BMP4诱导头颈鳞癌细胞上皮—间质转化及其转移的分子机制研究
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摘要
头颈鳞癌的早期转移一直是影响患者疗效的重要原因,因此寻找头颈鳞癌转移的关键分子及其作用的分子机制一直是人们研究的重点和热点。本文将分章讨论一新颖分子骨形态发生蛋白4(Bone morphogenetic protein 4, BMP4)在头颈鳞癌转移中的作用及机制。
第一章BMP4在头颈鳞癌中的异常表达及其临床意义
目的探讨头颈鳞癌组织中BMP4及其信号通路蛋白Smadl与p-Smad1的表达与病理分化、淋巴结转移等临床病理学参数的关系,并分析BMP4与头颈鳞癌预后的关系。
方法采用免疫组织化学方法对89例头颈鳞癌组织、20例癌旁正常组织的新鲜标本进行石蜡包埋,切片染色,检测BMP4、Smad1与p-Smadl的表达,分析其在头颈鳞癌组织中的表达与临床病理学参数的关系,采用Sperman相关统计学方法对BMP4与Smadl和p-Smad1表达的相关性进行分析,应用log-rank检验分析该三种蛋白的表达与头颈鳞癌预后的关系。
结果BMP4、Smad1与p-Smad1蛋白在头颈鳞癌组织中的表达均显著高于癌旁组织(P<0.05)。BMP4与p-Smad1的表达与头颈肿瘤的临床分期、病理分级、淋巴结转移、是否复发等因素相关(P<0.05),而与患者年龄无关(P>0.05)；Smad1的表达与头颈肿瘤的临床分期、病理分级有关(P<0.05),而与年龄、淋巴结转移、是否复发等因素无关(P>0.05)；BMP4蛋白与Smad1蛋白的表达不相关,而与p-Smad1的表达呈正相关(rs值分别为0.013和0.548),BMP4与p-Smad1的高表达与患者预后有关(P值分别为0.01562和0.0418),Smad1的表达与患者的预后无关(P=0.6587)。
结论以上结果提示检测BMP4、Smad1与p-Smad1的表达可更能有效地预测头颈鳞癌的发生、早期转移以及预后等,为头颈鳞癌转移机制研究提供新的线索。
第二章BMP4诱导头颈鳞癌上皮-间质转化(EMT)及侵袭转移的机制研究
目的探讨BMP4对头颈鳞癌细胞上皮-间质转化及侵袭转移能力的作用及机制。
方法重组人BMP4作用于头颈鳞癌细胞Hep-2、Tu686、Tu212、M2、M4和212LN。MTT试验检测其对各细胞株生长增殖能力的影响；激光共聚焦显微镜下观察BMP4对Tu686与Tu212细胞形态学方面的作用；Western blot或RT-PCR检测BMP4对Tu686与Tu212细胞EMT相关基因的影响；Transwell细胞侵袭试验与细胞划痕试验分别研究BMP4对两种细胞侵袭与迁移能力的影响。
结果不同浓度的BMP4刺激六株细胞72小时后,生长增殖能力均无显著改变(P>0.05)。Tu686与Tu212细胞的形状均变得更加狭长,呈梭形改变,细胞之间的连接变得松散；两种细胞中E-Cadherin表达均随着BMP4的干预呈浓度与时间依赖性下降,而Vimentin与p-Smad1的表达均随着BMP4的干预呈浓度与时间依赖性升高；与此同时,两种细胞的侵袭与迁移能力均显著增强(P<0.05)。
结论BMP4不影响头颈鳞癌细胞的生长增殖,但可诱导Tu686与Tu212细胞发生EMT改变,同时增强其侵袭与迁移能力,为进一步研究BMP4促进头颈肿瘤转移的机制提供了理论基础,也提示抑制BMP4在预防肿瘤的转移中存在的潜在应用价值。
第三章Smad1基因通过BMP4介导的信号通路对人头颈鳞癌细胞侵袭能力的影响
目的探讨Smad1基因上调或下调后,在BMP4刺激下,头颈肿瘤细胞侵袭转移能力与EMT相关基因表达的改变。
方法将pcDNA3.1(+) Smadl与siRNA Smadl分别瞬时转染Tu686和Tu212细胞,100ng/ml BMP4干预细胞72h,在mRNA水平或蛋白水平检测转染效率。成功上调或下调Smadl后,检测两种细胞中p-Smad1、E-Cadherin与Vimentin表达的变化,Transwell细胞侵袭试验与细胞划痕试验分别检测上述处理后细胞侵袭与迁移能力的变化。
结果瞬时转染pcDNA3.1(+) Smad1成功上调Smad1的表达后,在100ng/ml BMP4的刺激下,Tu686和Tu212细胞中E-Cadherin的表达均显著下降(P<0.05),p-Smad1与Vimentin的表达均显著上升(P<0.05)同时细胞的侵袭与迁移能力均显著增加(P<0.05)；瞬时转染siRNA Smadl并成功抑制Smad1表达后,在100ng/ml BMP4的刺激下,两细胞中E-Cadherin的表达均显著上升(P<0.05),而p-Smad1与Vimentin的表达均显著下降(P<0.05),同时细胞的侵袭与迁移能力均显著下降(P<0.05)。
结论Smadl的磷酸化在BMP4所诱导的头颈鳞癌细胞EMT及其侵袭转移能力的增强中起重要作用。这一实验结果对我们进一步探讨Smad1在头颈肿瘤转移中的作用具有重要启示。
Early metastasis has always been an important factor for the poor prognosis of Squamous cell carcinoma of the head and neck (SCCHN), So looking for the prediction of metastasis and studying the molecular mechanism of SCCHN are of great significance. This manuscript will discuss the effects and mechanisms of a novel molecule-BMP4 on the metastasis of SCCHN in separate chapters.
Chapter 1 The aberrant expression of BMP4 and its clinical significance in SCCHN
Objective. To evaluate the expressions of BMP4 and two related signal pathway proteins, Smadl and p-Smadl in human SCCHN, then to determine their relationships with lymph node metastasis, tumor differentiation, lymphatic metastasis and the prognosis of SCCHN.
Methods. Tissue samples of primary tumors from 89 SCCHN, and 20 normal tissue samples from pharynx or larynx were undergoing paraffin imbedding slices. Immunohistochemistry was used to detect the expressions of BMP4, Smadl and p-Smad1. The relationships between the pathological parameters and three proteins were analysed, Sperman correlation test was applied to analysis the relationships between expressions of BMP4 and Smadl, p-Smadl. Log-rank test was employed to analyse the relationships between the three proteins and the prognosis of SCCHN.
Results. The expressions of BMP4、Smadl and p-Smadl in SCCHN tissues were significantly higher than those in normal mucosa (P<0.05). The expressions of both BMP4 and p-Smad1 were correlated with clinical stage, pathological grade, lymph node metastasis and recurrence (P<0.05), but were not related to patients'age (P>0.05). The expression of Smad1 was correlated with clinical stage, pathological grade(P<0.05), but was not related to patients'age, lymph node metastasis and recurrence (P>0.05). The expression of BMP4 was not related to Smadl, while was positively correlated with p-Smadl (rs values were 0.013 and 0.548, respectively).The high expressions of BMP4 and p-Smadl were associated with the poor prognosis of SCCHN (P values were 0.01562 and 0.0418, respectively), the expression of Smadl was not related to the prognosis of SCCHN (P=0.6587).
Conclusions. All the results suggest that detection of BMP4, Smad1 and p-Smadl will be helpful for the prediction of carcinogenesis, early metastasis and prognosis of SCCHN, it provides new clues for the metastatic studies of SCCHN.
Chapter 2 Bone morphogenetic protein 4 induces invasiveness of the SCCHN cells through EMT in vitro
Objective. To study the mechanisms of BMP4 induced invasiveness of SCCHN cell in vitro.
Methods. Six SCCHN cell lines:Hep-2、Tu686、Tu212、M2、M4、212LN were treated with recombination human BMP4 for 72 hours, MTT test was used to detect the proliferations of each cell line after treatment. Confocal microscopy was applied to observe the phenotypic changes of EMT in both Tu686 and Tu212 after treatment of BMP4; western blot or RT-PCR was applied to detect the expressions of associated genes after treatment by BMP4; Transwell invasive test and scratch test were employed to detect the changes of invasive cell number and migrating cell number of Tu686 and Tu212 after treatment by BMP4, respectively.
Results. There was no statistic difference in proliferation between the BMP4 treated groups and there respective control groups (P>0.05) in all six cell lines after treatment for 72 hours. Both Tu686 and Tu212 epithelial cells turned into more narrow, long strip or fusiform shapes, stretch out silipues boundary, undergoing EMT. The expressions of p-Smad1 and Vimentin in Tu686 and Tu212 cells showed dose and time-dependent increases after treatment with BMP4, while the expression of E-Cadherin were dose and time-dependent decreased after treatment with BMP4. The invasive and migratory abilities of both Tu686 and Tu212 cells were increased significantly after treatment with BMP4 for 72 hours(P<0.05).
Conclusions. BMP4 doesn't affect the proliferation of SCCHN cells, it induces Tu686 and Tu212 cells undergoing EMT in vitro, and facilitates the invasiveness and migration in two cells, so it gives theorical foundations for the further study of BMP4 induced invasiveness in SCCHN, the latent applied values of BMP4 will be proved in the prevention of metastasis in SCCHN.
Chapter 3 The effect of Smadl on the metastasis of SCCHN through BMP4 mediated signal pathways
Objective. To study the effects of Smadl on the invasiveness and the expressions of EMT associated genes in SCCHN cell lines with the stimulation of BMP4 in vitro.
Methods. Tu686 and Tu212 cells were transfected with siRNA Smad1 or pcDNA3.1(+) Smad1, then followed by the treatment of 100ng/ml BMP4 for 72 hours, the efficiencies of transfection were detected on both gene and protein levels. Western blot was applied to detect the changes of p-Smad1, E-cadherin and Vimentin after successfully up or down regulating the expression of Smad1 in two cells. Transwell invasive test or scratch test were employed to detect the invasive and migratory ability after treatment, respectively.
Results. After transfection of Tu686 and Tu212 cells with Smadl gene, Smadl was successfully up-regulated, under the stimulation of 100ng/ml BMP4 for 72 hours, the expressions of E-Cadherin were all significantly down-regulated(P<0.05), the expressions of p-Smad1 and Vimentin were significantly up-regulated(P<0.05). The invasive and migratory abilities of two cells were both decreased significantly(P<0.05). While Smadl was successfully knocked down, in Tu686 and Tu212 cells, the expressions of E-Cadherin were significantly up-regulated(P<0.05), the expression of p-Smad1 and Vimentin were significantly down-regulated(P<0.05). The invasive and migratory abilities of two cells were all decreased significantly(P<0.05).
Conclusions. Smadl and p-Smadl play important roles in the BMP4 induced EMT and invasiveness in SCCHN cells. It paves the way for the further study of Smadl on the metastasis of SCCHN.
第一章BMP4在头颈鳞癌中的异常表达及其临床意义
目的探讨头颈鳞癌组织中BMP4及其信号通路蛋白Smadl与p-Smad1的表达与病理分化、淋巴结转移等临床病理学参数的关系,并分析BMP4与头颈鳞癌预后的关系。
方法采用免疫组织化学方法对89例头颈鳞癌组织、20例癌旁正常组织的新鲜标本进行石蜡包埋,切片染色,检测BMP4、Smad1与p-Smadl的表达,分析其在头颈鳞癌组织中的表达与临床病理学参数的关系,采用Sperman相关统计学方法对BMP4与Smadl和p-Smad1表达的相关性进行分析,应用log-rank检验分析该三种蛋白的表达与头颈鳞癌预后的关系。
结果BMP4、Smad1与p-Smad1蛋白在头颈鳞癌组织中的表达均显著高于癌旁组织(P<0.05)。BMP4与p-Smad1的表达与头颈肿瘤的临床分期、病理分级、淋巴结转移、是否复发等因素相关(P<0.05),而与患者年龄无关(P>0.05)；Smad1的表达与头颈肿瘤的临床分期、病理分级有关(P<0.05),而与年龄、淋巴结转移、是否复发等因素无关(P>0.05)；BMP4蛋白与Smad1蛋白的表达不相关,而与p-Smad1的表达呈正相关(rs值分别为0.013和0.548),BMP4与p-Smad1的高表达与患者预后有关(P值分别为0.01562和0.0418),Smad1的表达与患者的预后无关(P=0.6587)。
结论以上结果提示检测BMP4、Smad1与p-Smad1的表达可更能有效地预测头颈鳞癌的发生、早期转移以及预后等,为头颈鳞癌转移机制研究提供新的线索。
第二章BMP4诱导头颈鳞癌上皮-间质转化(EMT)及侵袭转移的机制研究
目的探讨BMP4对头颈鳞癌细胞上皮-间质转化及侵袭转移能力的作用及机制。
方法重组人BMP4作用于头颈鳞癌细胞Hep-2、Tu686、Tu212、M2、M4和212LN。MTT试验检测其对各细胞株生长增殖能力的影响；激光共聚焦显微镜下观察BMP4对Tu686与Tu212细胞形态学方面的作用；Western blot或RT-PCR检测BMP4对Tu686与Tu212细胞EMT相关基因的影响；Transwell细胞侵袭试验与细胞划痕试验分别研究BMP4对两种细胞侵袭与迁移能力的影响。
结果不同浓度的BMP4刺激六株细胞72小时后,生长增殖能力均无显著改变(P>0.05)。Tu686与Tu212细胞的形状均变得更加狭长,呈梭形改变,细胞之间的连接变得松散；两种细胞中E-Cadherin表达均随着BMP4的干预呈浓度与时间依赖性下降,而Vimentin与p-Smad1的表达均随着BMP4的干预呈浓度与时间依赖性升高；与此同时,两种细胞的侵袭与迁移能力均显著增强(P<0.05)。
结论BMP4不影响头颈鳞癌细胞的生长增殖,但可诱导Tu686与Tu212细胞发生EMT改变,同时增强其侵袭与迁移能力,为进一步研究BMP4促进头颈肿瘤转移的机制提供了理论基础,也提示抑制BMP4在预防肿瘤的转移中存在的潜在应用价值。
第三章Smad1基因通过BMP4介导的信号通路对人头颈鳞癌细胞侵袭能力的影响
目的探讨Smad1基因上调或下调后,在BMP4刺激下,头颈肿瘤细胞侵袭转移能力与EMT相关基因表达的改变。
方法将pcDNA3.1(+) Smadl与siRNA Smadl分别瞬时转染Tu686和Tu212细胞,100ng/ml BMP4干预细胞72h,在mRNA水平或蛋白水平检测转染效率。成功上调或下调Smadl后,检测两种细胞中p-Smad1、E-Cadherin与Vimentin表达的变化,Transwell细胞侵袭试验与细胞划痕试验分别检测上述处理后细胞侵袭与迁移能力的变化。
结果瞬时转染pcDNA3.1(+) Smad1成功上调Smad1的表达后,在100ng/ml BMP4的刺激下,Tu686和Tu212细胞中E-Cadherin的表达均显著下降(P<0.05),p-Smad1与Vimentin的表达均显著上升(P<0.05)同时细胞的侵袭与迁移能力均显著增加(P<0.05)；瞬时转染siRNA Smadl并成功抑制Smad1表达后,在100ng/ml BMP4的刺激下,两细胞中E-Cadherin的表达均显著上升(P<0.05),而p-Smad1与Vimentin的表达均显著下降(P<0.05),同时细胞的侵袭与迁移能力均显著下降(P<0.05)。
结论Smadl的磷酸化在BMP4所诱导的头颈鳞癌细胞EMT及其侵袭转移能力的增强中起重要作用。这一实验结果对我们进一步探讨Smad1在头颈肿瘤转移中的作用具有重要启示。
Early metastasis has always been an important factor for the poor prognosis of Squamous cell carcinoma of the head and neck (SCCHN), So looking for the prediction of metastasis and studying the molecular mechanism of SCCHN are of great significance. This manuscript will discuss the effects and mechanisms of a novel molecule-BMP4 on the metastasis of SCCHN in separate chapters.
Chapter 1 The aberrant expression of BMP4 and its clinical significance in SCCHN
Objective. To evaluate the expressions of BMP4 and two related signal pathway proteins, Smadl and p-Smadl in human SCCHN, then to determine their relationships with lymph node metastasis, tumor differentiation, lymphatic metastasis and the prognosis of SCCHN.
Methods. Tissue samples of primary tumors from 89 SCCHN, and 20 normal tissue samples from pharynx or larynx were undergoing paraffin imbedding slices. Immunohistochemistry was used to detect the expressions of BMP4, Smadl and p-Smad1. The relationships between the pathological parameters and three proteins were analysed, Sperman correlation test was applied to analysis the relationships between expressions of BMP4 and Smadl, p-Smadl. Log-rank test was employed to analyse the relationships between the three proteins and the prognosis of SCCHN.
Results. The expressions of BMP4、Smadl and p-Smadl in SCCHN tissues were significantly higher than those in normal mucosa (P<0.05). The expressions of both BMP4 and p-Smad1 were correlated with clinical stage, pathological grade, lymph node metastasis and recurrence (P<0.05), but were not related to patients'age (P>0.05). The expression of Smad1 was correlated with clinical stage, pathological grade(P<0.05), but was not related to patients'age, lymph node metastasis and recurrence (P>0.05). The expression of BMP4 was not related to Smadl, while was positively correlated with p-Smadl (rs values were 0.013 and 0.548, respectively).The high expressions of BMP4 and p-Smadl were associated with the poor prognosis of SCCHN (P values were 0.01562 and 0.0418, respectively), the expression of Smadl was not related to the prognosis of SCCHN (P=0.6587).
Conclusions. All the results suggest that detection of BMP4, Smad1 and p-Smadl will be helpful for the prediction of carcinogenesis, early metastasis and prognosis of SCCHN, it provides new clues for the metastatic studies of SCCHN.
Chapter 2 Bone morphogenetic protein 4 induces invasiveness of the SCCHN cells through EMT in vitro
Objective. To study the mechanisms of BMP4 induced invasiveness of SCCHN cell in vitro.
Methods. Six SCCHN cell lines:Hep-2、Tu686、Tu212、M2、M4、212LN were treated with recombination human BMP4 for 72 hours, MTT test was used to detect the proliferations of each cell line after treatment. Confocal microscopy was applied to observe the phenotypic changes of EMT in both Tu686 and Tu212 after treatment of BMP4; western blot or RT-PCR was applied to detect the expressions of associated genes after treatment by BMP4; Transwell invasive test and scratch test were employed to detect the changes of invasive cell number and migrating cell number of Tu686 and Tu212 after treatment by BMP4, respectively.
Results. There was no statistic difference in proliferation between the BMP4 treated groups and there respective control groups (P>0.05) in all six cell lines after treatment for 72 hours. Both Tu686 and Tu212 epithelial cells turned into more narrow, long strip or fusiform shapes, stretch out silipues boundary, undergoing EMT. The expressions of p-Smad1 and Vimentin in Tu686 and Tu212 cells showed dose and time-dependent increases after treatment with BMP4, while the expression of E-Cadherin were dose and time-dependent decreased after treatment with BMP4. The invasive and migratory abilities of both Tu686 and Tu212 cells were increased significantly after treatment with BMP4 for 72 hours(P<0.05).
Conclusions. BMP4 doesn't affect the proliferation of SCCHN cells, it induces Tu686 and Tu212 cells undergoing EMT in vitro, and facilitates the invasiveness and migration in two cells, so it gives theorical foundations for the further study of BMP4 induced invasiveness in SCCHN, the latent applied values of BMP4 will be proved in the prevention of metastasis in SCCHN.
Chapter 3 The effect of Smadl on the metastasis of SCCHN through BMP4 mediated signal pathways
Objective. To study the effects of Smadl on the invasiveness and the expressions of EMT associated genes in SCCHN cell lines with the stimulation of BMP4 in vitro.
Methods. Tu686 and Tu212 cells were transfected with siRNA Smad1 or pcDNA3.1(+) Smad1, then followed by the treatment of 100ng/ml BMP4 for 72 hours, the efficiencies of transfection were detected on both gene and protein levels. Western blot was applied to detect the changes of p-Smad1, E-cadherin and Vimentin after successfully up or down regulating the expression of Smad1 in two cells. Transwell invasive test or scratch test were employed to detect the invasive and migratory ability after treatment, respectively.
Results. After transfection of Tu686 and Tu212 cells with Smadl gene, Smadl was successfully up-regulated, under the stimulation of 100ng/ml BMP4 for 72 hours, the expressions of E-Cadherin were all significantly down-regulated(P<0.05), the expressions of p-Smad1 and Vimentin were significantly up-regulated(P<0.05). The invasive and migratory abilities of two cells were both decreased significantly(P<0.05). While Smadl was successfully knocked down, in Tu686 and Tu212 cells, the expressions of E-Cadherin were significantly up-regulated(P<0.05), the expression of p-Smad1 and Vimentin were significantly down-regulated(P<0.05). The invasive and migratory abilities of two cells were all decreased significantly(P<0.05).
Conclusions. Smadl and p-Smadl play important roles in the BMP4 induced EMT and invasiveness in SCCHN cells. It paves the way for the further study of Smadl on the metastasis of SCCHN.
引文
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