恶性黑素瘤中SOX4的表达及其对Wnt/β-catenin信号途径作用的研究
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摘要
第一部分SOX4在人恶性黑素瘤组织中的表达
目的：研究SOX4在人类恶性黑素瘤组织中的表达情况,探讨SOX4与恶性黑素瘤之间可能存在的关系。
方法：用免疫组化SP法检测30例恶性黑素瘤组织中的SOX4的表达情况。
结果：在恶性黑素瘤组织中,肿瘤细胞的细胞核内可见棕黄色至深褐色颗粒,胞浆也可着色。30例恶性黑素瘤组织中,有17例SOX4表达为阳性,阳性率为56.7%,而正常人皮肤组织中未见阳性表达,两组间SOX4表达阳性率具有显著性差异(P<0.05)。
结论：在恶性黑素瘤组织中SOX4出现异常的阳性表达,SOX4可能与恶性黑素瘤的发病机制有关。
第二部分采用RNA干扰技术抑制恶性黑素瘤细胞中SOX4的表达并研究其对Wnt/β-catenin信号途径活性的影响
目的：研究恶性黑素瘤A375细胞中SOX4对Wnt/β-catenin信号途径中Wnt3A及β-catenin的表达的影响以及对Wnt/β-catenin信号途径活性的影响,探讨恶性黑素瘤A375细胞中SOX4对Wnt/β-catenin信号途径的调控作用及其可能的机制。
方法：采用RNA干扰技术,将两段SOX4 siRNA导入恶性黑素瘤A375细胞,使SOX4基因沉默,分别采用实时荧光定量PCR法和蛋白质印迹法检测干扰后Wnt/p-catenin信号途径中Wnt3A及β-catenin的mRNA及蛋白表达情况的变化,并采用TOPflash/FOPflash双质粒报告基因系统检测恶性黑素瘤A375细胞中Wnt/β-catenin信号途径活性随RNA干扰变化的情况。
结果：本研究使用的两段SOX4 siRNA均成功转染恶性黑素瘤A375细胞并有效抑制SOX4基因表达(P<0.05),发挥了对SOX4的基因沉默作用。转染SOX4 siRNA对Wnt3A的mRNA及蛋白表达水平无显著影响(P>0.05),对β-catenin的mRNA表达水平亦无显著性影响,但使得细胞内β-catenin蛋白量减少(P<0.05)。同时,转染了SOX4 siRNA的A375内Wnt/β-catenin信号途径活性较转染非特异性siRNA的A375细胞及空白对照组为低,差异具有显著性(P<0.05)。
结论：在恶性黑素瘤A375细胞中,SOX4对Wnt/β-catenin信号途径具有正向调控作用,这种调控作用与β-catenin有关。SOX4上调A375细胞中β-catenin蛋白含量,其作用发生在转录后水平,可能是SOX4抑制β-catenin降解的结果,也有可能与转录后调控或翻译调控等有关。
第三部分SOX4 siRNA对恶性黑素瘤细胞中Survivin的表达及细胞增殖的影响
目的：研究SOX4对恶性黑素瘤A375细胞中Wnt/β-catenin信号途径的靶基因Survivin的基因表达的影响及对A375细胞增殖活力的影响
方法：分别用实时荧光定量PCR法和蛋白质印迹法检测RNA干扰后A375细胞Survivin的mRNA及蛋白表达水平的变化；用MTT法检测A375细胞的增殖活力。
结果：(1)SOX4 siRNA使得A375细胞Survivin的mRNA及蛋白表达水平均显著下降(P<0.05)。(2)转染了SOX4 siRNA的A375细胞增殖活力较对照组明显下降(P<0.05)。
结论：SOX4对恶性黑素瘤A375细胞的增殖具有促进作用,其机制可能与SOX4增强Wnt/β-catenin信号途径活性而上调Survivin的基因表达有关。
Part 1 Expression of SOX4 in melanoma
Objective:To study the expression of SOX4 in melanoma tissues and to explore the possible role of SOX4 in hunman melanoma.
Methods:SOX4 protein was detected by immunohistochemistry and normal skin of human was used as control.
Results:Positive expression of SOX4 in nuclear was detected in 17 of all 30 melanoma tissues.However,no nuclear expression was found in all normal skin tissues.
Conclusions:Our work showed that SOX4 was overexpressed in melanoma tissues.There should be some relationship between SOX4 and melanoma.
Part 2 Gene silence of SOX4 by RNA interference and its influence on Wnt/β-catenin pathway in melanoma cells
Objective:To investigate the effects of siRNA mediated SOX4 gene silencing on Wnt/β-catenin pathway of human malignant melanoma cells.
Methods:Two types of dsRNA of SOX4 were constructed and transfected into A375 cells,untreated cells and cells transfected by scramble RNA were used as control groups.The expression levels of mRNA and protein of SOX4,Wnt3A,P-catenin were detected by real-time PCR and Western blot respectively. TOPflash/FOPflash reporter assay was uesd for assessing Wnt/β-catenin signaling pathway activity.
Results:Our results showed that the two types of SOX4 siRNA were transferred into A375 cells successfully.Compared with control cells, SOX4 siRNAs had no significant influence on Wnt3A.Nevertheless, SOX4 siRNAs led to the decrease ofβ-catenin protein without significant change ofβ-catenin mRNA expression. Wnt/β-catenin signaling pathway activity was inhibited significantly.
Conclusions:Our study suggested that SOX4 may play an important role in Wnt/β-catenin signaling pathway in human malignant melanoma cells by influenceβ-catenin protein.lt may be a possible mechanism of SOX4 in the progression of malignant melanoma.
Part 3 Effects of SOX4 siRNA on Survivin expression and proliferation of melanoma cells
Objective:To explore the role of SOX4 in A375 cell proliferation and the possible mechanism.
Methods:The expression levels of mRNA and protein of survivin were detected by real-time PCR and Western blot respectively. MTT assay was used to observe cell proliferation.
Resuls:Our results showed that SOX4 siRNA reduced Survivin expression at both mRNA level and protein level. SOX4 siRNAs inhibited proliferation of A375 cells significantly.
Conclusions:SOX4 promotes Survivin expression and cell proliferation of A375 cells by one possible mechanism of increasing the activity of Wnt/β-catenin signaling pathway.
目的：研究SOX4在人类恶性黑素瘤组织中的表达情况,探讨SOX4与恶性黑素瘤之间可能存在的关系。
方法：用免疫组化SP法检测30例恶性黑素瘤组织中的SOX4的表达情况。
结果：在恶性黑素瘤组织中,肿瘤细胞的细胞核内可见棕黄色至深褐色颗粒,胞浆也可着色。30例恶性黑素瘤组织中,有17例SOX4表达为阳性,阳性率为56.7%,而正常人皮肤组织中未见阳性表达,两组间SOX4表达阳性率具有显著性差异(P<0.05)。
结论：在恶性黑素瘤组织中SOX4出现异常的阳性表达,SOX4可能与恶性黑素瘤的发病机制有关。
第二部分采用RNA干扰技术抑制恶性黑素瘤细胞中SOX4的表达并研究其对Wnt/β-catenin信号途径活性的影响
目的：研究恶性黑素瘤A375细胞中SOX4对Wnt/β-catenin信号途径中Wnt3A及β-catenin的表达的影响以及对Wnt/β-catenin信号途径活性的影响,探讨恶性黑素瘤A375细胞中SOX4对Wnt/β-catenin信号途径的调控作用及其可能的机制。
方法：采用RNA干扰技术,将两段SOX4 siRNA导入恶性黑素瘤A375细胞,使SOX4基因沉默,分别采用实时荧光定量PCR法和蛋白质印迹法检测干扰后Wnt/p-catenin信号途径中Wnt3A及β-catenin的mRNA及蛋白表达情况的变化,并采用TOPflash/FOPflash双质粒报告基因系统检测恶性黑素瘤A375细胞中Wnt/β-catenin信号途径活性随RNA干扰变化的情况。
结果：本研究使用的两段SOX4 siRNA均成功转染恶性黑素瘤A375细胞并有效抑制SOX4基因表达(P<0.05),发挥了对SOX4的基因沉默作用。转染SOX4 siRNA对Wnt3A的mRNA及蛋白表达水平无显著影响(P>0.05),对β-catenin的mRNA表达水平亦无显著性影响,但使得细胞内β-catenin蛋白量减少(P<0.05)。同时,转染了SOX4 siRNA的A375内Wnt/β-catenin信号途径活性较转染非特异性siRNA的A375细胞及空白对照组为低,差异具有显著性(P<0.05)。
结论：在恶性黑素瘤A375细胞中,SOX4对Wnt/β-catenin信号途径具有正向调控作用,这种调控作用与β-catenin有关。SOX4上调A375细胞中β-catenin蛋白含量,其作用发生在转录后水平,可能是SOX4抑制β-catenin降解的结果,也有可能与转录后调控或翻译调控等有关。
第三部分SOX4 siRNA对恶性黑素瘤细胞中Survivin的表达及细胞增殖的影响
目的：研究SOX4对恶性黑素瘤A375细胞中Wnt/β-catenin信号途径的靶基因Survivin的基因表达的影响及对A375细胞增殖活力的影响
方法：分别用实时荧光定量PCR法和蛋白质印迹法检测RNA干扰后A375细胞Survivin的mRNA及蛋白表达水平的变化；用MTT法检测A375细胞的增殖活力。
结果：(1)SOX4 siRNA使得A375细胞Survivin的mRNA及蛋白表达水平均显著下降(P<0.05)。(2)转染了SOX4 siRNA的A375细胞增殖活力较对照组明显下降(P<0.05)。
结论：SOX4对恶性黑素瘤A375细胞的增殖具有促进作用,其机制可能与SOX4增强Wnt/β-catenin信号途径活性而上调Survivin的基因表达有关。
Part 1 Expression of SOX4 in melanoma
Objective:To study the expression of SOX4 in melanoma tissues and to explore the possible role of SOX4 in hunman melanoma.
Methods:SOX4 protein was detected by immunohistochemistry and normal skin of human was used as control.
Results:Positive expression of SOX4 in nuclear was detected in 17 of all 30 melanoma tissues.However,no nuclear expression was found in all normal skin tissues.
Conclusions:Our work showed that SOX4 was overexpressed in melanoma tissues.There should be some relationship between SOX4 and melanoma.
Part 2 Gene silence of SOX4 by RNA interference and its influence on Wnt/β-catenin pathway in melanoma cells
Objective:To investigate the effects of siRNA mediated SOX4 gene silencing on Wnt/β-catenin pathway of human malignant melanoma cells.
Methods:Two types of dsRNA of SOX4 were constructed and transfected into A375 cells,untreated cells and cells transfected by scramble RNA were used as control groups.The expression levels of mRNA and protein of SOX4,Wnt3A,P-catenin were detected by real-time PCR and Western blot respectively. TOPflash/FOPflash reporter assay was uesd for assessing Wnt/β-catenin signaling pathway activity.
Results:Our results showed that the two types of SOX4 siRNA were transferred into A375 cells successfully.Compared with control cells, SOX4 siRNAs had no significant influence on Wnt3A.Nevertheless, SOX4 siRNAs led to the decrease ofβ-catenin protein without significant change ofβ-catenin mRNA expression. Wnt/β-catenin signaling pathway activity was inhibited significantly.
Conclusions:Our study suggested that SOX4 may play an important role in Wnt/β-catenin signaling pathway in human malignant melanoma cells by influenceβ-catenin protein.lt may be a possible mechanism of SOX4 in the progression of malignant melanoma.
Part 3 Effects of SOX4 siRNA on Survivin expression and proliferation of melanoma cells
Objective:To explore the role of SOX4 in A375 cell proliferation and the possible mechanism.
Methods:The expression levels of mRNA and protein of survivin were detected by real-time PCR and Western blot respectively. MTT assay was used to observe cell proliferation.
Resuls:Our results showed that SOX4 siRNA reduced Survivin expression at both mRNA level and protein level. SOX4 siRNAs inhibited proliferation of A375 cells significantly.
Conclusions:SOX4 promotes Survivin expression and cell proliferation of A375 cells by one possible mechanism of increasing the activity of Wnt/β-catenin signaling pathway.
引文
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