结直肠癌肝转移相关分子标志物的筛选与鉴定
摘要
结直肠癌是消化道常见恶性肿瘤,在我国其发病率和死亡率分别位居恶性肿瘤的第四位和第五位。肝脏转移是结直肠癌治疗失败的主要原因。目前结直肠癌肝转移的治疗仍以综合治疗为主,手术切除是主要的治疗手段。目前临床尚缺少客观的标准指导治疗。肿瘤的发生发展是一个多因素、多阶段、多基因参与的过程,每个阶段基因异常改变的不同为我们通过探测基因的改变来预知疾病进展和风险,从而准确地指导治疗提供了依据。
本研究通过建立结直肠癌实验性动物肝转移模型,比较分析高低肝转移的结直肠癌细胞差异表达基因谱筛选肝转移相关分子标志物,进一步在临床病例的组织标本中验证,最终得到可以用于临床,指导治疗的分子标志物。
通过体内筛选本室建立的高粘附结直肠癌细胞系SW1116-P_(21),得到肝脏高转移细胞系SW1116-P_(21)V_2。采用全基因组芯片比较分析获得体内实验性肝转移细胞的差异表达基因谱。其中在肝转移灶上调表达的基因383个,下调表达的基因356个。根据生物信息学分析和文献调研体内实验模型的差异表达基因谱中的上调基因,本研究从这些上调基因中选择了8个与结直肠癌肝转移相关的基因,即LGALS3、SNCG、CCND3、SERPINE1、IQGAP1、CCL2、CYR61和LGALS3BP。在临床结直肠癌组织标本中进一步研究其作为预示结直肠癌肝转移的分子标志物的可能性。
选择收集217例结直肠癌肝转移和无肝转移的临床原发瘤组织标本切片。采用免疫组化法检测分析了上述8个候选分子标志物在20例结直肠癌组织中的表达及其与临床的关系。结果CCL2和SNCG在肝转移组的阳性率(86%和60%)显著高于无肝转移组(29%和20%)。扩大病例至217例,检测结果显示肝转移组CCL2和SNCG的阳性率分别为67%和68%,无肝转移组的阳性率分别为31%和28%。表明这2个基因的表达具有预示结直肠癌肝转移的临床应用价值。逻辑回归分析显示,CCL2和SNCG表达阳性者的转移风险分别是表达阴性者的4.28倍(95%CI,1.92～9.52,P＜0.05)和6.99倍(95%CI,3.14～15.6,P＜0.05)。联合分析这2个分子的表达显示其预示肝转移的概率为85%。结合肿瘤直径、T分期、N分期等临床因素联合分析这2个分子预示肝转移的概率达97%。分析CCL2和SNCG的表达与结直肠癌分期的关系还发现,CCL2表达阳性与结直肠癌大体分型和TNM分期呈正相关(P＜0.05),特别是与淋巴转移的相关性更加密切(P=0.001)。SNCG表达阳性与T分期和TNM分期也呈正相关(P＜0.05)。此外还发现SNCG的表达与否与结直肠癌病人的预后密切相关。SNCG表达阴性者预后优于表达阳性者,其中位生存期分别为12.6个月和8.2个月(Log Rank,P=0.037)。COX多因素分析显示只有SNCG是肝转移预后的危险因素,表达阳性者发生转移的风险是阴性者的1.83倍(95%CI:1.03～3.26,P=0.04)。这些结果表明我们通过建立实验性肝转移模型筛选检测原发瘤中表达的基因预示结直肠癌肝转移的分子标志物是可行的。
为了解能否应用配对组织标本差异表达基因谱筛选预示结直肠癌肝转移相关基因,我们还选取6例结直肠癌肝转移病例原发瘤与肝转移灶组织配对标本进行差异表达基因谱分析。聚类分析结果表明结直肠癌肝转移的基因表达谱有其共同性,也有其显著的个性。共同上调基因的功能分析发现,绝大部分基因的功能是涉及代谢、转录和增殖等功能。共同下调表达基因的功能绝大部分与癌细胞侵袭、迁移、粘附、增殖和分化等功能相关。比较分析实验性肝转移模型基因表达谱与结直肠癌肝转移临床配对组织标本基因表达谱,结果表明实验性肝转移模型基因表达谱不同于临床病人配对组织标本差异表达基因谱。配对组织标本肝转移和原发瘤的差异表达基因谱可能不适合筛选预示肝转移的相关基因,可能更适合进行筛选肝转移灶表达上调的可用于靶向肝转移治疗的分子靶标。
As the prevalent malignancy of alimental track,the incidence and mortality for colorectal cancer(CRC) ascended to the fourth and fifth place in China,respectively.The therapy for CRC most fails to hepatic metastasis.At present,the combination of multiple therapies plays a great role in CRC,especially surgical therapy.It's necessary to have a precise evaluation on the prognosis.However the clinical examinations can not meet with the request.Detection of the changes in the molecular level will assist in tumor therapy.
Based on the hepatic colorectal metastasis model of nude mouse,the research screened the molecular biomarkers on colon adenacarcinoma metastasis through differential cDNA profiles between the high and low metastastic potential cells.Through the verification by human tissue specimens,we succeeded in uncovering a molecular marker profiles for prediction of hepatic colorectal metastasis.
SW1116-P_(21) cell line with high adhesion ability is cultured in our lab.Descendent of SW1116-P_(21) cell line by screening in vivo,SW1116-P_(21) cell line has a higher metastasis potential than its parent.The differential gene profile of hepatic metastasis was analyzed by comparing SW1116-P_(21) with SW1116-P_(21) in cDNA microarray.Through analyses of the up-regulated genes in the gene profile in vivo,a panel of 8 molecular biomarkers including LGALS3,SNCG,CCND3,SERPINE1,IQGAP1,CCL2,CYR61 and LGALS3BP,were selected for the follow-up in the clinicalpathological relevant research.
One hundred and seventeen cases of advanced CRC with liver metastasis,and one hundred and four cases of advanced CRC without liver metastasis with a follow-up time for at least 5 years after resection of the primary CRC were selected.Obvious positive expressing difference was observed in CCL2 and SNCG in the analysis of 8 molecular biomarkers by immunohistochemistry(IHC).CCL2 and SNCG were all found to be significantly higher in the cases of CRC with liver metastasis than in cases of non-metastatic CRC.Then we analyzed the clinicopathological factors and the expression of the two biological factors,CCL2 and SNCG,respectively.CCL2 was associated with the gross type of CRC and TNM stage(P＜0.05),especially with lymph node metastasis (P=0.001).SNCG was associated with the T term and TNM stage(P＜0.05).In the group of synchronous liver metastasis,the median survival time of SNCG-negative was superior to SNCG-positive,12.6 months and 8.2 months respectively(Log Rank,P=0.037).By multivariate Cox's analysis,SNCG was the only independent prognostic variable(95%CI: 1.03～3.26,P=0.04).Logistic regression analysis showed that tumor diameter,T term, lymph node metastasis,the expression of CCL2 and the expression of SNCG were independent factors.If all five factors were positive,the probability of liver metastasis became 97%.The index of metastasis risks for SNCG and CCL2 are 6.99(95%CI, 3.14～15.6,P＜0.05) and 4.28(95%CI,1.92～9.52,P＜0.05),respectively.
To identify the genes involved in metastasis from the gene profile of the paired tissue specimens,the cDNA microarray was used to detect differences in gene expression between colorectal tumors and paired liver metastases isolated from 6 patients.The cluster analysis revealed that 4 of 6 paired gene profiles have more similarity with each other and the others not.It can be interpreted as that commonness and individual character both exited in the gene profile of liver metastasis from colorectal cancer.Subsequent analysis of up-regulated genes showed their involvement in metabolism,transcription and proliferation.The down-regulated genes were involved in invasion,motility,adhesion, proliferation and cell differentiation.It was informed that the gene profiles from animal model and from the paired tissue specimen were completely different.So the differences in gene expression between colorectal tumors and paired liver metastases may play a role in the research on molecular targeted therapy but not in screening the metastasis biomarkers.
本研究通过建立结直肠癌实验性动物肝转移模型,比较分析高低肝转移的结直肠癌细胞差异表达基因谱筛选肝转移相关分子标志物,进一步在临床病例的组织标本中验证,最终得到可以用于临床,指导治疗的分子标志物。
通过体内筛选本室建立的高粘附结直肠癌细胞系SW1116-P_(21),得到肝脏高转移细胞系SW1116-P_(21)V_2。采用全基因组芯片比较分析获得体内实验性肝转移细胞的差异表达基因谱。其中在肝转移灶上调表达的基因383个,下调表达的基因356个。根据生物信息学分析和文献调研体内实验模型的差异表达基因谱中的上调基因,本研究从这些上调基因中选择了8个与结直肠癌肝转移相关的基因,即LGALS3、SNCG、CCND3、SERPINE1、IQGAP1、CCL2、CYR61和LGALS3BP。在临床结直肠癌组织标本中进一步研究其作为预示结直肠癌肝转移的分子标志物的可能性。
选择收集217例结直肠癌肝转移和无肝转移的临床原发瘤组织标本切片。采用免疫组化法检测分析了上述8个候选分子标志物在20例结直肠癌组织中的表达及其与临床的关系。结果CCL2和SNCG在肝转移组的阳性率(86%和60%)显著高于无肝转移组(29%和20%)。扩大病例至217例,检测结果显示肝转移组CCL2和SNCG的阳性率分别为67%和68%,无肝转移组的阳性率分别为31%和28%。表明这2个基因的表达具有预示结直肠癌肝转移的临床应用价值。逻辑回归分析显示,CCL2和SNCG表达阳性者的转移风险分别是表达阴性者的4.28倍(95%CI,1.92～9.52,P＜0.05)和6.99倍(95%CI,3.14～15.6,P＜0.05)。联合分析这2个分子的表达显示其预示肝转移的概率为85%。结合肿瘤直径、T分期、N分期等临床因素联合分析这2个分子预示肝转移的概率达97%。分析CCL2和SNCG的表达与结直肠癌分期的关系还发现,CCL2表达阳性与结直肠癌大体分型和TNM分期呈正相关(P＜0.05),特别是与淋巴转移的相关性更加密切(P=0.001)。SNCG表达阳性与T分期和TNM分期也呈正相关(P＜0.05)。此外还发现SNCG的表达与否与结直肠癌病人的预后密切相关。SNCG表达阴性者预后优于表达阳性者,其中位生存期分别为12.6个月和8.2个月(Log Rank,P=0.037)。COX多因素分析显示只有SNCG是肝转移预后的危险因素,表达阳性者发生转移的风险是阴性者的1.83倍(95%CI:1.03～3.26,P=0.04)。这些结果表明我们通过建立实验性肝转移模型筛选检测原发瘤中表达的基因预示结直肠癌肝转移的分子标志物是可行的。
为了解能否应用配对组织标本差异表达基因谱筛选预示结直肠癌肝转移相关基因,我们还选取6例结直肠癌肝转移病例原发瘤与肝转移灶组织配对标本进行差异表达基因谱分析。聚类分析结果表明结直肠癌肝转移的基因表达谱有其共同性,也有其显著的个性。共同上调基因的功能分析发现,绝大部分基因的功能是涉及代谢、转录和增殖等功能。共同下调表达基因的功能绝大部分与癌细胞侵袭、迁移、粘附、增殖和分化等功能相关。比较分析实验性肝转移模型基因表达谱与结直肠癌肝转移临床配对组织标本基因表达谱,结果表明实验性肝转移模型基因表达谱不同于临床病人配对组织标本差异表达基因谱。配对组织标本肝转移和原发瘤的差异表达基因谱可能不适合筛选预示肝转移的相关基因,可能更适合进行筛选肝转移灶表达上调的可用于靶向肝转移治疗的分子靶标。
As the prevalent malignancy of alimental track,the incidence and mortality for colorectal cancer(CRC) ascended to the fourth and fifth place in China,respectively.The therapy for CRC most fails to hepatic metastasis.At present,the combination of multiple therapies plays a great role in CRC,especially surgical therapy.It's necessary to have a precise evaluation on the prognosis.However the clinical examinations can not meet with the request.Detection of the changes in the molecular level will assist in tumor therapy.
Based on the hepatic colorectal metastasis model of nude mouse,the research screened the molecular biomarkers on colon adenacarcinoma metastasis through differential cDNA profiles between the high and low metastastic potential cells.Through the verification by human tissue specimens,we succeeded in uncovering a molecular marker profiles for prediction of hepatic colorectal metastasis.
SW1116-P_(21) cell line with high adhesion ability is cultured in our lab.Descendent of SW1116-P_(21) cell line by screening in vivo,SW1116-P_(21) cell line has a higher metastasis potential than its parent.The differential gene profile of hepatic metastasis was analyzed by comparing SW1116-P_(21) with SW1116-P_(21) in cDNA microarray.Through analyses of the up-regulated genes in the gene profile in vivo,a panel of 8 molecular biomarkers including LGALS3,SNCG,CCND3,SERPINE1,IQGAP1,CCL2,CYR61 and LGALS3BP,were selected for the follow-up in the clinicalpathological relevant research.
One hundred and seventeen cases of advanced CRC with liver metastasis,and one hundred and four cases of advanced CRC without liver metastasis with a follow-up time for at least 5 years after resection of the primary CRC were selected.Obvious positive expressing difference was observed in CCL2 and SNCG in the analysis of 8 molecular biomarkers by immunohistochemistry(IHC).CCL2 and SNCG were all found to be significantly higher in the cases of CRC with liver metastasis than in cases of non-metastatic CRC.Then we analyzed the clinicopathological factors and the expression of the two biological factors,CCL2 and SNCG,respectively.CCL2 was associated with the gross type of CRC and TNM stage(P＜0.05),especially with lymph node metastasis (P=0.001).SNCG was associated with the T term and TNM stage(P＜0.05).In the group of synchronous liver metastasis,the median survival time of SNCG-negative was superior to SNCG-positive,12.6 months and 8.2 months respectively(Log Rank,P=0.037).By multivariate Cox's analysis,SNCG was the only independent prognostic variable(95%CI: 1.03～3.26,P=0.04).Logistic regression analysis showed that tumor diameter,T term, lymph node metastasis,the expression of CCL2 and the expression of SNCG were independent factors.If all five factors were positive,the probability of liver metastasis became 97%.The index of metastasis risks for SNCG and CCL2 are 6.99(95%CI, 3.14～15.6,P＜0.05) and 4.28(95%CI,1.92～9.52,P＜0.05),respectively.
To identify the genes involved in metastasis from the gene profile of the paired tissue specimens,the cDNA microarray was used to detect differences in gene expression between colorectal tumors and paired liver metastases isolated from 6 patients.The cluster analysis revealed that 4 of 6 paired gene profiles have more similarity with each other and the others not.It can be interpreted as that commonness and individual character both exited in the gene profile of liver metastasis from colorectal cancer.Subsequent analysis of up-regulated genes showed their involvement in metabolism,transcription and proliferation.The down-regulated genes were involved in invasion,motility,adhesion, proliferation and cell differentiation.It was informed that the gene profiles from animal model and from the paired tissue specimen were completely different.So the differences in gene expression between colorectal tumors and paired liver metastases may play a role in the research on molecular targeted therapy but not in screening the metastasis biomarkers.
引文
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