Department of Experimental Medicine, University of Parma, Via Volturno 39, 43100 Parma, Italy.
Oncogene. 2009 Dec 10;28(49):4344-52. doi: 10.1038/onc.2009.286.
ApoJ/Clusterin (CLU) is a heterodimeric protein localized in the nucleus, cytoplasm or secretory organelles and involved in cell survival and neoplastic transformation. Its function in human cancer is still highly controversial. In this study, we examined the prostate of mice in which CLU has been genetically inactivated. Surprisingly, we observed transformation of the prostate epithelium in the majority of CLU knockout mice. Either PIN (prostate intraepithelial neoplasia) or differentiated carcinoma was observed in 100 and 87% of mice with homozygous or heterozygous deletion of CLU, respectively. Crossing CLU knockout with TRAMP (prostate cancer prone) mice results in a strong enhancement of metastatic spread. Finally, CLU depletion causes tumourigenesis in female TRAMP mice, which are normally cancer free. Mechanistically, deletion of CLU induces activation of nuclear factor-kB, a potentially oncogenic transcription factor important for the proliferation and survival of prostate cells.
载脂蛋白 J/ 簇集素（CLU）是一种定位于细胞核、细胞质或分泌细胞器的异二聚体蛋白，参与细胞存活和肿瘤转化。其在人类癌症中的功能仍存在很大争议。在这项研究中，我们检查了 CLU 基因失活的小鼠的前列腺。令人惊讶的是，我们观察到大多数 CLU 敲除小鼠的前列腺上皮发生转化。在 CLU 纯合或杂合缺失的小鼠中，分别有 100%和 87%观察到 PIN（前列腺上皮内瘤变）或分化型癌。将 CLU 敲除与 TRAMP（前列腺癌易感）小鼠杂交导致转移扩散的强烈增强。最后，CLU 耗竭导致通常无癌的雌性 TRAMP 小鼠发生肿瘤形成。从机制上讲，CLU 的缺失诱导核因子-κB 的激活，核因子-κB 是一种潜在的致癌转录因子，对前列腺细胞的增殖和存活很重要。
