大肠癌中Annexin A1表达与K-ras基因突变的相关性分析
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摘要
研究目的
大肠癌是结肠癌和直肠癌的总称,是消化系统最常见的恶性肿瘤之一。近年来,建立在分子生物学基础上的靶向治疗,已经取得了实质性的疗效,以表皮生长因子受体(EGFR)为靶点的单克隆抗体治疗晚期大肠癌为标志,预示着大肠癌进入了分子靶向治疗的新纪元。作为抗EGFR单抗的靶点,EGFR目前受到高度的关注。研究表明Annexin A1(简称ANXA1)起到抑癌基因作用,其可以调节EGFR的内吞及降解,促进凋亡,抑制肿瘤形成。本研究通过检测大肠癌组织中ANXA1在K-ras、BRAF基因野生型及K-ras、BRAF基因突变型大肠癌组织的转录及表达水平,及相应癌旁正常粘膜组织ANXA1的表达情况,分析不同组织中ANXA1的转录和表达的异同,旨在探讨ANXA1与大肠癌的临床、病理及分子生物学特征的关系,分析ANXA1表达情况与K-ras及BRAF基因突变的相关性,为大肠癌的诊断、治疗及预后判断提供客观的参考指标。同时,探讨ANXA1的表达水平是否可以替代K-ras基因突变检测,作为分子靶向药物应用于大肠癌临床治疗的参考指标。
研究方法
1、收集大肠癌及相应癌旁正常粘膜组织,部分液氮保存,部分石蜡包埋。同时收集样本临床病理资料。
2、抽提基因组DNA,通过基因测序方法检测大肠癌的基因突变情况。
3、应用免疫组织化学、Real-time PCR及Western blot蛋白印迹等方法检测ANXA1在K-ras、BRAF基因野生型及K-ras、BRAF基因突变型大肠癌组织及对应正常粘膜组织的转录及表达水平,分析不同组中ANXA1的转录和表达水平的异同。
结果
1、在20例大肠癌标本中,检测出K-ras基因突变6例,突变率为30%,正常粘膜均未检测出K-ras基因突变。然而在20例标本及正常粘膜中均未检测出BRAF突变。
2、在K-ras基因野生型组,大肠癌组织中ANXA1 mRNA的转录水平较癌旁正常组织显著下降,是癌旁正常组织的0.122±0.057倍,其差异具有统计学意义(单样本t检验,t=10.61,P<0.001),大肠癌组织中ANXA1蛋白的表达水平较癌旁正常组织显著下降,是癌旁正常组织的0.729±0.034倍,其差异具有统计学意义(单样本t检验,t=5.953,P<0.001)；在K-ras基因突变型组,大肠癌组织中ANXA1 mRNA的表达水平显著高于自身对照的癌旁正常组织,是癌旁正常组织的168.60±46.67倍,其差异具有统计学意义(单样本t检验,t=5.865,P<0.01),大肠癌组织中ANXA1蛋白的表达水平显著高于自身对照的癌旁正常组织,是癌旁正常组织的1.854±0.216倍,其差异具有统计学意义(单样本t检验,t=3.790,P<0.05)。因此,在K-ras基因野生型大肠癌组织中ANXA1表达下调；而在K-ras基因突变型大肠癌组织中ANXA1表达上调；与K-ras基因野生型标本相比,ANXA1在K-ras基因突变型标本中无论在转录水平还是在蛋白表达水平都显著增加。
3、大肠癌伴有K-ras基因突变者肿瘤的浸润深度较深,病理学分型较差,且出现淋巴结转移及远端转移的比例较高；在ANXA1表达上调的样本中肿瘤发生淋巴结转移及远端转移的比例明显高于ANXA1表达下调的样本(P>0.05)。且在ANXA1表达上调的样本中K-ras基因的突变率明显高于ANXA1表达下调的样本(P<0.001)。
结论
1、本研究首次阐述了ANXA1在大肠癌中的表达与K-ras基因突变的关系。数据显示在K-ras基因野生型大肠癌样本中,ANXA1表达下调；而在K-ras基因突变型大肠癌样本中,ANXA1表达显著上调。ANXA1的表达水平可能成为潜在的预测大肠癌基因型,替代K-ras基因突变检测,实现临床筛查,指导临床应用分子靶向药物的参考指标,具有广泛的临床应用价值。
2、研究中发现在ANXA1表达上调的样本中肿瘤发生淋巴结转移及远端转移的比例高于ANXA1表达下调的样本(P>0.05),且在ANXA1表达上调的样本中K-ras基因的突变率明显高于ANXA1表达下调的样本(P<0.001),提示在大肠癌中ANXA1表达上调可能与肿瘤的转移有关,ANXA1表达情况是否可能成为预测肿瘤预后的指标还需进一步论证。
3、ANXA1对EGFR及下游Ras/Raf/MEK/ERK/MAPK细胞信号通路的调控作用是通过调节EGFR的内吞及降解实现的。并且ERK/MAPK对EGFR具有负反馈作用,ERK/MAPK通过负反馈作用下调EGFR,而这种下调可能是通过上调ANXA1,加速EGFR的内吞及降解而实现的。当K-ras基因突变时,Raf/MEK/ERK/MAPK细胞信号通路的激活将不依赖EGFR的活化,因此ANXA1的上调及EGFR的下调将失去调节作用,无法抑制该通路的激活。对于ERK/MAPK对ANXA1是否有正反馈作用,还需要进一步研究。
Objective
Colorectal cancer, also called cancer of the colon or rectum, is one of most frequently digestive system malignant tumor. In recent years, targeted therapies depending on molecular biology have acquired therapeutic effect. Cetuximab and panitumumab are monoclonal antibodies to treat final stage colorectal cancer that block the ligand binding site of the EGFR, thus inhibiting intracellular signaling. As a target of anti-EGFR monoclonal antibodies, EGFR is currently subject to a high degree of attention. Annexin A1 is a kind of tumor suppressor genes. Studies have shown that Annexin A1 could regulate endocytosis and degradation of EGFR, promote apoptosis and inhibit tumor formation. In this study, we investigated the expression of ANXA1 in colorectal cancer, explored the relationship of clinical, pathological and molecular biological characteristics between ANXA1 and colorectal cancer, and analyzed whether the expression of ANXA1 is correlated with K-ras mutation and BRAF mutation in Colorectal Cancer. Research into this area can enhance our understanding of the possible role of ANXA1 in diagnosis, treatment and prognosis. At the same time, such investigations can also perhaps lead to the possible identification of ANXA1 as a potential reference index in colorectal cancer molecular target treatment.
Method
1. Colorectal cancer and corresponding adjacent normal mucosa were collected. Samples were saved in liquid nitrigen or processed for paraffin-embeding. Clinical and pathological data were also collected.
2. Genomic DNA was extracted. Colorectal cancer gene mutations were detected by gene sequencing.
3. By using immunohistochemical, real-time PCR and Western blot, the transcription and expression of ANXA1 were examined from K-ras gene mutation colorectal cancer and K-ras wild-type colorectal cancer.
Results
1. Twenty patients were included in this study. K-ras mutation were found in 6 of 20 colorectal cancers. The frequency of K-ras mutation was 6/20 (30%). All of the normal mucosa were wild type for K-ras. None of 20 cases of colorectal cancers and normal mucosa specimens were detected with a BRAF mutation.
2. In K-ras gene Wild-Type group, mRNA transcription of ANXA1 in colorectal cancer tissues were decreased significantly (0.122±0.057 fold, t= 10.61, P< 0.001) than that in normal mucosa tissues. Protein expression of ANXA1 in colorectal cancer tissues were decreased significantly (0.729±0.034 fold, t= 5.953, P< 0.001) than that in normal mucosa tissues. In K-ras gene mutation group, mRNA transcription of ANXA1 in colorectal cancer tissues were increased significantly (168.60±46.67 fold, t= 5.865, P< 0.01) than that in normal mucosa tissues. Protein expression of ANXA1 in colorectal cancer tissues were increased significantly (1.854±0.216 fold, t= 3.790, P< 0.05) than that in normal mucosa tissues. Thus, the transcription and expression of ANXA1 in the K-ras gene mutation group were significantly increased than that in the K-ras gene Wild-Type group.
3. The colorectal cancers containing K-ras mutation could infiltrate deeper and have worse pathological types than those of K-ras Wild-Type. The frequencies of lymph node metastasis and distant metastasis in K-ras gene mutation group were higher than those in K-ras gene Wild-Type group. The frequencies of lymph node metastasis and distant metastasis in ANXA1 up-regulation group were higher than those in ANXA1 down-regulation group.
Conclusion
1. Our study describes for the first time that ANXA1 expression in colorectal cancer are related to K-ras gene mutation. The expression of ANXA1 decreases in K-ras gene Wild-Type colorectal cancer. The expression of ANXA1 increases in K-ras gene mutation colorectal cancer. The level of ANXA1 expression can predict colorectal cancer genetype, implement clinical survey and guide clinical use of molecular targeted drugs.
2. The study has found that the frequencies of lymph node metastasis and distant metastasis in ANXA1 up-regulation group are higher than those in ANXA1 down-regulation group (P> 0.05). The frequency of K-ras mutation in the sample of ANXA1 express up-regulation are higher than those of ANXA1 express down-regulation (P<0.001). The result suggest that ANXA1 express up-regulation may be related with tumor metastasis. It needs further proof that whether ANXA1 expression can be used as indicators of tumor prognosis.
3. By regulating EGFR endocytosis and degradation, ANXA1 can regulate EGFR and the Ras/Raf/MEK/ERK/MAPK signaling pathway. K-ras mutation can active the Raf/MEK/ERK/MAPK signaling pathway independent of EGFR. ERK/MAPK negative feedback effect can down-regulate the expression of EGFR. This kind of down-regulation is achieved through up-regulating ANXA1 expression and accelerating EGFR endocytosis or degradation. It needs for further research that whether ERK/MAPK positive feedback effect can up-regulate the expression of ANXA1.
大肠癌是结肠癌和直肠癌的总称,是消化系统最常见的恶性肿瘤之一。近年来,建立在分子生物学基础上的靶向治疗,已经取得了实质性的疗效,以表皮生长因子受体(EGFR)为靶点的单克隆抗体治疗晚期大肠癌为标志,预示着大肠癌进入了分子靶向治疗的新纪元。作为抗EGFR单抗的靶点,EGFR目前受到高度的关注。研究表明Annexin A1(简称ANXA1)起到抑癌基因作用,其可以调节EGFR的内吞及降解,促进凋亡,抑制肿瘤形成。本研究通过检测大肠癌组织中ANXA1在K-ras、BRAF基因野生型及K-ras、BRAF基因突变型大肠癌组织的转录及表达水平,及相应癌旁正常粘膜组织ANXA1的表达情况,分析不同组织中ANXA1的转录和表达的异同,旨在探讨ANXA1与大肠癌的临床、病理及分子生物学特征的关系,分析ANXA1表达情况与K-ras及BRAF基因突变的相关性,为大肠癌的诊断、治疗及预后判断提供客观的参考指标。同时,探讨ANXA1的表达水平是否可以替代K-ras基因突变检测,作为分子靶向药物应用于大肠癌临床治疗的参考指标。
研究方法
1、收集大肠癌及相应癌旁正常粘膜组织,部分液氮保存,部分石蜡包埋。同时收集样本临床病理资料。
2、抽提基因组DNA,通过基因测序方法检测大肠癌的基因突变情况。
3、应用免疫组织化学、Real-time PCR及Western blot蛋白印迹等方法检测ANXA1在K-ras、BRAF基因野生型及K-ras、BRAF基因突变型大肠癌组织及对应正常粘膜组织的转录及表达水平,分析不同组中ANXA1的转录和表达水平的异同。
结果
1、在20例大肠癌标本中,检测出K-ras基因突变6例,突变率为30%,正常粘膜均未检测出K-ras基因突变。然而在20例标本及正常粘膜中均未检测出BRAF突变。
2、在K-ras基因野生型组,大肠癌组织中ANXA1 mRNA的转录水平较癌旁正常组织显著下降,是癌旁正常组织的0.122±0.057倍,其差异具有统计学意义(单样本t检验,t=10.61,P<0.001),大肠癌组织中ANXA1蛋白的表达水平较癌旁正常组织显著下降,是癌旁正常组织的0.729±0.034倍,其差异具有统计学意义(单样本t检验,t=5.953,P<0.001)；在K-ras基因突变型组,大肠癌组织中ANXA1 mRNA的表达水平显著高于自身对照的癌旁正常组织,是癌旁正常组织的168.60±46.67倍,其差异具有统计学意义(单样本t检验,t=5.865,P<0.01),大肠癌组织中ANXA1蛋白的表达水平显著高于自身对照的癌旁正常组织,是癌旁正常组织的1.854±0.216倍,其差异具有统计学意义(单样本t检验,t=3.790,P<0.05)。因此,在K-ras基因野生型大肠癌组织中ANXA1表达下调；而在K-ras基因突变型大肠癌组织中ANXA1表达上调；与K-ras基因野生型标本相比,ANXA1在K-ras基因突变型标本中无论在转录水平还是在蛋白表达水平都显著增加。
3、大肠癌伴有K-ras基因突变者肿瘤的浸润深度较深,病理学分型较差,且出现淋巴结转移及远端转移的比例较高；在ANXA1表达上调的样本中肿瘤发生淋巴结转移及远端转移的比例明显高于ANXA1表达下调的样本(P>0.05)。且在ANXA1表达上调的样本中K-ras基因的突变率明显高于ANXA1表达下调的样本(P<0.001)。
结论
1、本研究首次阐述了ANXA1在大肠癌中的表达与K-ras基因突变的关系。数据显示在K-ras基因野生型大肠癌样本中,ANXA1表达下调；而在K-ras基因突变型大肠癌样本中,ANXA1表达显著上调。ANXA1的表达水平可能成为潜在的预测大肠癌基因型,替代K-ras基因突变检测,实现临床筛查,指导临床应用分子靶向药物的参考指标,具有广泛的临床应用价值。
2、研究中发现在ANXA1表达上调的样本中肿瘤发生淋巴结转移及远端转移的比例高于ANXA1表达下调的样本(P>0.05),且在ANXA1表达上调的样本中K-ras基因的突变率明显高于ANXA1表达下调的样本(P<0.001),提示在大肠癌中ANXA1表达上调可能与肿瘤的转移有关,ANXA1表达情况是否可能成为预测肿瘤预后的指标还需进一步论证。
3、ANXA1对EGFR及下游Ras/Raf/MEK/ERK/MAPK细胞信号通路的调控作用是通过调节EGFR的内吞及降解实现的。并且ERK/MAPK对EGFR具有负反馈作用,ERK/MAPK通过负反馈作用下调EGFR,而这种下调可能是通过上调ANXA1,加速EGFR的内吞及降解而实现的。当K-ras基因突变时,Raf/MEK/ERK/MAPK细胞信号通路的激活将不依赖EGFR的活化,因此ANXA1的上调及EGFR的下调将失去调节作用,无法抑制该通路的激活。对于ERK/MAPK对ANXA1是否有正反馈作用,还需要进一步研究。
Objective
Colorectal cancer, also called cancer of the colon or rectum, is one of most frequently digestive system malignant tumor. In recent years, targeted therapies depending on molecular biology have acquired therapeutic effect. Cetuximab and panitumumab are monoclonal antibodies to treat final stage colorectal cancer that block the ligand binding site of the EGFR, thus inhibiting intracellular signaling. As a target of anti-EGFR monoclonal antibodies, EGFR is currently subject to a high degree of attention. Annexin A1 is a kind of tumor suppressor genes. Studies have shown that Annexin A1 could regulate endocytosis and degradation of EGFR, promote apoptosis and inhibit tumor formation. In this study, we investigated the expression of ANXA1 in colorectal cancer, explored the relationship of clinical, pathological and molecular biological characteristics between ANXA1 and colorectal cancer, and analyzed whether the expression of ANXA1 is correlated with K-ras mutation and BRAF mutation in Colorectal Cancer. Research into this area can enhance our understanding of the possible role of ANXA1 in diagnosis, treatment and prognosis. At the same time, such investigations can also perhaps lead to the possible identification of ANXA1 as a potential reference index in colorectal cancer molecular target treatment.
Method
1. Colorectal cancer and corresponding adjacent normal mucosa were collected. Samples were saved in liquid nitrigen or processed for paraffin-embeding. Clinical and pathological data were also collected.
2. Genomic DNA was extracted. Colorectal cancer gene mutations were detected by gene sequencing.
3. By using immunohistochemical, real-time PCR and Western blot, the transcription and expression of ANXA1 were examined from K-ras gene mutation colorectal cancer and K-ras wild-type colorectal cancer.
Results
1. Twenty patients were included in this study. K-ras mutation were found in 6 of 20 colorectal cancers. The frequency of K-ras mutation was 6/20 (30%). All of the normal mucosa were wild type for K-ras. None of 20 cases of colorectal cancers and normal mucosa specimens were detected with a BRAF mutation.
2. In K-ras gene Wild-Type group, mRNA transcription of ANXA1 in colorectal cancer tissues were decreased significantly (0.122±0.057 fold, t= 10.61, P< 0.001) than that in normal mucosa tissues. Protein expression of ANXA1 in colorectal cancer tissues were decreased significantly (0.729±0.034 fold, t= 5.953, P< 0.001) than that in normal mucosa tissues. In K-ras gene mutation group, mRNA transcription of ANXA1 in colorectal cancer tissues were increased significantly (168.60±46.67 fold, t= 5.865, P< 0.01) than that in normal mucosa tissues. Protein expression of ANXA1 in colorectal cancer tissues were increased significantly (1.854±0.216 fold, t= 3.790, P< 0.05) than that in normal mucosa tissues. Thus, the transcription and expression of ANXA1 in the K-ras gene mutation group were significantly increased than that in the K-ras gene Wild-Type group.
3. The colorectal cancers containing K-ras mutation could infiltrate deeper and have worse pathological types than those of K-ras Wild-Type. The frequencies of lymph node metastasis and distant metastasis in K-ras gene mutation group were higher than those in K-ras gene Wild-Type group. The frequencies of lymph node metastasis and distant metastasis in ANXA1 up-regulation group were higher than those in ANXA1 down-regulation group.
Conclusion
1. Our study describes for the first time that ANXA1 expression in colorectal cancer are related to K-ras gene mutation. The expression of ANXA1 decreases in K-ras gene Wild-Type colorectal cancer. The expression of ANXA1 increases in K-ras gene mutation colorectal cancer. The level of ANXA1 expression can predict colorectal cancer genetype, implement clinical survey and guide clinical use of molecular targeted drugs.
2. The study has found that the frequencies of lymph node metastasis and distant metastasis in ANXA1 up-regulation group are higher than those in ANXA1 down-regulation group (P> 0.05). The frequency of K-ras mutation in the sample of ANXA1 express up-regulation are higher than those of ANXA1 express down-regulation (P<0.001). The result suggest that ANXA1 express up-regulation may be related with tumor metastasis. It needs further proof that whether ANXA1 expression can be used as indicators of tumor prognosis.
3. By regulating EGFR endocytosis and degradation, ANXA1 can regulate EGFR and the Ras/Raf/MEK/ERK/MAPK signaling pathway. K-ras mutation can active the Raf/MEK/ERK/MAPK signaling pathway independent of EGFR. ERK/MAPK negative feedback effect can down-regulate the expression of EGFR. This kind of down-regulation is achieved through up-regulating ANXA1 expression and accelerating EGFR endocytosis or degradation. It needs for further research that whether ERK/MAPK positive feedback effect can up-regulate the expression of ANXA1.
引文
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[24]PAWELETZ CP, ORNSTEIN DK, ROTH MJ, et al. Loss of annexin 1 correlates with early onset of tumorigenesis in esophageal and prostate carcinoma[J]. Cancer Res,2000,60(22): 6293-6297.
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