摘要
前列腺癌是男性泌尿生殖系统最常见的肿瘤。在美国它的发病率仅次于肺癌,是第二位癌症致死病因。我国前列腺癌的发病率明显上升,已位居泌尿系恶性肿瘤的第三位。抑癌基因失表达可能是前列腺癌形成的机制之一。组蛋白乙酰化/去乙酰化修饰染色质在基因表达中起关键作用。组蛋白乙酰化促进基因表达,而去乙酰化则抑制基因表达。组蛋白乙酰化/去乙酰化是由两种作用不同的酶调节,这两种酶分别是组蛋白乙酰转移酶和组蛋白去乙酰化酶。它们改变抑癌基因的表达并参与肿瘤的形成。
早期前列腺癌为雄激素依赖性,手术可以治愈,雄激素阻断治疗也可以获得良好的疗效。晚期前列腺癌为雄激素非依赖性,雄激素阻断治疗通常无效。诱导雄激素非依赖性前列腺癌细胞凋亡被认为是较好的控制肿瘤生长的策略。组蛋白去乙酰化酶抑制剂诱导癌细胞凋亡和组蛋白乙酰化,后者可能与抑癌基因的表达相关。目前本实验研究包括以下二部分:
第一部分RARβ在前列腺癌组织中的表达及与乙酰化组蛋白H3关系的研究
目的:研究良性前列腺增生和前列腺癌组织RARβ与乙酰化组蛋白H3的表达及其临床意义,并分析两者之间的关系。
方法:用免疫组织化学方法检测41例前列腺癌和10例良性前列腺增生标本中RARβ和乙酰化组蛋白H3的表达。
结果:前列腺癌患者中RARβ和乙酰化组蛋白H3总表达率,均低于良性前列腺增生组织(p＜0.05)。高分化的前列腺癌RARβ表达高于低分化者(p＜0.01):晚期前列腺癌RARβ表达低于早期前列腺癌(p＜0.01);雄激素非依赖性前列腺癌RARβ表达低于雄激素依赖性前列腺癌(p＜0.05)。组蛋白H3乙酰化程度和前列腺癌分级、分期负相关(p＜0.05)。前列腺癌RARβ表达与乙酰化组蛋白H3正相关(p＜0.01)。
结论:RARβ表达与前列腺癌的病变程度呈相反趋势,且与组蛋白H3乙酰化程度密切相关。
第二部分TSA和ATRA结合对RARβ在雄激素非依赖性前列腺癌细胞DU-145中表达的影响
目的:探讨组蛋白去酰化酶抑制剂TSA结合ATRA干预维甲酸抵抗的雄激素非依赖性前列腺细胞DU-145,能否诱导RARβ表达并协同抑制DU-145细胞生长。
方法:将ATRA、TSA或TSA结合ATRA分别干预前列腺癌细胞DU-145 8～24小时,采用MTT检测DU-145细胞生长状况;Western blotting检测乙酰化组蛋白H3的表达程度;RT-PCR检测RARβmRNA转录情况。
结果:ATRA结合TSA协同抑制DU-145细胞。TSA单独或结合ATRA干预DU-145细胞均能诱导乙酰化组蛋白H3和RARβmRNA表达。
结论:ATRA结合组蛋白去乙酰化酶抑制剂TSA协同抑制维甲酸抵抗的雄激素非依赖性前列腺癌细胞DU-145生长。这种抑制作用部分和RARβ表达有关。
Prostate cancer is the most common gentitourlogic malignancy. Apart from lung cancer, prostate cancer is the first leading cause of death in American men. The incidence of prostate cancer increase in our country, and it has become the third cancer of gentitourlogic malignancy. A reduction in tumor suppressor gene expression is one of the key mechanisms involved in prostate cancer. Modifications of chromatin structure by acetylation/deacetylation of the histone proteins play a central role in the regulation of gene expression. Histone acetylation contributes to expression of gene, while histone deacetylation leads to repression of gene expression. The levels of acetylation/deacetylation of histone proteins are determined by 2 opposing enzymes, histone acetyltransferases and histone deacetylases. These alterations of gene expression by histone acetyltransferases and histone deacetylases have been implicated in the process of prostate cancer.
The growth of most prostate tumors depends on androgens during the initial stages of tumor development. In early stage disease, surgery can be curative and anti-androgen therapy can be of significant benefit. In the final stages, it becomes androgen independent and is unresponsive to androgyne ablation therapy. At this stage, induction of apoptosis is considered as a better strategy to control cancer. Histone deacetylases inhibitors induced apoptosis and histone acetylation which can be correlated with the expression of antiproliferative genes. This study includes two parts as follows:
Part IExpression of the RARβand its relationship to acetylated histone H3 inprostate cancer
Purpose: To study expression of RARP and acetylated histone H3 in benign prostatic hyperplasia and prostate cancer, and their clinical significances, analyzing the relationship of RARp and acetylated histone H3.
Methods: The expression levels of RARβprotein and the acetylation levels of histone H3 in 41 prostate cancer and 10 benign prostatic hyperplasia were examined, using immunohistochemistry.
Results: The expression levels of RARβprotein and the acetylation levels of histone H3 in prostate cancer were lower than which were in the benign prostatic hyperplasia (p<0.05 ) . The expression levels of RARβprotein were higher in the well differentiated group than the poorly differentiated group (p<0.01) , lower in the final stages group than the early stages group (p<0.01) and lower in the hormone refractory ones than hormone dependent ones (p<0.05). The acetylation levels of histone H3 inversely correlated to pathological grade and stage(p<0.05). Immunostaining patterns of RARβand acetylated histone H3 were positively correlated (p<0.01) .
Conclusion: The expression levels of RARβprotein are inversely related to the development of prostate cancer, which are closely concerned with the acetylation levels of histone H3.
Part IIEffect of the trichostatin A in combination with all-trans retinoic acid onexpression of RARβin DU-145
Purpose: We tested whether combining histone deacetylase inhibitor trichostatin A with all-trans retinoic acid would restore RARβreceptor expression, leading to increased growth inhibition in retinoic acid resistant androgen independent prostate cancer cell DU-145.
Methods: ATRA, TSA or the combination of ATRA and TSA was added to the culture media respectively for 8 to 24 hours. The growth of each group was evaluated by MTT. Western blotting was used to detect the expression levels of acetylated histone H3 protein. RARβmRNA was determined using RT-PCR.
Results: Enhanced inhibition of the proliferation of DU-145 was observed with the combination of ATRA plus TSA. Western blotting analyses showed increased acetylation of histone H3 on treatment with increasing doses of TSA in the presence or absence of ATRA. Reactivation of RARβmRNA expression was observed in DU-145 treated with TSA alone or TSA in combination with ATRA.
Conclusion: The combination of ATRA and the histone deacetylase inhibitor TSA elicits an additive inhibition of cell proliferation in the retinoic acid resistant androgen independent prostate cancer cell DU-145. Enhanced inhitition of the proliferation of DU-145 treated with TSA in combination with ATRA in part is concerned with re-expression of RARβ.
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