Gurel Bora, Iwata Tsuyoshi, Koh Cheryl M, Jenkins Robert B, Lan Fusheng, Van Dang Chi, Hicks Jessica L, Morgan James, Cornish Toby C, Sutcliffe Siobhan, Isaacs William B, Luo Jun, De Marzo Angelo M
Department of Pathology, The Johns Hopkins University, School of Medicine, Baltimore, MD 21231, USA.
Mod Pathol. 2008 Sep;21(9):1156-67. doi: 10.1038/modpathol.2008.111. Epub 2008 Jun 20.
The MYC onco-protein is a transcription factor that regulates cell proliferation, metabolism, protein synthesis, mitochondrial function and stem cell renewal. A region on chromosome 8q24 encompassing the MYC locus is amplified in prostate cancer, but this occurs mostly in advanced disease suggesting that MYC alterations occur late in prostate cancer. In contrast, MYC mRNA is elevated in most prostate cancers, even those of relatively low stage and grade (eg Gleason score 6) suggesting that MYC plays a role in initiation. However, since MYC protein levels are tightly regulated, elevated MYC mRNA does not necessarily imply elevated MYC protein. Thus, it is critical to determine whether MYC protein is elevated in human prostate cancer, and if so, at what stage of the disease this elevation occurs. Prior studies of MYC protein localization have been hampered by lack of suitable antibodies and controls. We utilized a new anti-MYC antibody coupled with genetically defined control experiments to localize MYC protein within human tissue microarrays consisting of normal, atrophy, PIN, primary adenocarcinoma, and metastatic adenocarcinoma. Nuclear overexpression of MYC protein occurred frequently in luminal cells of PIN, as well as in most primary carcinomas and metastatic disease. MYC protein did not correlate with gain of 8q24, suggesting alternative mechanisms for MYC overexpression. These results provide evidence that upregulation of nuclear MYC protein expression is a highly prevalent and early change in prostate cancer and suggest that increased nuclear MYC may be a critical oncogenic event driving human prostate cancer initiation and progression.
MYC癌蛋白是一种转录因子，可调节细胞增殖、代谢、蛋白质合成、线粒体功能和干细胞更新。8号染色体q24区域包含MYC基因座，在前列腺癌中会发生扩增，但这种情况大多出现在晚期疾病中，这表明MYC改变发生在前列腺癌的晚期。相比之下，MYC mRNA在大多数前列腺癌中升高，即使是那些相对低分期和低分级的癌症（如Gleason评分为6分），这表明MYC在肿瘤起始中发挥作用。然而，由于MYC蛋白水平受到严格调控，MYC mRNA升高并不一定意味着MYC蛋白升高。因此，确定MYC蛋白在人类前列腺癌中是否升高，以及如果升高的话，在疾病的哪个阶段发生这种升高至关重要。先前关于MYC蛋白定位的研究因缺乏合适的抗体和对照而受到阻碍。我们利用一种新的抗MYC抗体并结合基因定义的对照实验，在由正常、萎缩、前列腺上皮内瘤变（PIN）、原发性腺癌和转移性腺癌组成的人类组织微阵列中定位MYC蛋白。MYC蛋白的核过表达在PIN的管腔细胞中频繁出现，在大多数原发性癌和转移性疾病中也很常见。MYC蛋白与8q24增益无关，提示MYC过表达存在其他机制。这些结果提供了证据，表明核MYC蛋白表达上调是前列腺癌中一种高度普遍且早期的变化，并表明核MYC增加可能是驱动人类前列腺癌起始和进展的关键致癌事件。
