Id1在前列腺癌中的表达及干涉抑制Id1对前列腺癌细胞的体内外影响
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摘要
近年研究表明Id1(inhibitot of differentiation or inhibitor of DNAbinding 1)蛋白的过度表达与肿瘤的发生、发展有关,国内外研究均证实Id1在多种恶性肿瘤中有高表达,而且这种高表达与某些肿瘤的分化、浸润、血管生成等有关系。澳大利亚学者在2001年首次提出在人局限性前列腺癌中Id1基因有差异表达,随后的研究进一步证实Id1蛋白在动物前列腺癌模型和人前列腺癌组织中均有过度表达,但其与临床病理分级、分期、预后等临床指标的相关性需要进一步证实。Id1与前列腺癌密切相关的雄激素之间是否有关尚不清楚。
本研究论文首先观测人前列腺癌组织中Id1mRNA和蛋白的表达,并统计分析其与临床相关指标的关系,以进一步明确Id1在前列腺癌中表达的临床意义,探索Id1在临床检测应用的可能性。由于雄激素和前列腺癌发生发展密切相关,本研究采用雄激素依赖性和非依赖性的两种前列腺癌细胞株,观察在雄激素刺激和雄激素受体阻滞情况下,Id1基因的表达变化,以探索雄激素和Id1表达之间是否有关。为进一步明确Id1基因在前列腺癌细胞中的作用,本研究论文采用小RNA干涉技术和裸鼠移植瘤模型,从细胞和整体水平观察下调Id1基因表达对前列腺癌的影响,同时观测姜黄素和Id1小干涉RNA合用,对雄激素非依赖性PC3细胞的联合效应,为临床综合治疗前列腺癌提供相关的理论依据。
实验结果如下:
1.Id1mRNA和蛋白在正常前列腺组织中无表达,在前列腺良性增生组织中无或弱表达,而在所有前列腺癌组织中都呈阳性表达。Id1mRNA和Id1蛋白表达水平与表示细胞分化的Gleason分级成正相关(r=0.9695,P＜0.05或r_s=0.63,P＜0.01);患者血清前列腺抗原含量低于10ng/ml的前列腺组织中Id1mRNA和蛋白表达量较低,而超过10ng/ml的前列腺癌组织中Id1表达量显著升高(P＜0.01),但两者不成直线相关或等级相关。Id1表达与前列腺癌体积、TNM分期无显著相关。
2.雄激素依赖性的前列腺癌LNCaP细胞中,用雄激素——二氢睾酮刺激后,细胞Id1mRNA和Id1蛋白表达均有所升高(P＜0.05);雄激素受体阻滞剂-氟他胺不仅阻断二氢睾酮引起的Id1表达,对于LNCaP细胞基础表达的Id1也几乎完全阻断;同一剂量的氟他胺作用于雄激素非依赖性的前列腺癌PC3细胞,对Id1mRNA表达则无LNCaP细胞样的阻断作用。
3.在雄激素非依赖性的前列腺癌PC3细胞中,采用小干涉mRNA抑制Id1基因表达后,细胞增殖活性明显降低,早期和晚期凋亡细胞比率均增多,细胞老化率也明显增高;Id1小干涉RNA和姜黄素合用后可进一步抑制细胞的增殖活性、促使细胞凋亡,说明两者联合可起协同抑制PC3细胞的效应。
4.裸鼠皮下PC3细胞移植瘤内直接注射Id1小干涉RNA后,肿瘤组织内Id1的表达被明显抑制(P＜0.01),肿瘤生长体积有一定程度减小;肿瘤组织中反映细胞增殖能力的核增殖抗原(Proliferating cell nuclear antigen,PCNA)以及与肿瘤侵袭能力有关的基质金属蛋白酶2(Matrix metalloproteinase2,MMP2)的mRNA表达量均降低,说明在整体瘤组织中干涉抑制Id1的表达,可抑制肿瘤生长增殖,减弱其侵袭浸润能力。
本论文结果进一步证实了Id1在前列腺癌中的高表达和前列腺癌组织恶性程度呈正相关,可以和Gleason分级、血清PSA一起对临床前列腺癌的发生发展进行综合分析判断。前列腺癌的发生发展与雄激素密切相关,本论文结果表明,在雄激素依赖性的前列腺癌细胞中,雄激素-受体途径可能是Id1表达的重要途径;雄激素非依赖性的前列腺癌细胞中,Id1的高表达依赖雄激素-受体以外的途径。在雄激素非依赖性的PC3细胞中干涉抑制Id1基因表达,在细胞和整体水平均可抑制前列腺癌细胞的生长增殖;干涉抑制Id1基因和姜黄素合用对PC3细胞具有协同抑制效应,说明针对Id1的基因治疗研究对于前列腺癌的综合防治具有极大的应用潜力。
Inhibitor of DNA binding-1(Id1) is a dominant-negative regulator of basic helix-loop-helix transcription factor,which control malignant cell behaviors in several types of carcinomas.Recent studies have shown that Id1 over expressed in some types of human cancer.Id1 has much wider tumor biological roles that impinge on tumor differentiation,invasion and angiogenesis.Chetcuti A et al(2001) first identified differentially expressed Id1 gene in human organ-confined prostate cancer by gene expression array.Id1 overexpression was further confirmed in animal prostate cancer models and human prostate cancer specimens.However,there was only little clinical study on the relationship between Id1 and tumor differentiation,tumor stage, metastasis or prognosis on human prostate cancer.The relationship between Id1 and androgen,which is closely related to prostate cancer,remains unclear.
In the present study,using immunohistochemistry and real time RT-PCR assay, we firstly observed Id1 expression in human prostate cancer and also their relationship to some clinical parameters.Androgen has closely relationship with the development of prostate cancer.To study if Id1 was regulated by androgen,we also observed the effects of androgen and androgen inhibitor on Id1 expression in androgen-dependent and independent prostate cancer cell lines.In order to confirm the in vitro and in vivo effects of Id1 gene in prostate cancer,we further observed the down regulation effect of Id1 gene by small interferon RNA(SiRNA-Id1) in androgen-independent PC3 cells and its combination effects with curcumin.We also observed the subcutaneous injection effects of SiRNA-Id1 on nude mice tumors transplanted with PC3 cells.The results were as follows:
1.The levels of Id1 mRNA and protein were observed increased significantly in all prostate cancer specimens,while no Id1 expression in normal prostate cancer. Only weak expression in some benign prostate hypertrophy(BPH) samples was observed.The increased levels of Id1mRNA and protein correlated well with Gleason grade in prostate cancer specimens(r=0.9695,P＜0.05 or r_s=0.63,P＜0.01).Id1 expression was obviously higher in some samples that serum prostate specific antigen (PSA) level was more than 10ng/ml(P＜0.01),but no straight line relation between them.Id1 overexpression had no significant association with TNM stage and tumor size.
2.Androgen-dihydrotestosterone(DHT) could up-regulate Id1 expression in androgen-dependent LNCaP cells(P＜0.05).Flutamide,the inhibitor of androgen receptor,not only blocked the up-regnlated Id1 expression by DHT,but also blocked the basic Id1 expression in LNCaP cells.The same concentration of flutamide did not have same block effect on Id1 expression in androgen independent PC3 cells.
3.Down-regnlation of Id1 gene by small interferon RNA(SiRNA-Id1) in PC3 cells decreased cell viability,increased cell apoptosis and senescence rate.Synergistic effects of decreased cell viability and increased cell apoptosis were observed when the cells were treated by SiRNA-Id1 combination with curcumin.
4.Down-regulation of Id1 gene by intratumor injection of SiRNA-Id1 in prostate carcinoma PC3 transplanted tumor in nude mice was confirmed by real time PCR and immunohistochemistry assay.The tumor volumes were smaller in SiRNA-Id1 treated mice than that of nonspecific SiRNA control(P＜0.05).The mRNA expression of proliferating cell nuclear antigen(PCNA) and matrix metalloproteinase2(MMP2) in the tumors were also decreased significantly in SiRNA-Id1 treated mice(P＜0.01).
This study showed that overexpression of Id1 positively correlated with cell malignancy in human prostate cancer.Id1 expression,Gleason grade and serum PSA could be used together in the prognosis of prostate cancer.This study also identified that androgen and androgen receptor pathway might be great importance for Id1 expression in androgen-dependent prostate cancer cells.In androgen-independent cancer cells,down-regulation of Id1 gene could inhibit prostate cancer cell proliferation in vitro and in vivo,and had a synergistic effect on cell suppressor when combined with curcumin.This study implied that Id1 gene inhibition could be used as a new potential target of gene therapy on prostate cancer.
本研究论文首先观测人前列腺癌组织中Id1mRNA和蛋白的表达,并统计分析其与临床相关指标的关系,以进一步明确Id1在前列腺癌中表达的临床意义,探索Id1在临床检测应用的可能性。由于雄激素和前列腺癌发生发展密切相关,本研究采用雄激素依赖性和非依赖性的两种前列腺癌细胞株,观察在雄激素刺激和雄激素受体阻滞情况下,Id1基因的表达变化,以探索雄激素和Id1表达之间是否有关。为进一步明确Id1基因在前列腺癌细胞中的作用,本研究论文采用小RNA干涉技术和裸鼠移植瘤模型,从细胞和整体水平观察下调Id1基因表达对前列腺癌的影响,同时观测姜黄素和Id1小干涉RNA合用,对雄激素非依赖性PC3细胞的联合效应,为临床综合治疗前列腺癌提供相关的理论依据。
实验结果如下:
1.Id1mRNA和蛋白在正常前列腺组织中无表达,在前列腺良性增生组织中无或弱表达,而在所有前列腺癌组织中都呈阳性表达。Id1mRNA和Id1蛋白表达水平与表示细胞分化的Gleason分级成正相关(r=0.9695,P＜0.05或r_s=0.63,P＜0.01);患者血清前列腺抗原含量低于10ng/ml的前列腺组织中Id1mRNA和蛋白表达量较低,而超过10ng/ml的前列腺癌组织中Id1表达量显著升高(P＜0.01),但两者不成直线相关或等级相关。Id1表达与前列腺癌体积、TNM分期无显著相关。
2.雄激素依赖性的前列腺癌LNCaP细胞中,用雄激素——二氢睾酮刺激后,细胞Id1mRNA和Id1蛋白表达均有所升高(P＜0.05);雄激素受体阻滞剂-氟他胺不仅阻断二氢睾酮引起的Id1表达,对于LNCaP细胞基础表达的Id1也几乎完全阻断;同一剂量的氟他胺作用于雄激素非依赖性的前列腺癌PC3细胞,对Id1mRNA表达则无LNCaP细胞样的阻断作用。
3.在雄激素非依赖性的前列腺癌PC3细胞中,采用小干涉mRNA抑制Id1基因表达后,细胞增殖活性明显降低,早期和晚期凋亡细胞比率均增多,细胞老化率也明显增高;Id1小干涉RNA和姜黄素合用后可进一步抑制细胞的增殖活性、促使细胞凋亡,说明两者联合可起协同抑制PC3细胞的效应。
4.裸鼠皮下PC3细胞移植瘤内直接注射Id1小干涉RNA后,肿瘤组织内Id1的表达被明显抑制(P＜0.01),肿瘤生长体积有一定程度减小;肿瘤组织中反映细胞增殖能力的核增殖抗原(Proliferating cell nuclear antigen,PCNA)以及与肿瘤侵袭能力有关的基质金属蛋白酶2(Matrix metalloproteinase2,MMP2)的mRNA表达量均降低,说明在整体瘤组织中干涉抑制Id1的表达,可抑制肿瘤生长增殖,减弱其侵袭浸润能力。
本论文结果进一步证实了Id1在前列腺癌中的高表达和前列腺癌组织恶性程度呈正相关,可以和Gleason分级、血清PSA一起对临床前列腺癌的发生发展进行综合分析判断。前列腺癌的发生发展与雄激素密切相关,本论文结果表明,在雄激素依赖性的前列腺癌细胞中,雄激素-受体途径可能是Id1表达的重要途径;雄激素非依赖性的前列腺癌细胞中,Id1的高表达依赖雄激素-受体以外的途径。在雄激素非依赖性的PC3细胞中干涉抑制Id1基因表达,在细胞和整体水平均可抑制前列腺癌细胞的生长增殖;干涉抑制Id1基因和姜黄素合用对PC3细胞具有协同抑制效应,说明针对Id1的基因治疗研究对于前列腺癌的综合防治具有极大的应用潜力。
Inhibitor of DNA binding-1(Id1) is a dominant-negative regulator of basic helix-loop-helix transcription factor,which control malignant cell behaviors in several types of carcinomas.Recent studies have shown that Id1 over expressed in some types of human cancer.Id1 has much wider tumor biological roles that impinge on tumor differentiation,invasion and angiogenesis.Chetcuti A et al(2001) first identified differentially expressed Id1 gene in human organ-confined prostate cancer by gene expression array.Id1 overexpression was further confirmed in animal prostate cancer models and human prostate cancer specimens.However,there was only little clinical study on the relationship between Id1 and tumor differentiation,tumor stage, metastasis or prognosis on human prostate cancer.The relationship between Id1 and androgen,which is closely related to prostate cancer,remains unclear.
In the present study,using immunohistochemistry and real time RT-PCR assay, we firstly observed Id1 expression in human prostate cancer and also their relationship to some clinical parameters.Androgen has closely relationship with the development of prostate cancer.To study if Id1 was regulated by androgen,we also observed the effects of androgen and androgen inhibitor on Id1 expression in androgen-dependent and independent prostate cancer cell lines.In order to confirm the in vitro and in vivo effects of Id1 gene in prostate cancer,we further observed the down regulation effect of Id1 gene by small interferon RNA(SiRNA-Id1) in androgen-independent PC3 cells and its combination effects with curcumin.We also observed the subcutaneous injection effects of SiRNA-Id1 on nude mice tumors transplanted with PC3 cells.The results were as follows:
1.The levels of Id1 mRNA and protein were observed increased significantly in all prostate cancer specimens,while no Id1 expression in normal prostate cancer. Only weak expression in some benign prostate hypertrophy(BPH) samples was observed.The increased levels of Id1mRNA and protein correlated well with Gleason grade in prostate cancer specimens(r=0.9695,P＜0.05 or r_s=0.63,P＜0.01).Id1 expression was obviously higher in some samples that serum prostate specific antigen (PSA) level was more than 10ng/ml(P＜0.01),but no straight line relation between them.Id1 overexpression had no significant association with TNM stage and tumor size.
2.Androgen-dihydrotestosterone(DHT) could up-regulate Id1 expression in androgen-dependent LNCaP cells(P＜0.05).Flutamide,the inhibitor of androgen receptor,not only blocked the up-regnlated Id1 expression by DHT,but also blocked the basic Id1 expression in LNCaP cells.The same concentration of flutamide did not have same block effect on Id1 expression in androgen independent PC3 cells.
3.Down-regnlation of Id1 gene by small interferon RNA(SiRNA-Id1) in PC3 cells decreased cell viability,increased cell apoptosis and senescence rate.Synergistic effects of decreased cell viability and increased cell apoptosis were observed when the cells were treated by SiRNA-Id1 combination with curcumin.
4.Down-regulation of Id1 gene by intratumor injection of SiRNA-Id1 in prostate carcinoma PC3 transplanted tumor in nude mice was confirmed by real time PCR and immunohistochemistry assay.The tumor volumes were smaller in SiRNA-Id1 treated mice than that of nonspecific SiRNA control(P＜0.05).The mRNA expression of proliferating cell nuclear antigen(PCNA) and matrix metalloproteinase2(MMP2) in the tumors were also decreased significantly in SiRNA-Id1 treated mice(P＜0.01).
This study showed that overexpression of Id1 positively correlated with cell malignancy in human prostate cancer.Id1 expression,Gleason grade and serum PSA could be used together in the prognosis of prostate cancer.This study also identified that androgen and androgen receptor pathway might be great importance for Id1 expression in androgen-dependent prostate cancer cells.In androgen-independent cancer cells,down-regulation of Id1 gene could inhibit prostate cancer cell proliferation in vitro and in vivo,and had a synergistic effect on cell suppressor when combined with curcumin.This study implied that Id1 gene inhibition could be used as a new potential target of gene therapy on prostate cancer.
引文
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