微管相关蛋白（MAP4）影响食管鳞癌细胞侵袭迁移的分子机制研究
摘要
食管癌依然是严重危害人类健康的恶性肿瘤,抑制肿瘤细胞对周围组织的侵袭以及转移是有效治疗食管癌提高患者生存率的关键。寻找与食管癌侵袭迁移密切相关的基因、并对之进行功能研究,是当前的主要研究方向之一。我们实验室前期工作中发现了与肿瘤细胞侵袭、迁移和失巢凋亡相关的基因CTTN (cortactin),利用GST-Pull Down和LC-MS/MS技术,鉴定出微管相关蛋白(Microtubule-associated protein4, MAP4)存在于CTTN蛋白的复合体中。
MAP4基因定位于3p21,其编码蛋白的主要功能是通过与微管蛋白结合稳定微管结构。目前MAP4在肿瘤中的功能几乎没有报道,为此我们对该基因在食管癌中发挥的功能以及作用机制进行了深入研究。利用组织微阵列联合免疫组织化学技术分析发现MAP4在364例食管癌中存在过表达,阳性率为62.6%。统计学分析发现,MAP4表达与淋巴结转移(P=0.0003)、病理分期(P=0.0010)以及患者术后生存时间较短(P=0.026)相关,Cox回归分析表明MAP4可作为食管鳞癌患者的独立预后因子(P=0.007)。
我们选取高表达MAP4的Eca109和KYSE150,以及低表达MAP4的KYSE180食管癌系进行了体外功能实验,结果显示MAP4过表达不影响细胞的增殖、细胞周期和粘附能力,但敲降MAP4能明显抑制肿瘤细胞的划痕愈合、运动穿膜以及Matrigel侵袭能力。动物体内实验显示,MAP4表达降低可抑制裸鼠皮下瘤生长和实验性肺转移。
针对MAP4影响食管癌细胞侵袭迁移能力这一表型,我们进一步探讨了MAP4发挥功能的分子机制。当降低MAP4表达时,Real-time PCR和Western blot结果显示,血管内皮生长因子(VEGFA)在mRNA和蛋白水平均下调,敲降VEGFA后,食管癌细胞的侵袭迁移能力降低。检钡VEGFA的受体VEGFRl和、EGFR2,发现在食管癌细胞系中VEGFRl表达量远远高于、EGFIR2,而且降低VEGFR1表达,细胞侵袭迁移能力也降低。这些结果提示,食管癌细胞系中MAP4在转录水平调节VEGFA,并通过VEGFA/VEGFRl下游通路影响食管癌细胞侵袭迁移能力。利用相同食管癌手术组织的连续切片分析发现,MAP4与VEGFA和VEGFR1蛋白的表达显著正相关。
我们继而检测了与细胞侵袭迁移相关的信号通路关键节点分子,发现MAP4影响ERKl/2的磷酸化水平。敲降ERKl/2,发现细胞侵袭迁移的能力降低,而且VEGFA蛋白水平下降。免疫共沉淀(CO-IP)结果提示MAP4能与ERK1/2相互作用。机制分析结果显示,MAP4通过与ERKl/2相互作用,调节VEGFA,而且VEGFA和ERK1/2存在反馈调节,最终影响食管癌细胞的侵袭迁移。
抑瘤实验结果显示,利用食管癌细胞诱导的皮下瘤内注射MAP4-siRNA,肿瘤的体积在注射两天后开始缩小；尾静脉注射贝伐单抗也能抑制瘤体生长；当瘤体注射MAP4-siRNA联合尾静脉注射贝伐单抗时,抑瘤效果不仅高于单独注射MAP4-siRNA,也优于单独注射贝伐单抗。
这些资料表明,MAP4通过激活ERK1/2-VEGFA/VEGFR1-ERK1/2通路增强食管癌细胞的侵袭迁移能力,MAP4有可能可以作为独立的食管鳞癌预后标志物,并且可能成为食管鳞癌治疗的的分子靶点。
Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies in the world. Cell invasion and migration are crucial steps in carcinogenesis progression that significantly contribute to tumor metastasis. We have previously reported that CTTN (cortactin) is an oncogene and exerts functions in tumor metastasis in ESCC. With GST-Pull Down and LC-MS/MS, we found that MAP4is in the CTTN-complex.
The molecular mechanism underlying the role of MAP4in esophageal squamous cells remain unclear. We detected that high expression of MAP4is228(62.6%) in the364ESCCs, The high expression of MAP4was significantly associated with tumor stage (P=0.0010) and lymph node metastasis (P=0.0003). Kaplan-Meier analysis showed that patients with high MAP4expression had significantly poor overall survival (P=0.026). Multivariate Cox regression analysis indicated that MAP4high expression (P=0.007) was an independent prognostic factor.
In order to characterize the role of MAP4in ESCC, we performed functional analysis by siRNA-mediated silencing. The results showed that MAP4did not influence cell proliferation, cell cycle and adhesion. Whereas MAP4RNAi decreased the ability of wound healing, haptotactic migration and matrigel invasion in Eca109and KYSE150cells.In vivo assay showed that inhibition of MAP4expression decreased tumor growth and metastasis in mouse models.
At the molecular level, Real-time PCR and Western blot analysis showed that VEGFA were significantly reduced in MAP4-siRNA transfected Eca109and KYSE150cells and also in their culture supernatants. We then detected the levels of VEGFR1and VEGFR2expression in Eca109and KYSE150cells. The results indicated that VEGFR1expression was much higher than VEGFR2. Silencing VEGFA and VEGFR1expression also markedly inhibited the invasion and migration of Eca109and KYSE150cells. IHC showed a positive correlation between MAP4, VEGFA and VEGFR1expressions in the ESCC tissues.
Futher analysis showed that the phosphorylation levels of ERK1/2were dramatically decreased in MAP4silenced cells, Knockdown of ERK1/2not only inhibited VEGFA expression but also suppressed the invasion and migration of Eca109and KYSE150cells. Co-immunoprecipitation (Co-Ip) assays showed that MAP4was co-immunoprecipitated with ERK1/2(Fig.4h), Knockdown of VEGFA or VEGFR1decreased the levels of phosphorylated ERK1/2. Collectively, these data suggest that there is a reciprocal activation between VEGFA/VEGFR1and ERK1/2, which contributes to the invasion and migration by MAP4in esophageal cancer cells regulated.
An injection of MAP4-siRNA directly into the induced tumors, led to a decrease of the volume of tumor by86%as compared with the control. Injection of Bevacizumab via tail vein into nude mice suppressed the increase of the tumor volume. When combined intratumoral-injection of MAP4-siRNA with injection of Bevacizumab via tail vein, the inhibition to tumor growth was superior to that of Bevacizumab or MAP4-siRNA alone.
In conclusion, We show that MAP4is of prognostic and therapeutic relevance. Elevated expression of MAP4protein is an independent indicator for shorter survival of the patients with ESCC. As an important regulator of ERK1/2-VEGFA/VEGFR1signaling, MAP4may serve as a candidate molecular target for ESCC therapy.
MAP4基因定位于3p21,其编码蛋白的主要功能是通过与微管蛋白结合稳定微管结构。目前MAP4在肿瘤中的功能几乎没有报道,为此我们对该基因在食管癌中发挥的功能以及作用机制进行了深入研究。利用组织微阵列联合免疫组织化学技术分析发现MAP4在364例食管癌中存在过表达,阳性率为62.6%。统计学分析发现,MAP4表达与淋巴结转移(P=0.0003)、病理分期(P=0.0010)以及患者术后生存时间较短(P=0.026)相关,Cox回归分析表明MAP4可作为食管鳞癌患者的独立预后因子(P=0.007)。
我们选取高表达MAP4的Eca109和KYSE150,以及低表达MAP4的KYSE180食管癌系进行了体外功能实验,结果显示MAP4过表达不影响细胞的增殖、细胞周期和粘附能力,但敲降MAP4能明显抑制肿瘤细胞的划痕愈合、运动穿膜以及Matrigel侵袭能力。动物体内实验显示,MAP4表达降低可抑制裸鼠皮下瘤生长和实验性肺转移。
针对MAP4影响食管癌细胞侵袭迁移能力这一表型,我们进一步探讨了MAP4发挥功能的分子机制。当降低MAP4表达时,Real-time PCR和Western blot结果显示,血管内皮生长因子(VEGFA)在mRNA和蛋白水平均下调,敲降VEGFA后,食管癌细胞的侵袭迁移能力降低。检钡VEGFA的受体VEGFRl和、EGFR2,发现在食管癌细胞系中VEGFRl表达量远远高于、EGFIR2,而且降低VEGFR1表达,细胞侵袭迁移能力也降低。这些结果提示,食管癌细胞系中MAP4在转录水平调节VEGFA,并通过VEGFA/VEGFRl下游通路影响食管癌细胞侵袭迁移能力。利用相同食管癌手术组织的连续切片分析发现,MAP4与VEGFA和VEGFR1蛋白的表达显著正相关。
我们继而检测了与细胞侵袭迁移相关的信号通路关键节点分子,发现MAP4影响ERKl/2的磷酸化水平。敲降ERKl/2,发现细胞侵袭迁移的能力降低,而且VEGFA蛋白水平下降。免疫共沉淀(CO-IP)结果提示MAP4能与ERK1/2相互作用。机制分析结果显示,MAP4通过与ERKl/2相互作用,调节VEGFA,而且VEGFA和ERK1/2存在反馈调节,最终影响食管癌细胞的侵袭迁移。
抑瘤实验结果显示,利用食管癌细胞诱导的皮下瘤内注射MAP4-siRNA,肿瘤的体积在注射两天后开始缩小；尾静脉注射贝伐单抗也能抑制瘤体生长；当瘤体注射MAP4-siRNA联合尾静脉注射贝伐单抗时,抑瘤效果不仅高于单独注射MAP4-siRNA,也优于单独注射贝伐单抗。
这些资料表明,MAP4通过激活ERK1/2-VEGFA/VEGFR1-ERK1/2通路增强食管癌细胞的侵袭迁移能力,MAP4有可能可以作为独立的食管鳞癌预后标志物,并且可能成为食管鳞癌治疗的的分子靶点。
Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies in the world. Cell invasion and migration are crucial steps in carcinogenesis progression that significantly contribute to tumor metastasis. We have previously reported that CTTN (cortactin) is an oncogene and exerts functions in tumor metastasis in ESCC. With GST-Pull Down and LC-MS/MS, we found that MAP4is in the CTTN-complex.
The molecular mechanism underlying the role of MAP4in esophageal squamous cells remain unclear. We detected that high expression of MAP4is228(62.6%) in the364ESCCs, The high expression of MAP4was significantly associated with tumor stage (P=0.0010) and lymph node metastasis (P=0.0003). Kaplan-Meier analysis showed that patients with high MAP4expression had significantly poor overall survival (P=0.026). Multivariate Cox regression analysis indicated that MAP4high expression (P=0.007) was an independent prognostic factor.
In order to characterize the role of MAP4in ESCC, we performed functional analysis by siRNA-mediated silencing. The results showed that MAP4did not influence cell proliferation, cell cycle and adhesion. Whereas MAP4RNAi decreased the ability of wound healing, haptotactic migration and matrigel invasion in Eca109and KYSE150cells.In vivo assay showed that inhibition of MAP4expression decreased tumor growth and metastasis in mouse models.
At the molecular level, Real-time PCR and Western blot analysis showed that VEGFA were significantly reduced in MAP4-siRNA transfected Eca109and KYSE150cells and also in their culture supernatants. We then detected the levels of VEGFR1and VEGFR2expression in Eca109and KYSE150cells. The results indicated that VEGFR1expression was much higher than VEGFR2. Silencing VEGFA and VEGFR1expression also markedly inhibited the invasion and migration of Eca109and KYSE150cells. IHC showed a positive correlation between MAP4, VEGFA and VEGFR1expressions in the ESCC tissues.
Futher analysis showed that the phosphorylation levels of ERK1/2were dramatically decreased in MAP4silenced cells, Knockdown of ERK1/2not only inhibited VEGFA expression but also suppressed the invasion and migration of Eca109and KYSE150cells. Co-immunoprecipitation (Co-Ip) assays showed that MAP4was co-immunoprecipitated with ERK1/2(Fig.4h), Knockdown of VEGFA or VEGFR1decreased the levels of phosphorylated ERK1/2. Collectively, these data suggest that there is a reciprocal activation between VEGFA/VEGFR1and ERK1/2, which contributes to the invasion and migration by MAP4in esophageal cancer cells regulated.
An injection of MAP4-siRNA directly into the induced tumors, led to a decrease of the volume of tumor by86%as compared with the control. Injection of Bevacizumab via tail vein into nude mice suppressed the increase of the tumor volume. When combined intratumoral-injection of MAP4-siRNA with injection of Bevacizumab via tail vein, the inhibition to tumor growth was superior to that of Bevacizumab or MAP4-siRNA alone.
In conclusion, We show that MAP4is of prognostic and therapeutic relevance. Elevated expression of MAP4protein is an independent indicator for shorter survival of the patients with ESCC. As an important regulator of ERK1/2-VEGFA/VEGFR1signaling, MAP4may serve as a candidate molecular target for ESCC therapy.
引文
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