APOBEC3C介导的NF-κB激活增强了清晰的细胞肾细胞癌进展
APOBEC3C-mediated NF-κB activation enhances clear cell renal cell carcinoma progression
影响因子:4.50000
分区:医学2区 / 肿瘤学3区
发表日期:2025 Jan
作者:
Nora Hase, Danny Misiak, Helge Taubert, Stefan Hüttelmaier, Michael Gekle, Marcel Köhn
摘要
透明细胞肾细胞癌（CCRCC）以肾癌的主要形式而闻名，由于其特定的表达谱以及明显的免疫细胞浸润，表现出对免疫疗法的敏感性。尽管如此，有效治疗转移性CCRCC仍然是一个重大挑战，需要对控制其进展的基本分子机制有更深入的理解。在这里，我们揭示了RNA结合蛋白DNA DC→DU-编辑酶Apobec-3C（Apobec3c;也称为A3C）在CCRCC组织和CCRCC衍生的细胞系中的表达增强，可通过扩增核因子-kappa b（nF-κB）活性。通过在CCRCC衍生的细胞系中采用RNA序列和基于细胞的测定，我们确定A3C是应激响应因子，对于细胞存活至关重要。此外，我们确定A3C结合并可能稳定编码NF-κB途径阳性调节剂的信使RNA（mRNA）。在A3C耗竭后，NF-κB家族的基本亚基在细胞质中受到异常约束，导致NF-κB靶基因的失调。我们的研究阐明了A3C在促进CCRCC肿瘤发展中的关键作用，将其定位为未来治疗策略的前瞻性目标。
Abstract
Renowned as the predominant form of kidney cancer, clear cell renal cell carcinoma (ccRCC) exhibits susceptibility to immunotherapies due to its specific expression profile as well as notable immune cell infiltration. Despite this, effectively treating metastatic ccRCC remains a significant challenge, necessitating a more profound comprehension of the underlying molecular mechanisms governing its progression. Here, we unveil that the enhanced expression of the RNA-binding protein DNA dC → dU-editing enzyme APOBEC-3C (APOBEC3C; also known as A3C) in ccRCC tissue and ccRCC-derived cell lines serves as a catalyst for tumor growth by amplifying nuclear factor-kappa B (NF-κB) activity. By employing RNA-sequencing and cell-based assays in ccRCC-derived cell lines, we determined that A3C is a stress-responsive factor and crucial for cell survival. Furthermore, we identified that A3C binds and potentially stabilizes messenger RNAs (mRNAs) encoding positive regulators of the NF-κB pathway. Upon A3C depletion, essential subunits of the NF-κB family are abnormally restrained in the cytoplasm, leading to deregulation of NF-κB target genes. Our study illuminates the pivotal role of A3C in promoting ccRCC tumor development, positioning it as a prospective target for future therapeutic strategies.