TGF-β1、wt-p53和RhoA基因在人前列腺癌组织中的表达及其意义
摘要
目的:探讨TGF-β1、wt-p53和RhoA基因在人前列腺癌组织中的表达及其意义。
方法:本次实验采集标本42例,6例正常前列腺组织来自手术非正常死亡的人体,36例前列腺癌标本为吉林大学前列腺疾病防治研究中心应用经直肠超声引导下前列腺6点活检技术穿刺采集或手术采集。用HE染色确定前列腺标本的病理类型,采用免疫组织化学、RT-PCR、Western-blot等技术定性和定量检测各标本中TGF-β1、wt-p53和RhoA基因在正常前列腺组织和前列腺癌组织中的表达。采用免疫组织化学方法检测了体外培养的人前列腺癌细胞系PC3细胞的TGF-β1、和RhoA蛋白的表达,并采用明胶酶谱法检测了PC3细胞培养上清中MMP-2和MMP-9的表达。
结果:①正常前列腺外腺和癌旁组织间的TGF-β1、wt-p53和RhoA表达无差异(P>0.05),均未发现wt-p53基因突变;②与正常前列腺组织和癌旁组织相比,TGF-β1和RhoA在前列腺癌组织中高表达(P<0.01),wt-p53低表达(P<0.01),且部分基因突变为mt-p53;③免疫组织化学结果显示,随着前列腺癌分化程度的降低,TGF-β1、和RhoA的表达都增高,呈负相关关系(r =-0.7884,P=0.0023;r =-0.6758,P=0.0158);④随着前列腺癌分化程度的降低,mt-p53表达逐渐增强,呈负相关关系(r =-0.7662,P=0.0037),说明wt-p53基因的突变率增加,mt-P53蛋白在细胞内积聚;⑤RT-PCR和Western-blot结果显示,已发生远处转移的前列腺癌组织中TGF-β1、wt-p53和RhoA的mRNA转录和蛋白表达,与无转移灶者相比差异有统计学意义(P<0.01);⑥光学显微镜下可以见到在PC3细胞的细胞核和细胞质中均有棕黄色颗粒,表明TGF-β1、和RhoA的表达均呈阳性;⑦PC3细胞培养上清中有MMP-2和MMP-9的表达。
结论:无论是临床标本还是体外培养的细胞系检测结果均表明TGF-β1、wt-p53和RhoA基因与前列腺癌的发生和进展相关,并在前列腺癌的浸润转移中起重要作用,利用联合检测TGF-β1、wt-p53和RhoA基因的表达可有助于对前列腺癌进行早期诊断,评估肿瘤的浸润性进展过程,评价化疗治疗效果和预后。
Prostate cancer is the most common malignancy generated from the male reproductive system. In the United States and Europe, it has the highest incidence among the cancer-related deseases and is ranked as the second cause of mortality which is only less than lung cancer. In China, previously its incidence and mortality rates were relatively low but they have shown a rapid upward tendency in recent years, while the age structure, lifestyle and living standard of the society changes. Most cases of the prostate cancer are currently diagnosed at the terminal stage because the location of the prostate is hidden and the clinical symptoms appear later, and many men has lost the opportunity to treat.
Since 1989, an application of the serum PSA screening has been conducted nation-widely for prostate cancer in the United States and early detection and early treatment for prostate cancer have been achieved. Since 2000, both serum prostate-specific antigen and B-ultrasound-guided transrectal prostate biopsy were applied to screen prostate cancer for men over the age of 50 in Changchun City by Jilin University Research Center for the Control and Prevention Prostate Disease. The prostate cancer detection rate was 1.7%, and approximately 42% of advanced cases, of which 18% of patients associated with bone metastasis. As a result, the early detection of patients with initial inspection rate(from 28% to 58%)greatly improved. Men currently diagnosed at the early stages of prostate cancer can, in many cases, be effectively treated by surgery or radiation and survive for 10 years. However, androgen deprivation therapy is only a palliative treatment for one third of the patients. About 12-18 months later, the disease will recur and ultimately develop into hormone-refractory prostate cancer and metastatic prostate cancers that are essentially incurable and not sensitive to either chemotherapy or radiation therapy. These patients always lead lives of poor quality because of urinary tract obstruction and spinal metastasis, and their prognosis is poor. Therefore, it is very important for us to improve the Group screening project to raise the early detection rate, to study the factors which affect the tumor metastasis, and to further explore the ways to reverse or slow down the process. Thus, it is being received increasing attention to diagnose and treat prostate carcinoma by the method of tumor gene.
TGF-β1 (transforming growth factor beta 1) has a wide range of biological activity in vivo or in vitro, including the regulation of cell growth, differentiation, apoptosis and extracellular matrix protein synthesis. Under normal physiological conditions, TGF-β1 can induce the apoptosis of both body cells and tumor cells.
When TGF-β1 mediated signal transduction pathway mutates in the tumor progression, TGF-β1 is over-expressed and increases tumor proliferation, migration and invasion. As TGF-β1 can promote tumor angiogenesis, cell spread, immune suppression and synthesis of extracellular matrix, etc, it can provide an appropriate micro-environment for the proliferation, migration and invasion of human tumor.
Wt-p53 gene is the most relevant to a variety of human tumors among the genes discovered so far. The mutation of wt-p53 is the most common change of tumor genetics, and it is necessary for mt-p53 to maintain the proliferation of human carcinoma cells. Not wt-P53 but mt-P53 is detected by the routine immunohistochemical methods. The intracellular concentration of mt-P53 is a general resultant to the extent of wt-p53 mutations. p53 gene in the normal cells is wild-type p53 gene without mutations, whose function is monitoring the integrity of the genome, controlling the cell division cycle, and inducing cell apoptosis. Therefore it can inhibit the genesis and proliferation of the tumor cell. Either the reactivation of wt-p53 or the inactivation of mt-p53 in the tumor cells can lead the tumor cells to apoptosis. RhoA (Ras homology A) is an important member of the intracellular signaling transducers. It can mediate actin polymerization, actomyosin contraction and microtubule dynamics, so its function is to maintain the cytoskeleton, basic movement, mitosis and directional differentiation of stem cells. Therefore, RhoA is very important in the biological developmental process. RhoA is highly expressed and actived in tumor cells during tumor development and progression, which can regulate the expression and activity of cell cycle-related gene or protein to promote the division and clonal expansion of the undifferentiated cell and increase the tumor grade. It also induces the changes of skeleton, morphology and adhesion of the tumor cell in order to facilitate cell migration movement. It may regulate TGF-β1, VEGF expression, etc to promote tumor angiogenesis, too. On the other hand, we can partially reverse the malignant phenotype of cancer cells and inhibit the proliferation of tumor cells by reducing the expression of RhoA.
Matrix metalloproteinases (MMPs) are a large family in the protease category. They are a kind of endo-protease which depend on Zn~(2+) and Ca~(2+) and they can completely degrade the extracellular matrix(ECM)and basement membrane(BM), which provide a premise for the tumor to invade and metastasize in the body. TGF-β1 and RhoA can regulate the extracellular matrix and basement membrane degradation and reconstructionby by regulating MMPs and TIMP level and thus promote the local tumor infiltration.
In this paper, we select TGF-β1, wt-P53, and RhoA as the experiment target genes because they are closely related to the genesis and development of the majority of human tumors. To investigate their relationship with the malignant degree and metastasis of prostate cancer, we first adopt immunohistochemistry, RT-PCR, Western-blot methods to observe their expressions and changes in human prostate normal, carcinomatous and paraneoplastic tissues; then we adopt immunohistochemistry to observe the expressions of TGF-β1 and RhoA protein in cultured human prostate cancer cell lines PC3 in vitro; finally, we use gelatin zymography to detect the MMP-2 and MMP-9 expressions in the supernatant of PC3 cell culture. Thus, we can find some new valuable reference indexes for the early diagnosis of prostate cancer and assess the tumorous invasive power, therapeutic effect and prognosis, and even provide some new valuable ideas for the treatment of prostate cancer.
Objective:
①To detect the mRNA and protein expressions of TGF-β1, wt-p53 and the RhoA genes in prostate normal tissues and prostate cancerous tissues;
②To analyse the relationship between expressions and changes of the TGF-β1, wt-p53, RhoA genes and the malignant degree of the prostate cancer;
③To analysis the relationship between expressions and changes of the TGF-β1, wt-p53, RhoA genes and the metastasis of the prostate cancer;
④To discuss the association of TGF-β1, wt-p53, RhoA and their roles to determine the progression and prognosis of prostate cancer.
Methods:
①The pathological classification of all specimens was determined by HE staining methods.
②Immunohistochemistry, RT-PCR and Western-blot techniques were used to qualitatively and quantitatively detect the protein and mRNA expressed by TGF-β1, wt-P53 and RhoA genes in normal prostatic, cancerous and paraneoplastic tissues.
③The method of Immunohistochemistry was used to detect the expressions of TGF-β1 and RhoA protein in PC3 cells cultured in vitro.
④Gelatin zymography was performed to examine the presence of MMP-9 and MMP-2 in the culture supernatants from PC3 cells.
Results:
①It is similar for TGF-β1, wt-p53, and RhoA genes to be expressed between in the prostate normal external gland and in the prostatic paraneoplastic tissues(P>0.05), and wt-p53 gene isn’t found to have mutated.
②TGF-β1, wt-p53 and RhoA genes were more expressed in the prostate cancer tissues than in prostate normal and paraneoplastic tissues (P<0.01). On the contrary, wt-p53 gene was less expressed(P<0.01), and a part of it has mutated into mt-p53 gene.
③The immunohistochemistry results shown that the expressions of TGF-β1 and RhoA protein increased along with the degree of differentiation of prostate cancer decreasing. There is a negative correlationship between them(r =-0.7884,P=0.0023;r =-0.6758,P=0.0158).
④With the degree of differentiation of prostate cancer decreasing, the expressions of mt-p53 gradually increased(r =-0.7662,P=0.0037). This indicated that the mutation rate of wt-p53 gene increased and mt-P53 protein accumulated in the cancerous cell.
⑤RT-PCR and Western-blot results showed that the mRNA transcriptions and protein expressions of TGF-β1, wt-p53 and RhoA genes were statistically different in the prostate cancerous cell when distant metastasis had occurred and when metastasis had not happened(P<0.01)and such a diffrence is statistically meaningful.
⑥It was shown that TGF-β1 and RhoA protein were expressed in the PC3 cells from the results of immunohistochemistry.
⑦We could see that two electrophoretic bands of MMP-9 and MMP-2 were showed significantly in the Gelatin zymography for the culture supernatants of PC3 cells.
Conclusions:
In this experiment, we used immunohistochemistry, RT-PCR, Western-blot techniques to detect the expressions of TGF-β1, wt-p53 and RhoA genes in human normal prostate tissues, carcinomatous and paraneoplastic tissues, adopted immunohistochemistry methods to observe the expressions of TGF-β1 and RhoA protein in PC3 cells in vitro,and also usesd gelatin zymography to detect the MMP-2 and MMP-9 expressions in the supernatant of PC3 cells’culture supernatant. From the results, we find them relative to the incidence and metastasis of human prostate cancer and we can conclude that these genes play important roles in the progression of prostate cancer. Therefore, the joint detection of TGF-β1, wt-p53 and RhoA genes is helpful to the early diagnosis of prostate cancer or assessment of neoplastic invasive power, therapeutic effect and prognosis.
方法:本次实验采集标本42例,6例正常前列腺组织来自手术非正常死亡的人体,36例前列腺癌标本为吉林大学前列腺疾病防治研究中心应用经直肠超声引导下前列腺6点活检技术穿刺采集或手术采集。用HE染色确定前列腺标本的病理类型,采用免疫组织化学、RT-PCR、Western-blot等技术定性和定量检测各标本中TGF-β1、wt-p53和RhoA基因在正常前列腺组织和前列腺癌组织中的表达。采用免疫组织化学方法检测了体外培养的人前列腺癌细胞系PC3细胞的TGF-β1、和RhoA蛋白的表达,并采用明胶酶谱法检测了PC3细胞培养上清中MMP-2和MMP-9的表达。
结果:①正常前列腺外腺和癌旁组织间的TGF-β1、wt-p53和RhoA表达无差异(P>0.05),均未发现wt-p53基因突变;②与正常前列腺组织和癌旁组织相比,TGF-β1和RhoA在前列腺癌组织中高表达(P<0.01),wt-p53低表达(P<0.01),且部分基因突变为mt-p53;③免疫组织化学结果显示,随着前列腺癌分化程度的降低,TGF-β1、和RhoA的表达都增高,呈负相关关系(r =-0.7884,P=0.0023;r =-0.6758,P=0.0158);④随着前列腺癌分化程度的降低,mt-p53表达逐渐增强,呈负相关关系(r =-0.7662,P=0.0037),说明wt-p53基因的突变率增加,mt-P53蛋白在细胞内积聚;⑤RT-PCR和Western-blot结果显示,已发生远处转移的前列腺癌组织中TGF-β1、wt-p53和RhoA的mRNA转录和蛋白表达,与无转移灶者相比差异有统计学意义(P<0.01);⑥光学显微镜下可以见到在PC3细胞的细胞核和细胞质中均有棕黄色颗粒,表明TGF-β1、和RhoA的表达均呈阳性;⑦PC3细胞培养上清中有MMP-2和MMP-9的表达。
结论:无论是临床标本还是体外培养的细胞系检测结果均表明TGF-β1、wt-p53和RhoA基因与前列腺癌的发生和进展相关,并在前列腺癌的浸润转移中起重要作用,利用联合检测TGF-β1、wt-p53和RhoA基因的表达可有助于对前列腺癌进行早期诊断,评估肿瘤的浸润性进展过程,评价化疗治疗效果和预后。
Prostate cancer is the most common malignancy generated from the male reproductive system. In the United States and Europe, it has the highest incidence among the cancer-related deseases and is ranked as the second cause of mortality which is only less than lung cancer. In China, previously its incidence and mortality rates were relatively low but they have shown a rapid upward tendency in recent years, while the age structure, lifestyle and living standard of the society changes. Most cases of the prostate cancer are currently diagnosed at the terminal stage because the location of the prostate is hidden and the clinical symptoms appear later, and many men has lost the opportunity to treat.
Since 1989, an application of the serum PSA screening has been conducted nation-widely for prostate cancer in the United States and early detection and early treatment for prostate cancer have been achieved. Since 2000, both serum prostate-specific antigen and B-ultrasound-guided transrectal prostate biopsy were applied to screen prostate cancer for men over the age of 50 in Changchun City by Jilin University Research Center for the Control and Prevention Prostate Disease. The prostate cancer detection rate was 1.7%, and approximately 42% of advanced cases, of which 18% of patients associated with bone metastasis. As a result, the early detection of patients with initial inspection rate(from 28% to 58%)greatly improved. Men currently diagnosed at the early stages of prostate cancer can, in many cases, be effectively treated by surgery or radiation and survive for 10 years. However, androgen deprivation therapy is only a palliative treatment for one third of the patients. About 12-18 months later, the disease will recur and ultimately develop into hormone-refractory prostate cancer and metastatic prostate cancers that are essentially incurable and not sensitive to either chemotherapy or radiation therapy. These patients always lead lives of poor quality because of urinary tract obstruction and spinal metastasis, and their prognosis is poor. Therefore, it is very important for us to improve the Group screening project to raise the early detection rate, to study the factors which affect the tumor metastasis, and to further explore the ways to reverse or slow down the process. Thus, it is being received increasing attention to diagnose and treat prostate carcinoma by the method of tumor gene.
TGF-β1 (transforming growth factor beta 1) has a wide range of biological activity in vivo or in vitro, including the regulation of cell growth, differentiation, apoptosis and extracellular matrix protein synthesis. Under normal physiological conditions, TGF-β1 can induce the apoptosis of both body cells and tumor cells.
When TGF-β1 mediated signal transduction pathway mutates in the tumor progression, TGF-β1 is over-expressed and increases tumor proliferation, migration and invasion. As TGF-β1 can promote tumor angiogenesis, cell spread, immune suppression and synthesis of extracellular matrix, etc, it can provide an appropriate micro-environment for the proliferation, migration and invasion of human tumor.
Wt-p53 gene is the most relevant to a variety of human tumors among the genes discovered so far. The mutation of wt-p53 is the most common change of tumor genetics, and it is necessary for mt-p53 to maintain the proliferation of human carcinoma cells. Not wt-P53 but mt-P53 is detected by the routine immunohistochemical methods. The intracellular concentration of mt-P53 is a general resultant to the extent of wt-p53 mutations. p53 gene in the normal cells is wild-type p53 gene without mutations, whose function is monitoring the integrity of the genome, controlling the cell division cycle, and inducing cell apoptosis. Therefore it can inhibit the genesis and proliferation of the tumor cell. Either the reactivation of wt-p53 or the inactivation of mt-p53 in the tumor cells can lead the tumor cells to apoptosis. RhoA (Ras homology A) is an important member of the intracellular signaling transducers. It can mediate actin polymerization, actomyosin contraction and microtubule dynamics, so its function is to maintain the cytoskeleton, basic movement, mitosis and directional differentiation of stem cells. Therefore, RhoA is very important in the biological developmental process. RhoA is highly expressed and actived in tumor cells during tumor development and progression, which can regulate the expression and activity of cell cycle-related gene or protein to promote the division and clonal expansion of the undifferentiated cell and increase the tumor grade. It also induces the changes of skeleton, morphology and adhesion of the tumor cell in order to facilitate cell migration movement. It may regulate TGF-β1, VEGF expression, etc to promote tumor angiogenesis, too. On the other hand, we can partially reverse the malignant phenotype of cancer cells and inhibit the proliferation of tumor cells by reducing the expression of RhoA.
Matrix metalloproteinases (MMPs) are a large family in the protease category. They are a kind of endo-protease which depend on Zn~(2+) and Ca~(2+) and they can completely degrade the extracellular matrix(ECM)and basement membrane(BM), which provide a premise for the tumor to invade and metastasize in the body. TGF-β1 and RhoA can regulate the extracellular matrix and basement membrane degradation and reconstructionby by regulating MMPs and TIMP level and thus promote the local tumor infiltration.
In this paper, we select TGF-β1, wt-P53, and RhoA as the experiment target genes because they are closely related to the genesis and development of the majority of human tumors. To investigate their relationship with the malignant degree and metastasis of prostate cancer, we first adopt immunohistochemistry, RT-PCR, Western-blot methods to observe their expressions and changes in human prostate normal, carcinomatous and paraneoplastic tissues; then we adopt immunohistochemistry to observe the expressions of TGF-β1 and RhoA protein in cultured human prostate cancer cell lines PC3 in vitro; finally, we use gelatin zymography to detect the MMP-2 and MMP-9 expressions in the supernatant of PC3 cell culture. Thus, we can find some new valuable reference indexes for the early diagnosis of prostate cancer and assess the tumorous invasive power, therapeutic effect and prognosis, and even provide some new valuable ideas for the treatment of prostate cancer.
Objective:
①To detect the mRNA and protein expressions of TGF-β1, wt-p53 and the RhoA genes in prostate normal tissues and prostate cancerous tissues;
②To analyse the relationship between expressions and changes of the TGF-β1, wt-p53, RhoA genes and the malignant degree of the prostate cancer;
③To analysis the relationship between expressions and changes of the TGF-β1, wt-p53, RhoA genes and the metastasis of the prostate cancer;
④To discuss the association of TGF-β1, wt-p53, RhoA and their roles to determine the progression and prognosis of prostate cancer.
Methods:
①The pathological classification of all specimens was determined by HE staining methods.
②Immunohistochemistry, RT-PCR and Western-blot techniques were used to qualitatively and quantitatively detect the protein and mRNA expressed by TGF-β1, wt-P53 and RhoA genes in normal prostatic, cancerous and paraneoplastic tissues.
③The method of Immunohistochemistry was used to detect the expressions of TGF-β1 and RhoA protein in PC3 cells cultured in vitro.
④Gelatin zymography was performed to examine the presence of MMP-9 and MMP-2 in the culture supernatants from PC3 cells.
Results:
①It is similar for TGF-β1, wt-p53, and RhoA genes to be expressed between in the prostate normal external gland and in the prostatic paraneoplastic tissues(P>0.05), and wt-p53 gene isn’t found to have mutated.
②TGF-β1, wt-p53 and RhoA genes were more expressed in the prostate cancer tissues than in prostate normal and paraneoplastic tissues (P<0.01). On the contrary, wt-p53 gene was less expressed(P<0.01), and a part of it has mutated into mt-p53 gene.
③The immunohistochemistry results shown that the expressions of TGF-β1 and RhoA protein increased along with the degree of differentiation of prostate cancer decreasing. There is a negative correlationship between them(r =-0.7884,P=0.0023;r =-0.6758,P=0.0158).
④With the degree of differentiation of prostate cancer decreasing, the expressions of mt-p53 gradually increased(r =-0.7662,P=0.0037). This indicated that the mutation rate of wt-p53 gene increased and mt-P53 protein accumulated in the cancerous cell.
⑤RT-PCR and Western-blot results showed that the mRNA transcriptions and protein expressions of TGF-β1, wt-p53 and RhoA genes were statistically different in the prostate cancerous cell when distant metastasis had occurred and when metastasis had not happened(P<0.01)and such a diffrence is statistically meaningful.
⑥It was shown that TGF-β1 and RhoA protein were expressed in the PC3 cells from the results of immunohistochemistry.
⑦We could see that two electrophoretic bands of MMP-9 and MMP-2 were showed significantly in the Gelatin zymography for the culture supernatants of PC3 cells.
Conclusions:
In this experiment, we used immunohistochemistry, RT-PCR, Western-blot techniques to detect the expressions of TGF-β1, wt-p53 and RhoA genes in human normal prostate tissues, carcinomatous and paraneoplastic tissues, adopted immunohistochemistry methods to observe the expressions of TGF-β1 and RhoA protein in PC3 cells in vitro,and also usesd gelatin zymography to detect the MMP-2 and MMP-9 expressions in the supernatant of PC3 cells’culture supernatant. From the results, we find them relative to the incidence and metastasis of human prostate cancer and we can conclude that these genes play important roles in the progression of prostate cancer. Therefore, the joint detection of TGF-β1, wt-p53 and RhoA genes is helpful to the early diagnosis of prostate cancer or assessment of neoplastic invasive power, therapeutic effect and prognosis.
引文
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