Department of Urology, University of Washington, Seattle, WA, USA.
Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Oncogene. 2023 Aug;42(32):2428-2438. doi: 10.1038/s41388-023-02759-7. Epub 2023 Jul 3.
The complement system is a major component of the innate immune system that works through the cytolytic effect of the membrane attack complex (MAC). Complement component 7 (C7) is essential for MAC assembly and its precisely regulated expression level is crucial for the cytolytic activity of MAC. We show that C7 is specifically expressed by the stromal cells in both mouse and human prostates. The expression level of C7 inversely correlates with clinical outcomes in prostate cancer. C7 is positively regulated by androgen signaling in the mouse prostate stromal cells. The androgen receptor directly transcriptionally regulates the mouse and human C7. Increasing C7 expression in the C57Bl/6 syngeneic RM-1 and Pten-Kras allografts suppresses tumor growth in vivo. Conversely, C7 haploinsufficiency promotes tumor growth in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Interestingly, replenishing C7 in androgen-sensitive Pten-Kras tumors during androgen depletion only slightly enhances cellular apoptosis, highlighting the diverse mechanisms employed by tumors to counteract complement activity. Collectively, our research indicates that augmenting complement activity could be a promising therapeutic approach to impede the development of castration resistance in prostate cancer.
补体系统是先天免疫系统的主要组成部分，通过膜攻击复合物（MAC）的细胞溶解作用发挥作用。补体成分 7（C7）是 MAC 组装所必需的，其精确调节的表达水平对于 MAC 的细胞溶解活性至关重要。我们表明，C7 特异性地在小鼠和人前列腺的基质细胞中表达。C7 的表达水平与前列腺癌的临床结果呈负相关。在小鼠前列腺基质细胞中，雄激素信号正向调节 C7 的表达。雄激素受体直接转录调控小鼠和人 C7。增加 C57Bl/6 同基因 RM-1 和 Pten-Kras 同种异体移植物中的 C7 表达可抑制体内肿瘤生长。相反，C7 半合子不足会促进转基因前列腺腺癌（TRAMP）模型中的肿瘤生长。有趣的是，在雄激素耗竭期间补充雄激素敏感的 Pten-Kras 肿瘤中的 C7 仅略微增加细胞凋亡，这突出了肿瘤采用的多种机制来对抗补体活性。总的来说，我们的研究表明，增强补体活性可能是一种有前途的治疗方法，可以阻止前列腺癌发生去势抵抗。
