Differential CARM1 expression in prostate and colorectal cancers.
Differential CARM1 expression in prostate and colorectal cancers.
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DOI：
10.1186/1471-2407-10-197
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发表时间：
2010-05-13
期刊：
影响因子：
3.8
通讯作者：
Jung C
中科院分区：
文献类型：
--
作者：
Kim YR;Lee BK;Park RY;Nguyen NT;Bae JA;Kwon DD;Jung C
辅活化子相关的精氨酸甲基转移酶1(CARM1)是雄激素受体(AR)介导的信号转导的转录辅活化子。相应地，CARM1的过度表达与前列腺癌的发生发展以及向雄激素非依赖性前列腺癌的进展有关。然而，在我们的初步研究中，CARM1对雄激素刺激的AR靶基因表达的促进作用微乎其微。这些结果表明，与CARM1相关的AR靶基因的表达可能主要来自非激素依赖的活动。本研究的目的是确定CARM1在人类肿瘤中的表达模式，并确定CARM1在高表达肿瘤中的作用机制。采用组织芯片技术，通过免疫组织化学方法检测CARM1在肿瘤组织中的表达。我们还评估了CARM1在前列腺和结直肠手术标本中的表达，并复习了所有病例的临床记录。此外，使用前列腺特异性抗原(PSA)启动子的报告转录实验被用来确定与CARM1相关的非激素介导的信号激活所涉及的信号通路。组织芯片显示CARM1在结直肠癌中高表达，而在前列腺癌和乳腺癌中不表达。使用手术标本的进一步研究表明，CARM1在75%的结直肠癌中高度过度表达(65例中有49例)，但在雄激素非依赖性前列腺癌中不表达。此外，CARM1的S对整个PSA启动子的共激活作用在雄激素依赖和雄激素非依赖的PCa细胞中都非常有限。这些结果表明，在PSA的调节中，还有其他因素与CARM1的表达有关。事实上，CARM1显著调控P53和NF-κB靶基因转录。这项研究的结果表明，除了在类固醇受体的激活中发挥作用外，CARM1还通过改变许多转录因子的活性而发挥转录调节器的作用，特别是在雄激素非依赖性前列腺癌和结直肠癌中。
Coactivator-associated arginine methyltransferase 1 (CARM1) functions as a transcriptional coactivator of androgen receptor (AR)-mediated signaling. Correspondingly, overexpression of CARM1 has been associated with the development of prostate cancer (PCa) and its progression to androgen-independent PCa. In our preliminary study, however, the promoting effects of CARM1, with regard to androgen-stimulated AR target gene expression were minimal. These results suggested that the AR target gene expression associated with CARM1 may result primarily from non-hormone dependent activity. The goal of this study was to confirm the pattern of expression of CARM1 in human tumors and determine the mechanism of action in CARM1 overexpressed tumors. Tissue microarray was used to determine the pattern of expression of CARM1 in human cancers by immunohistochemistry. CARM1 expression was also evaluated in prostate and colorectal surgical specimens and the clinical records of all cases were reviewed. In addition, a reporter transcription assay using the prostate-specific antigen (PSA) promoter was used to identify the signaling pathways involved in non-hormone-mediated signal activation associated with CARM1. The tissue microarray showed that CARM1 was particularly overexpressed in the colorectal cancers while CARM1 expression was not prevalent in the prostate and breast cancers. Further studies using surgical specimens demonstrated that CARM1 was highly overexpressed in 75% of colorectal cancers (49 out of 65) but not in the androgen-independent PCa. In addition, CARM1's coactivating effect on the entire PSA promoter was very limited in both androgen-dependent and androgen-independent PCa cells. These results suggest that there are other factors associated with CARM1 expression in PSA regulation. Indeed, CARM1 significantly regulated both p53 and NF-κB target gene transcription. The results of this study suggest that, in addition to its role in activation of steroid receptors, CARM1 functions as a transcriptional modulator by altering the activity of many transcriptional factors, especially with regard to androgen independent PCa and colorectal cancers.
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DOI：
10.1073/pnas.0610792104
发表时间：
2007-07-24
影响因子：
11.1
作者：
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