Peng Yi, Li Caihong X, Chen Fei, Wang Zhengxin, Ligr Martin, Melamed Jonathan, Wei Jianjun, Gerald William, Pagano Michele, Garabedian Michael J, Lee Peng
Department of Pathology, New York University School of Medicine, New York Harbor Healthcare System, 423 E. 23rd St., Room 6140N, New York, NY 10010, USA.
Am J Pathol. 2008 Jan;172(1):225-35. doi: 10.2353/ajpath.2008.070065. Epub 2007 Dec 21.
ARA70 was first identified as a gene fused to the ret oncogene in thyroid carcinoma and subsequently as a co-activator for androgen receptor (AR). Two isoforms of ARA70 have been identified: a 70-kDa version called ARA70 alpha and an internally spliced 35-kDa variant termed ARA70 beta. We have previously reported that ARA70 alpha expression is reduced in prostate cancer, and its overexpression inhibits proliferation of LNCaP prostate cancer cells. However, the function of the ARA70 beta isoform in prostate cancer is not understood. In this report we examined the effects of ARA70 beta on AR transcriptional regulation as well as prostate cancer cellular proliferation and invasion. Although both ARA70 alpha and ARA70 beta functioned as transcriptional co-activators of AR in cell-based reporter assays, ARA70 beta overexpression, in contrast to ARA70 alpha, promoted prostate cancer cellular proliferation and invasion through Matrigel. Interestingly, genome-wide expression profiling of cells expressing ARA70 beta revealed an increase in the expression of genes involved in the control of cell division and adhesion, compatible with a role for ARA70 beta in proliferation and invasion. Consistent with its function in promoting cell growth and invasion, ARA70 beta expression was increased in prostate cancer. Our findings implicate ARA70 beta as a regulator of tumor cell growth and metastasis by affecting gene expression.
ARA70最初被鉴定为在甲状腺癌中与ret癌基因融合的一个基因，随后被鉴定为雄激素受体（AR）的共激活因子。已鉴定出ARA70的两种异构体：一种70 kDa的版本称为ARA70α，另一种内部剪接的35 kDa变体称为ARA70β。我们之前报道过，ARA70α在前列腺癌中的表达降低，其过表达抑制LNCaP前列腺癌细胞的增殖。然而，ARA70β异构体在前列腺癌中的功能尚不清楚。在本报告中，我们研究了ARA70β对AR转录调控以及前列腺癌细胞增殖和侵袭的影响。尽管在基于细胞的报告基因检测中，ARA70α和ARA70β均作为AR的转录共激活因子发挥作用，但与ARA70α相反，ARA70β的过表达通过基质胶促进了前列腺癌细胞的增殖和侵袭。有趣的是，对表达ARA70β的细胞进行全基因组表达谱分析发现，参与细胞分裂和黏附控制的基因表达增加，这与ARA70β在增殖和侵袭中的作用相符。与其促进细胞生长和侵袭的功能一致，ARA70β在前列腺癌中的表达增加。我们的研究结果表明，ARA70β通过影响基因表达而成为肿瘤细胞生长和转移的调节因子。
