Characterization of prostate cancer bone metastases according to expression levels of steroidogenic enzymes and androgen receptor splice variants.
Characterization of prostate cancer bone metastases according to expression levels of steroidogenic enzymes and androgen receptor splice variants.
复制标题
DOI：
10.1371/journal.pone.0077407
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Wikström P
中科院分区：
文献类型：
--
作者：
Jernberg E;Thysell E;Bovinder Ylitalo E;Rudolfsson S;Crnalic S;Widmark A;Bergh A;Wikström P
肿瘤内类固醇生成和组成性雄激素受体（AR）活性与去势抵抗性前列腺癌（CRPC）有关。本研究旨在检查 CRPC 骨转移是否比未经治疗的骨转移表达更高水平的类固醇转化酶。还分析了类固醇生成酶水平与组成型活性 AR 变体 (AR-V) 表达以及临床和病理变量的关系。从 54 名转移手术患者中获取未经治疗的、未接受激素治疗的 (HN，n = 9) 和 CRPC 骨转移样本 (n = 45)。从 13 个前列腺切除标本中获取非恶性和恶性前列腺样本。通过实时 RT-PCR、免疫组织化学和免疫印迹分析转录本和蛋白质水平。 CRPC 和 HN 骨转移之间没有检测到类固醇生成酶水平存在差异。然而，骨转移瘤中的 SRD5A1、AKR1C2、AKR1C3 和 HSD17B10 mRNA 水平显着高于非恶性和/或恶性前列腺组织，而转移瘤中的 CYP11A1、CYP17A1、HSD3B2、SRD5A2 和 HSD17B6 mRNA 水平显着较低。转移瘤亚组表达非常高水平的 AKR1C3，这不是由于拷贝数变异测定检查的基因扩增所致。未发现 AKR1C3 表达与核 AR 染色、肿瘤细胞增殖或转移手术后患者结果之间存在关联。除一处例外外，在 AKR1C3 水平低的骨转移瘤中发现了高 AR-V 蛋白水平，而 AKR1C3 水平高的转移瘤主要含有低 AR-V 水平，这表明个体骨转移瘤的去势抵抗背后存在不同的机制。 PC 骨转移的一个亚组中表明了将肾上腺衍生的类固醇转化为更有效的雄激素的诱导能力。这与 CRPC 无关，而仅与转移的晚期阶段相关。骨转移的亚组可以根据 AKR1C3 和 AR-V 的表达水平来识别，这可能与患者对二线雄激素剥夺治疗的反应相关。
Intra-tumoral steroidogenesis and constitutive androgen receptor (AR) activity have been associated with castration-resistant prostate cancer (CRPC). This study aimed to examine if CRPC bone metastases expressed higher levels of steroid-converting enzymes than untreated bone metastases. Steroidogenic enzyme levels were also analyzed in relation to expression of constitutively active AR variants (AR-Vs) and to clinical and pathological variables. Untreated, hormone-naïve (HN, n = 9) and CRPC bone metastases samples (n = 45) were obtained from 54 patients at metastasis surgery. Non-malignant and malignant prostate samples were acquired from 13 prostatectomy specimens. Transcript and protein levels were analyzed by real-time RT-PCR, immunohistochemistry and immunoblotting. No differences in steroidogenic enzyme levels were detected between CRPC and HN bone metastases. Significantly higher levels of SRD5A1, AKR1C2, AKR1C3, and HSD17B10 mRNA were however found in bone metastases than in non-malignant and/or malignant prostate tissue, while the CYP11A1, CYP17A1, HSD3B2, SRD5A2, and HSD17B6 mRNA levels in metastases were significantly lower. A sub-group of metastases expressed very high levels of AKR1C3, which was not due to gene amplification as examined by copy number variation assay. No association was found between AKR1C3 expression and nuclear AR staining, tumor cell proliferation or patient outcome after metastases surgery. With only one exception, high AR-V protein levels were found in bone metastases with low AKR1C3 levels, while metastases with high AKR1C3 levels primarily contained low AR-V levels, indicating distinct mechanisms behind castration-resistance in individual bone metastases. Induced capacity of converting adrenal-gland derived steroids into more potent androgens was indicated in a sub-group of PC bone metastases. This was not associated with CRPC but merely with the advanced stage of metastasis. Sub-groups of bone metastases could be identified according to their expression levels of AKR1C3 and AR-Vs, which might be of relevance for patient response to 2nd line androgen-deprivation therapy.
登录
查看更多内容
影响因子：
9.2
作者：
Guo Z;Qiu Y
通讯作者：
Qiu Y
影响因子：
28.2
作者：
Miyamoto DT;Lee RJ;Stott SL;Ting DT;Wittner BS;Ulman M;Smas ME;Lord JB;Brannigan BW;Trautwein J;Bander NH;Wu CL;Sequist LV;Smith MR;Ramaswamy S;Toner M;Maheswaran S;Haber DA
通讯作者：
Haber DA
DOI：
10.1016/j.jsbmb.2010.11.004
发表时间：
2011-05
影响因子：
4.1
作者：
Byrns, Michael C.;Jin, Yi;Penning, Trevor M.
通讯作者：
Penning, Trevor M.
影响因子：
--
作者：
Bauman, DR;Steckelbroeck, S;Penning, TM
通讯作者：
Penning, TM
影响因子：
45.3
作者：
Efstathiou, Eleni;Titus, Mark;Logothetis, Christopher J.
通讯作者：
Logothetis, Christopher J.