前列腺癌中雌激素、孕激素和雄激素受体的甲基化与失活

Methylation and inactivation of estrogen, progesterone, and androgen receptors in prostate cancer.

作者信息

Sasaki Masahiro, Tanaka Yuichiro, Perinchery Geetha, Dharia Abhipsa, Kotcherguina Ioulia, Fujimoto Sei ichiro, Dahiya Rajvir

机构信息

Department of Urology, University of California, San Francisco 94121, USA.

出版信息

J Natl Cancer Inst. 2002 Mar 6;94(5):384-90. doi: 10.1093/jnci/94.5.384.

DOI:10.1093/jnci/94.5.384

PMID:11880477

Abstract

BACKGROUND

Prostate cancer development is initially steroid hormone dependent. Estrogen receptors (ERs), androgen receptors (ARs), and progesterone receptors (PRs) have been identified in normal and cancerous prostate tissues. We investigated whether the promoter regions of these steroid receptor genes are methylated and inactivated in prostate cancer cells and tissues.

METHODS

The expression and promoter methylation status of three ERalpha isoforms (ERalpha-A, ERalpha-B, and ERalpha-C), ERbeta, two PR isoforms (PR-A and PR-B), and AR were investigated in five prostate cancer cell lines (ND1, DU145, PC3, LNCaP, and DUPro) and in pairs of normal and cancerous prostate tissues from 38 patients with prostate cancer. Methylation-specific polymerase chain reaction, reverse transcription--polymerase chain reaction, and 5' rapid amplification of complementary DNA ends were used. All statistical tests were two-sided.

RESULTS

ERalpha-C was expressed in all cell lines, but ERalpha-A and ERalpha-B were not expressed in any cell line. ERalpha-A and ERalpha-B promoters were methylated, but ERalpha-C was unmethylated. Promoters for ERbeta, AR, PR-A, and PR-B were methylated and thus inactivated in some cell lines but not in others. Treating cells with the demethylating reagent 5-aza-2'-deoxycytidine restored expression of all steroid receptor genes with previously methylated promoters. All 38 pairs of cancer and normal tissues had unmethylated ERalpha-C promoters. Thirty-six (95%) of 38 cancers had methylated ERalpha-A, 35 (92%) of 38 cancers had methylated ERalpha-B, but all normal tissues had unmethylated ERalpha-A and ERalpha-B (both P<.001). ERbeta was methylated in 30 (79%) of 38 cancers but unmethylated in all normal tissues. AR was methylated in three (8%) of 38 cancers but unmethylated in all normal tissues. PR-A and PR-B were unmethylated in all tissues.

CONCLUSION

Certain steroid receptor genes appear to be inactivated by CpG methylation in prostate cancer tissue and cell lines.

摘要

背景

前列腺癌的发生最初依赖于类固醇激素。在正常和癌性前列腺组织中已鉴定出雌激素受体（ERs）、雄激素受体（ARs）和孕激素受体（PRs）。我们研究了这些类固醇受体基因的启动子区域在前列腺癌细胞和组织中是否发生甲基化并失活。

方法

在五种前列腺癌细胞系（ND1、DU145、PC3、LNCaP和DUPro）以及38例前列腺癌患者的正常和癌性前列腺组织对中，研究了三种ERα亚型（ERα-A、ERα-B和ERα-C）、ERβ、两种PR亚型（PR-A和PR-B）以及AR的表达和启动子甲基化状态。使用甲基化特异性聚合酶链反应、逆转录-聚合酶链反应和5'互补DNA末端快速扩增。所有统计检验均为双侧检验。

结果

ERα-C在所有细胞系中均有表达，但ERα-A和ERα-B在任何细胞系中均未表达。ERα-A和ERα-B启动子发生甲基化，但ERα-C未发生甲基化。ERβ、AR、PR-A和PR-B的启动子在某些细胞系中发生甲基化并因此失活，但在其他细胞系中未发生。用去甲基化试剂5-氮杂-2'-脱氧胞苷处理细胞可恢复所有具有先前甲基化启动子的类固醇受体基因的表达。所有38对癌组织和正常组织的ERα-C启动子均未发生甲基化。38例癌症中有36例（95%）的ERα-A发生甲基化，38例癌症中有35例（92%）的ERα-B发生甲基化，但所有正常组织的ERα-A和ERα-B均未发生甲基化（P均<0.001）。38例癌症中有30例（79%）的ERβ发生甲基化，但所有正常组织的ERβ均未发生甲基化。38例癌症中有3例（8%）的AR发生甲基化，但所有正常组织的AR均未发生甲基化。PR-A和PR-B在所有组织中均未发生甲基化。