School of Life Science, Jiangsu Normal University, Xuzhou, Jiangsu, China.
Central Laboratory, Institute of Dermatology, Chinese Academy of Medical Science & Peking Union Medical College, Nanjing, Jiangsu, China.
Cell Signal. 2023 Dec;112:110914. doi: 10.1016/j.cellsig.2023.110914. Epub 2023 Oct 6.
Butyrophilin subfamily 3 member A3 (BTN3A3) is a member of the immunoglobulin superfamily and functions as a tumor suppressor in multiple cancer types. Our study has revealed that in clear cell renal cell carcinoma (ccRCC), patients who express high levels of BTN3A3 experience longer survival times than those with lower expression. Further, we have observed that BTN3A3 inhibits the proliferation, migration, and invasion of ccRCC cells. Through the utilization of an immunoprecipitation assay followed by mass spectrometry, we have discovered that BTN3A3 binds directly to RPS3A. Knockdown of BTN3A3 led to increased cell proliferation, migration, and invasion. However, this effect was significantly reduced when RPS3A was simultaneously overexpressed. Previous reports have demonstrated that RPS3A positively regulates mitochondrial function and reactive oxygen species (ROS) levels. Our study has shown that overexpression of both BTN3A3 and RPS3A can increase cellular oxygen consumption rate (OCR) and ROS levels. Furthermore, we have observed that the addition of HO can reverse the effects of BTN3A3 knockdown on cell proliferation and migration by increasing the cellular ROS level. ROS play a crucial role in regulating the MAPK pathway and tumor cell growth. To further explore this relationship, we examined RNA-Seq and immunoblotting data and found that BTN3A3 can negatively regulate the degree of activation of the MAPK signaling pathway. This finding suggests that the BTN3A3/RPS3A complex may regulate ccRCC progression by modulating MAPK pathways. Therefore, BTN3A3 could serve as both a prognostic marker and a potential therapeutic target for ccRCC patients.
BTN3A3 是免疫球蛋白超家族的成员，是多种癌症类型的肿瘤抑制因子。我们的研究表明，在透明细胞肾细胞癌（ccRCC）中，表达高水平 BTN3A3 的患者比表达水平较低的患者生存时间更长。此外，我们观察到 BTN3A3 抑制 ccRCC 细胞的增殖、迁移和侵袭。通过使用免疫沉淀测定 followed by mass spectrometry，我们发现 BTN3A3 直接与 RPS3A 结合。BTN3A3 的敲低导致细胞增殖、迁移和侵袭增加。然而，当同时过表达 RPS3A 时，这种效应显著降低。先前的报告表明，RPS3A 正向调节线粒体功能和活性氧（ROS）水平。我们的研究表明，BTN3A3 和 RPS3A 的共表达可以增加细胞耗氧率（OCR）和 ROS 水平。此外，我们观察到添加 HO 可以通过增加细胞内 ROS 水平来逆转 BTN3A3 敲低对细胞增殖和迁移的影响。ROS 在调节 MAPK 途径和肿瘤细胞生长中起着至关重要的作用。为了进一步探索这种关系，我们检查了 RNA-Seq 和免疫印迹数据，发现 BTN3A3 可以负调控 MAPK 信号通路的激活程度。这一发现表明，BTN3A3/RPS3A 复合物可能通过调节 MAPK 途径来调节 ccRCC 的进展。因此，BTN3A3 可以作为 ccRCC 患者的预后标志物和潜在治疗靶点。
