Caveolin-1 upregulation contributes to c-Myc-induced high-grade prostatic intraepithelial neoplasia and prostate cancer.
Caveolin-1 upregulation contributes to c-Myc-induced high-grade prostatic intraepithelial neoplasia and prostate cancer.
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DOI：
10.1158/1541-7786.mcr-11-0451
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发表时间：
2012-02
期刊：
影响因子：
--
通讯作者：
Thompson TC
中科院分区：
文献类型：
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作者：
Yang G;Goltsov AA;Ren C;Kurosaka S;Edamura K;Logothetis R;DeMayo FJ;Troncoso P;Blando J;DiGiovanni J;Thompson TC
以前我们报道了小窝蛋白-1（Cav-1）在前列腺癌（PCa）细胞中的过表达，并证明它促进了PCa的进展。在这里，我们报告，Cav-1过表达的41.7%（15 36）的高级别前列腺上皮内瘤（HGPIN）标本中获得的根治性前列腺切除术。Cav-1阳性（Cav-1+）HGPIN与Cav-1+原发性PCa之间存在正相关（rho = 0.655，P< 0.0001），Cav-1与c-Myc在HGPIN中的表达之间存在正相关（rho = 0.41，P = 0.032）。为了确定Cav-1是否与c-Myc在体内癌前病变和PCa的发展中合作，我们产生了由ARR 2 PB启动子驱动的c-Myc过表达的转基因小鼠。在该ARR 2 PB-c-myc模型中，在小鼠PIN（mPIN）病变和PCa细胞中发现Cav-1过表达，并且与mPIN病变中的增殖与凋亡标记的比率显著高于那些病变附近的Cav-1阴性上皮中的增殖与凋亡标记的比率相关（10.02 vs 4.34; P = 0.007）。Cav-1过表达还与P-Akt和VEGF-A水平升高相关，这两种蛋白先前分别与Cav-1诱导的PCa细胞存活和细胞Cav-1水平的正反馈调节相关。在多种PCa细胞系中，c-Myc转染诱导Cav-1蛋白（而不是mRNA），而VEGF siRNA转染废除c-Myc诱导的Cav-1过表达，表明c-Myc-VEGF-Cav-1信号轴。总体而言，我们的研究结果表明，Cav-1与c-Myc在HGPIN和PCa的发展。此外，HGPIN中的Cav-1过表达可能是早期鉴定倾向于发展Cav-1+原发性PCa的患者的生物标志物。
Previously we reported caveolin-1 (Cav-1) overexpression in prostate cancer (PCa) cells and demonstrated that it promotes PCa progression. Here, we report that Cav-1 was overexpressed in 41.7% (15 of 36) of high-grade prostatic intraepithelial neoplasia (HGPIN) specimens obtained during radical prostatectomies. Positive correlations exist between Cav-1–positive (Cav-1+) HGPIN and Cav-1+ primary PCa (rho = 0.655, P< 0.0001) and between Cav-1 and c-Myc expression in HGPIN (rho = 0.41, P = 0.032). To determine whether Cav-1 cooperates with c-Myc in development of premalignant lesions and PCa in vivo, we generated transgenic mice with c-Myc overexpression driven by the ARR2PB promoter. In this ARR2PB–c-myc model, Cav-1 overexpression was found in mouse PIN (mPIN) lesions and PCa cells and was associated with a significantly higher ratio of proliferative to apoptotic labeling in mPIN lesions than in the Cav-1–negative epithelia adjacent to those lesions (10.02 vs 4.34; P = 0.007). Cav-1 overexpression was also associated with increased levels of P-Akt and VEGF-A, which were previously associated with Cav-1–induced PCa cell survival and positive-feedback regulation of cellular Cav-1 levels, respectively. In multiple PCa cell lines, Cav-1 protein (but not mRNA) was induced by c-Myc transfection, whereas VEGF siRNA transfection abrogated c-Myc–induced Cav-1 overexpression, suggesting a c-Myc–VEGF–Cav-1 signaling axis. Overall, our results suggest that Cav-1 is associated with c-Myc in the development of HGPIN and PCa. Further, Cav-1 overexpression in HGPIN is potentially a biomarker for early identification of patients who tend to develop Cav-1+ primary PCa.