,细胞凋亡率上升至65.01%,提示雷帕霉素可以部分逆转HepG2-met细胞高表达c-Met造成的对索拉非尼一定耐药性。
结论：
1.通过慢病毒转染方式成功构建出c-Met过表达的HepG2-met细胞株,c-Met表达水平较HepG2明显升高。
2. HepG2-met细胞株c-Met的表达和磷酸化水平升高,同时其下游信号如mTOR信号途径中P70S6K、4E-BP1蛋白磷酸化较HepG2明显升高。
3. HepG2-met细胞株具有较HepG2更为活跃的细胞增殖能力。
4. HepG2-met具有一定的索拉非尼药物作用抵抗特征。
5.雷帕霉素通过抑制1mTOR信号途径中P70S6K、4E-BP1蛋白磷酸化可以部分逆转HepG2-met对索拉非尼的耐药作用。
第三部分裸鼠荷人肝癌皮下模型的建立
目的：通过临床肝癌标本建立裸鼠异种肝癌模型并对肝癌中HBV状态作初步检测。
方法：采集肝移植患者肝癌病理组织,种植于裸鼠皮下,经过多次传代生长后,获得可以稳定生长与传代的肝癌裸鼠模型。通过HE染色比较原代肝癌病例组织结构与多次传代后的移植性肝癌模型的病理结果,评价异种肝癌模型是否具有与原代相似的病理组织学特征。同时通过PCR方法检测与HBV相关性肝癌的动物模型中HBV DNA存在状态,初步探讨HBV与HCC相关关系。
结果：成功建立4例肝癌动物模型。异种移植肿瘤标本和病人原发肿瘤标本的病理学形态相似,保留了原发肿瘤的部分组织形态学特性。4例肝癌异种移植物模型肿瘤标本分别进行HBV DNA的S区、C区和X区三个独立区域检测,结果一例标本S区、C区和X区均呈阳性,一例标本S区和X区呈阳性,一例标本S区和C区呈阳性。
结论：
1.通过裸鼠皮下种植肝癌组织成功建立4例肝癌动物模型。
2.异种移植肿瘤标本和病人原发肿瘤标本的病理学形态相似,保留了原发肿瘤的部分组织形态学特性。
3.部分肝癌模型标本中存在HBV DNA,可能是重要的致癌因素。
Part one HGF/c-Met expression characteristics evaluation for patients with HCC
Objective To detect the serum HGF concentration and c-Met protein expression in liver of HCC patients.
Methods The level of serum HGF was detected by ELISA method. Immunohisto-chemistry was used to detect c-Met protein staining intensity within liver pathology specimens.
Results The serum HGF concentration in HCC group, cirrhosis group and normal control group were0.609±0.134ng/ml,0.378±0.116ng/ml, and0.271±0.083ng/ml, respectively. HGF levels in patients with HCC group were significantly higher than that in other two groups (P<0.01). There was a significant difference of HGF levels between different tumor volume (P<0.05). HCC tissues showed positive expression of c-Met staining, but the expressions were weakly in the paracancerous tissues, cirrhotic liver tissue and normal liver tissue (P<0.01). The intensity of c-Met expression closely related to the tumor differentiation and showed a negative correlation (P<0.05).
Conclusions1. The serum HGF level of HCC patients was significantly higher than that of liver cirrhosis patients and normal control group.2. The serum HGF levels of HCC were significantly associated with tumor size.3. The c-Met protein staining intensity in HCC tissue was significantly higher than in paracancerous and normal liver tissues.4. The c-Met protein staining intensity was closely related to HCC histological differentiation.
Part two The c-Met over-expression cell lines building and sorafenib-resistant features observing
Objective To evaluate the effect of c-Met overexpression and subsequent cell signaling abnormalities for sorafenib-resistance of HCC and to find countermeasures.
Methods The c-Met gene was transfected to HepG2cells by lentiviral vector, and selected the stably transfected cell lines HepG2-met by puromycin. Evaluated the cell cycle and apoptosis rate for HepG2cells and HepG2-met cells with sorafenib. The c-Met protein and its downstream mTOR signaling protein such as P70S6K,4E-BP1 and their phosphorylation levels were detected by Western Blot, to find out if c-Met overexpression can subsequently lead to mTOR signaling abnormalities. Then observed if the resistance to sorafenib could be reversed by combination with mTOR inhibiting drug rapamycin.
Results c-Met mRNA was determined by RT-PCR. The stable transfected cell lines HepG2-met was selected by2.5ug/ml puromycin for about10days. Western blot analysis showed that the c-Met, P70S6K and4E-BP1protein phosphorylation level in HepG2-met cells were significantly higher than in HepG2cells. HepG2-met had more proliferative activity. Sorafenib inhibited the proliferation of HepG2/HepG2-met cells, and the effects enhanced with drug concentration increased. HepG2-met cells had a certain resistance to sorafenib. HepG2-met cells S phase decreased and apoptosis rate increased when cultured with sorafenib combining small doses of rapamycin, the results suggested that the resistance to sorafenib could be reversed by combination with mTOR inhibiting drug.
Conclusions1. HepG2-met cells with high level c-Met expression were constructed.2. c-Met expression and phosphorylation levels increased in HepG2-met cells, while its downstream mTOR signaling protein phosphorylation of P70S6K and4E-BP1were as higher than in HepG2cells.3. HepG2-met cells were more proliferatively active.4. HepG2-met cells showed a certain degree of drug resistance to sorafenib.5. Rapamycin inhibited mTOR signaling pathway protein phosphorylation of P70S6K and4E-BP1partially reversing sorafenib resistance of HepG2-met.
Part three Establishment of nude mice bearing human liver tumor models
Objective Xenograft tumor models established by transplantation of human tumor into immunodifficient mice, and made the initial detection of HBV status in tumor.
Methods The fresh human liver tumor samples were selected from clinic patients, and implanted in nude mices. Compared the histopathological characteristics between the original liver cancer and the stabilized tumor model by HE staining. And then detected the HBV DNA existing status in tumor model by PCR methods.
Results We successfully established four cases of liver cancer animal models. The pathological characteristics of xenograft tumor samples and primary patient tumor specimens were similar. HBV S, C, and X sequences were respectively detected from three cases of liver cancer xenograft model tumor samples by PCR methods.
Conclusions1.Four cases of liver cancer xenograft models were established by subcutaneously implanting in the nude mices.2. Xenograft tumor samples and patients' primary tumor specimens had the similar histomorphometric characteristics.3. HBV DNA can be detected in the HCC model specimens, and it may be important carcinogenic factors.
引文
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