神经生长因子受体p75NTR抑制肝癌生长的机制研究
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摘要
p75NTR(p75 neurotrophin receptor)是神经生长因子(neurotrophin, NT)的低亲和力受体,由427个氨基酸组成,属于肿瘤坏死因子受体超家族(TNFR)的一员。p75NTR不仅在神经系统的发育中起重要作用,而且在肿瘤的发生发展中也起重要作用。
既往的研究表明,p75NTR是一个潜在的抑癌基因,它可以抑制前列腺癌细胞的生长。然而有报道认为p75NTR也可以作为生存受体促进黑色素瘤细胞的脑转移,这一矛盾提示p75NTR在不同的肿瘤中可能发挥了不同的作用。我科先前的研究发现,p75NTR在胃癌中的表达显著低于癌旁组织,p75NTR可以抑制胃癌的侵袭和转移。迄今为止,p75NTR在肝癌中的表达情况及在肝癌生长中的作用尚不清楚,本课题将对此进行探讨。
【目的】
1、研究p75NTR在肝癌及癌旁组织中的表达情况;2、研究p75NTR对肝癌细胞生长的影响;3、探讨p75NTR诱导肝癌细胞周期阻滞的可能机制。
【方法】
1、利用免疫组化方法研究p75NTR在肝癌及癌旁组织中的表达。2、Western Blot方法检测肝癌细胞系和正常肝细胞系中p75NTR的表达。3、通过基因重组方法构建p75NTR的siRNA载体,转染Chang细胞,G418筛选,获得稳定克隆。构建p75NTR的正义表达载体,转染HepG2细胞,G418筛选,获得稳定克隆。4、对稳定转染的细胞利用Western blot技术鉴定不同载体的转染效果。5、MTT法绘制转染细胞及对照细胞的生长曲线。6、流式细胞仪分析转染细胞和对照细胞的细胞周期分布。7、利用Hoechst33258染色法和流式细胞仪分析法检测转染细胞的凋亡百分率。8、软琼脂克隆形成实验观察转染细胞和对照细胞在体外的成瘤能力。9、裸鼠成瘤实验观察转染细胞及其对照细胞的体内成瘤能力。10、用Western blot法检测转染细胞中细胞周期相关分子表达水平的变化。
【结果】
1、利用免疫组化技术检测了p75NTR在肝癌和癌旁组织中的表达,发现p75NTR在肝癌组织中的表达显著低于癌旁组织,肝癌的分化程度越低、临床分期越差则p75NTR的表达也越低。2、Western Blot方法检测肝癌细胞系和正常肝细胞系中p75NTR蛋白的表达,发现p75NTR在正常肝细胞系中表达较高,而在肝癌细胞系中表达较低。3、构建了p75NTR的siRNA载体,将其转染Chang细胞,G418筛选获得稳定表达的克隆,经蛋白水平检测证实成功建立了p75NTR下调的稳定细胞系。同时构建了p75NTR的正义表达载体,将其转染HepG2细胞,G418筛选获得稳定表达的克隆,经蛋白水平检测证实成功建立了p75NTR上调的稳定细胞系。4、用MTT法检测细胞生长情况,结果发现,p75NTR-siRNA转染的Chang细胞生长加快,而p75NTR正义转染的HepG2细胞生长减慢。5、细胞周期检测显示,p75NTR-siRNA转染的Chang细胞增殖指数增加,G1/S期的转换加快;而p75NTR正义转染的的HepG2细胞增殖指数降低,发生G1/S期的阻滞。6、Hoechst33258染色法和流式细胞仪分析法检测转染细胞的凋亡情况,结果发现,p75NTR正义转染的HepG2细胞的凋亡百分率增加。7、软琼脂克隆形成实验显示,p75NTR正义转染的HepG2细胞生长减慢,克隆形成率显著低于对照细胞。8、裸鼠体内成瘤实验结果显示,p75NTR正义转染的HepG2细胞的成瘤性显著低于对照细胞。9、Western blot检测转染细胞的细胞周期相关分子发现,p75NTR表达的下调使PCNA、Cyclin D1和p-Rb的表达上调,但使Rb的表达下调;p75NTR表达的上调使PCNA、Cyclin D1和p-Rb的表达下调,但使Rb的表达上调。这提示p75NTR通过上述机制引起了G1/S期的阻滞。
【结论】
1、p75NTR在肝癌组织中的表达显著低于癌旁组织,肝癌的分化程度越低、临床分期越差则p75NTR的表达就越低。2、p75NTR可以抑制肝癌细胞的增殖,促进肝癌细胞的凋亡,从而抑制了肝癌细胞的生长和成瘤能力。3、p75NTR能够通过下调Cyclin D1、p-Rb和PCNA的表达和上调Rb的表达来诱导肝癌细胞的G1/S期阻滞,从而抑制了肝癌的生长。
The nerve growth factor receptor p75 (p75NTR), which contains 427 amino acids, is a low-affinity receptor of neurotrophin. P75NTR plays an important role not only in the development of nerve system, but also in the carcinogenesis and development of cancers.
Previous studies have shown that p75NTR has been identified as a potential tumor suppressor associated with growth inhibition, which could negatively regulate cell growth and proliferation in prostate cancer, however, it was also reported that p75NTR acted as a survival receptor in brain-metastatic melanoma cells. This results indicated that p75NTR play different roles in different kinds of tumors and cell context. Our previous showed that the expression of p75NTR was significantly decreased in gastric cancer tissues than the adjacent noncancerous counterparts, and p75NTR could inhibit the invasion and metastasis of gastric cancer.
Until now, it is unclear whether p75NTR was expressed in hepatocellular carcinoma and the effects of p75NTR on cell proliferation and apoptosis in hepatocellular carcinoma is still unknown. Our purposes in this study are as following:
【Objectives】
(1) To investigate the expression of p75NTR in hepatocellular carcinoma tissues and the adjacent noncancerous counterparts. (2) To study the relationship between p75NTR and growth of hepatocellular carcinoma by expressional and functional studies; (3) To examine the possible mechanisms of cell cycle arrest in hepatocellular carcinoma induced by p75NTR.
【Methods】
(1) The expression of p75NTR protein in hepatocellular carcinoma tissues and their adjacent noncancerous counterparts was investigated by immunohistochemistry assay. (2) The expression of p75NTR protein in hepatocellular carcinoma tissues and their adjacent noncancerous counterparts was measured by Western blot. And the expression of p75NTR protein in hepatocellular carcinoma cell lines and normal liver cell lines was also measured by Western blot. (3) Construct the siRNA vector of p75NTR, transfect it into Chang and select stable clones by G418 screening. Construct the sense expression vector of p75NTR, transfect it into HepG2 and select stable clones by G418 screening. (4) Perform Western blot on different stable clones to identify the effect of transfection. (5) Depict the growth curves of the transfected cells and the control cells. (6) Flow CytoMeter (FCM) is used to identify the cell cycle distribution of these cells. (7) To study the effect of p75NTR on cell apotosis, Hoechst/PI staining and Annexin V flow cytometric experiments were performed. (8) Cloning formation assay on soft agar is applied to test the in vitro tumorigenesis of the transfected HCC cells. (9) Tumor xenograft in nude mice is performed to test the in vivo tumorigenesis of the transfected HCC cells. (10) Identify the expression of the cell cycle associated molecules (cyclin D1, Rb, p-Rb, and PCNA) by Western blot.
【Results】
(1) The expression of p75NTR was decreased significantly in hepatocellular carcinoma tissues as compared with their adjacent noncancerous counterparts, and its expression levels were correlated with the degree of tumor differentiation. (2) The expression of p75NTR was also significantly decreased in various human hepatocellular carcinoma cell lines. (3) The siRNA vector of p75NTR was successfully constructed and transfected into Chang cells. The expression vector of p75NTR was also successfully constructed and transfected into HepG2 cells. The stable clones were selected and identified. (4) The growth of the p75NTR-siRNA transfected Chang cells was accelerated, but the growth of the p75NTR-expressing vector transfected HepG2 cells was slowed down. (5) The FCM indicated that p75NTR inhibited hepatocellular carcinoma cells entering S phase from G1 phase and the proliferative index was decreased. (6) The results of FCM and Hoechst33258/PI staining showed that p75NTR induced apoptosis in hepatocellular carcinoma cells. (7) The cloning formation assay showed that the clone formation rate of p75NTR-expressing vector transfected HepG2 cells was lower than the control cells. (8) The tumorigenicity of p75NTR-expressing vector transfected HepG2 cells was reduced compared with the control cells. (9) Western blot revealed that up-regulating p75NTR could down-regulate the expression of cyclin D1, p-Rb and PCNA, but up-regulate the expression of Rb. Conversely, the results were inverse when p75NTR was down-regulated by specific siRNA.
【Conclusion】
(1) The expression of p75NTR was decreased significantly in hepatocellular carcinoma tissues as compared with their adjacent noncancerous counterparts, and its expression levels were correlated with the degree of tumor differentiation. (2) P75NTR can inhibit the proliferation and induce apoptosis of hepatocellular carcinoma cells. (3) P75NTR can induce G1/S phase arrest throgh down-regulating the expression of cyclin D1, p-Rb and PCNA and up-regulating the expression of Rb.
既往的研究表明,p75NTR是一个潜在的抑癌基因,它可以抑制前列腺癌细胞的生长。然而有报道认为p75NTR也可以作为生存受体促进黑色素瘤细胞的脑转移,这一矛盾提示p75NTR在不同的肿瘤中可能发挥了不同的作用。我科先前的研究发现,p75NTR在胃癌中的表达显著低于癌旁组织,p75NTR可以抑制胃癌的侵袭和转移。迄今为止,p75NTR在肝癌中的表达情况及在肝癌生长中的作用尚不清楚,本课题将对此进行探讨。
【目的】
1、研究p75NTR在肝癌及癌旁组织中的表达情况;2、研究p75NTR对肝癌细胞生长的影响;3、探讨p75NTR诱导肝癌细胞周期阻滞的可能机制。
【方法】
1、利用免疫组化方法研究p75NTR在肝癌及癌旁组织中的表达。2、Western Blot方法检测肝癌细胞系和正常肝细胞系中p75NTR的表达。3、通过基因重组方法构建p75NTR的siRNA载体,转染Chang细胞,G418筛选,获得稳定克隆。构建p75NTR的正义表达载体,转染HepG2细胞,G418筛选,获得稳定克隆。4、对稳定转染的细胞利用Western blot技术鉴定不同载体的转染效果。5、MTT法绘制转染细胞及对照细胞的生长曲线。6、流式细胞仪分析转染细胞和对照细胞的细胞周期分布。7、利用Hoechst33258染色法和流式细胞仪分析法检测转染细胞的凋亡百分率。8、软琼脂克隆形成实验观察转染细胞和对照细胞在体外的成瘤能力。9、裸鼠成瘤实验观察转染细胞及其对照细胞的体内成瘤能力。10、用Western blot法检测转染细胞中细胞周期相关分子表达水平的变化。
【结果】
1、利用免疫组化技术检测了p75NTR在肝癌和癌旁组织中的表达,发现p75NTR在肝癌组织中的表达显著低于癌旁组织,肝癌的分化程度越低、临床分期越差则p75NTR的表达也越低。2、Western Blot方法检测肝癌细胞系和正常肝细胞系中p75NTR蛋白的表达,发现p75NTR在正常肝细胞系中表达较高,而在肝癌细胞系中表达较低。3、构建了p75NTR的siRNA载体,将其转染Chang细胞,G418筛选获得稳定表达的克隆,经蛋白水平检测证实成功建立了p75NTR下调的稳定细胞系。同时构建了p75NTR的正义表达载体,将其转染HepG2细胞,G418筛选获得稳定表达的克隆,经蛋白水平检测证实成功建立了p75NTR上调的稳定细胞系。4、用MTT法检测细胞生长情况,结果发现,p75NTR-siRNA转染的Chang细胞生长加快,而p75NTR正义转染的HepG2细胞生长减慢。5、细胞周期检测显示,p75NTR-siRNA转染的Chang细胞增殖指数增加,G1/S期的转换加快;而p75NTR正义转染的的HepG2细胞增殖指数降低,发生G1/S期的阻滞。6、Hoechst33258染色法和流式细胞仪分析法检测转染细胞的凋亡情况,结果发现,p75NTR正义转染的HepG2细胞的凋亡百分率增加。7、软琼脂克隆形成实验显示,p75NTR正义转染的HepG2细胞生长减慢,克隆形成率显著低于对照细胞。8、裸鼠体内成瘤实验结果显示,p75NTR正义转染的HepG2细胞的成瘤性显著低于对照细胞。9、Western blot检测转染细胞的细胞周期相关分子发现,p75NTR表达的下调使PCNA、Cyclin D1和p-Rb的表达上调,但使Rb的表达下调;p75NTR表达的上调使PCNA、Cyclin D1和p-Rb的表达下调,但使Rb的表达上调。这提示p75NTR通过上述机制引起了G1/S期的阻滞。
【结论】
1、p75NTR在肝癌组织中的表达显著低于癌旁组织,肝癌的分化程度越低、临床分期越差则p75NTR的表达就越低。2、p75NTR可以抑制肝癌细胞的增殖,促进肝癌细胞的凋亡,从而抑制了肝癌细胞的生长和成瘤能力。3、p75NTR能够通过下调Cyclin D1、p-Rb和PCNA的表达和上调Rb的表达来诱导肝癌细胞的G1/S期阻滞,从而抑制了肝癌的生长。
The nerve growth factor receptor p75 (p75NTR), which contains 427 amino acids, is a low-affinity receptor of neurotrophin. P75NTR plays an important role not only in the development of nerve system, but also in the carcinogenesis and development of cancers.
Previous studies have shown that p75NTR has been identified as a potential tumor suppressor associated with growth inhibition, which could negatively regulate cell growth and proliferation in prostate cancer, however, it was also reported that p75NTR acted as a survival receptor in brain-metastatic melanoma cells. This results indicated that p75NTR play different roles in different kinds of tumors and cell context. Our previous showed that the expression of p75NTR was significantly decreased in gastric cancer tissues than the adjacent noncancerous counterparts, and p75NTR could inhibit the invasion and metastasis of gastric cancer.
Until now, it is unclear whether p75NTR was expressed in hepatocellular carcinoma and the effects of p75NTR on cell proliferation and apoptosis in hepatocellular carcinoma is still unknown. Our purposes in this study are as following:
【Objectives】
(1) To investigate the expression of p75NTR in hepatocellular carcinoma tissues and the adjacent noncancerous counterparts. (2) To study the relationship between p75NTR and growth of hepatocellular carcinoma by expressional and functional studies; (3) To examine the possible mechanisms of cell cycle arrest in hepatocellular carcinoma induced by p75NTR.
【Methods】
(1) The expression of p75NTR protein in hepatocellular carcinoma tissues and their adjacent noncancerous counterparts was investigated by immunohistochemistry assay. (2) The expression of p75NTR protein in hepatocellular carcinoma tissues and their adjacent noncancerous counterparts was measured by Western blot. And the expression of p75NTR protein in hepatocellular carcinoma cell lines and normal liver cell lines was also measured by Western blot. (3) Construct the siRNA vector of p75NTR, transfect it into Chang and select stable clones by G418 screening. Construct the sense expression vector of p75NTR, transfect it into HepG2 and select stable clones by G418 screening. (4) Perform Western blot on different stable clones to identify the effect of transfection. (5) Depict the growth curves of the transfected cells and the control cells. (6) Flow CytoMeter (FCM) is used to identify the cell cycle distribution of these cells. (7) To study the effect of p75NTR on cell apotosis, Hoechst/PI staining and Annexin V flow cytometric experiments were performed. (8) Cloning formation assay on soft agar is applied to test the in vitro tumorigenesis of the transfected HCC cells. (9) Tumor xenograft in nude mice is performed to test the in vivo tumorigenesis of the transfected HCC cells. (10) Identify the expression of the cell cycle associated molecules (cyclin D1, Rb, p-Rb, and PCNA) by Western blot.
【Results】
(1) The expression of p75NTR was decreased significantly in hepatocellular carcinoma tissues as compared with their adjacent noncancerous counterparts, and its expression levels were correlated with the degree of tumor differentiation. (2) The expression of p75NTR was also significantly decreased in various human hepatocellular carcinoma cell lines. (3) The siRNA vector of p75NTR was successfully constructed and transfected into Chang cells. The expression vector of p75NTR was also successfully constructed and transfected into HepG2 cells. The stable clones were selected and identified. (4) The growth of the p75NTR-siRNA transfected Chang cells was accelerated, but the growth of the p75NTR-expressing vector transfected HepG2 cells was slowed down. (5) The FCM indicated that p75NTR inhibited hepatocellular carcinoma cells entering S phase from G1 phase and the proliferative index was decreased. (6) The results of FCM and Hoechst33258/PI staining showed that p75NTR induced apoptosis in hepatocellular carcinoma cells. (7) The cloning formation assay showed that the clone formation rate of p75NTR-expressing vector transfected HepG2 cells was lower than the control cells. (8) The tumorigenicity of p75NTR-expressing vector transfected HepG2 cells was reduced compared with the control cells. (9) Western blot revealed that up-regulating p75NTR could down-regulate the expression of cyclin D1, p-Rb and PCNA, but up-regulate the expression of Rb. Conversely, the results were inverse when p75NTR was down-regulated by specific siRNA.
【Conclusion】
(1) The expression of p75NTR was decreased significantly in hepatocellular carcinoma tissues as compared with their adjacent noncancerous counterparts, and its expression levels were correlated with the degree of tumor differentiation. (2) P75NTR can inhibit the proliferation and induce apoptosis of hepatocellular carcinoma cells. (3) P75NTR can induce G1/S phase arrest throgh down-regulating the expression of cyclin D1, p-Rb and PCNA and up-regulating the expression of Rb.
引文
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