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TMPRSS2-ERG regulation of androgen biosynthetic enzyme expression, DHT synthesis, and androgen receptor activation in prostate cancer.

机译：TMPRSS2-ERG对前列腺癌中雄激素生物合成酶表达，DHT合成和雄激素受体活化的调节。

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摘要

Intratumoral androgen synthesis in prostate cancer (PCa) contributes to the development of castration-resistant prostate cancer (CRPC). Several enzymes responsible for androgen biosynthesis have been shown to be overexpressed in CRPC, thus, contributing to CRPC in a castrated environment. Although intratumoral androgen synthesis is thought to contribute to the development and progression of CRPC, currently little is known regarding the regulation of androgen biosynthetic enzyme gene expression in PCa. The TMPRSS2-ERG transcription factor has been shown to be present in primary PCa tumors as well as CRPC tumors. The hypothesis was investigated that TMPRSS2-ERG fusions regulate androgen biosynthetic enzyme (ABE) gene expression and the production of androgens, which contributes to the development of CRPC. Data revealed that ERG regulated the expression of ABE, AKR1C3, in PCa cells via direct binding to the AKR1C3 gene region. Knockdown of ERG resulted in reduced AKR1C3 expression, which caused a reduction in both DHT synthesis and PSA expression in VCaP PCa cells treated with 5alpha-Androstanedione, a DHT precursor metabolite. Immunohistochemical staining revealed that ERG was co-expressed with AKR1C3 in PCa tissue samples. These data suggest that AKR1C3 catalyzes the biochemical reduction of 5alpha-Androstanedione to DHT in PCa cells, and that ERG regulates this step through upregulation of AKR1C3 expression. Elucidation of ERG regulation of ABEs in CRPC may help to stratify TMPRSS2-ERG fusion-positive PCa patients in the clinic for anti-hormone driven therapies; and AKR1C3 may serve as a valuable therapeutic target in the treatment of CRPC.
机译：前列腺癌（PCa）中的肿瘤内雄激素合成有助于去势抵抗性前列腺癌（CRPC）的发展。已显示负责雄激素生物合成的几种酶在CRPC中过表达，因此在cast割的环境中有助于CRPC。尽管据认为肿瘤内雄激素合成可促进CRPC的发展和进展，但目前对PCa中雄激素生物合成酶基因表达的调控知之甚少。已显示TMPRSS2-ERG转录因子存在于原发性PCa肿瘤和CRPC肿瘤中。假说研究了TMPRSS2-ERG融合体调节雄激素生物合成酶（ABE）基因表达和雄激素产生，这有助于CRPC的发展。数据显示，ERG通过直接结合到AKR1C3基因区域来调节PCa细胞中ABE AKR1C3的表达。减少ERG导致AKR1C3表达降低，这导致DHT前体代谢物5alpha-Androstanedione处理的VCaP PCa细胞中DHT合成和PSA表达均降低。免疫组织化学染色显示，ERa与AKR1C3在PCa组织样品中共表达。这些数据表明AKR1C3催化PCa细胞中5α-雄烷二酮还原成DHT的生化还原，并且ERG通过上调AKR1C3的表达来调节这一步骤。阐明CRPC中ABE的ERG调节可能有助于在临床上针对抗激素驱动疗法将TMPRSS2-ERG融合阳性PCa患者进行分层； AKR1C3可能是治疗CRPC的重要治疗靶点。

著录项

  • 作者

    Powell, Katelyn A.;

  • 作者单位

    Wayne State University.;

  • 授予单位 Wayne State University.;
  • 学科 Oncology.;Molecular biology.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 138 p.
  • 总页数 138
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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