透明细胞肾细胞癌 (ccRCC) 被认为是肾癌的主要形式，由于其特定的表达谱以及显着的免疫细胞浸润，对免疫疗法表现出敏感性。尽管如此，有效治疗转移性 ccRCC 仍然是一个重大挑战，需要更深入地理解控制其进展的潜在分子机制。在此，我们揭示了 ccRCC 组织和 ccRCC 衍生细胞系中 RNA 结合蛋白 DNA dC → dU 编辑酶 APOBEC-3C（APOBEC3C；也称为 A3C）的增强表达，通过放大核因子-κB (NF-κB) 活性。通过在 ccRCC 衍生细胞系中采用 RNA 测序和基于细胞的检测，我们确定 A3C 是一种应激反应因子，对细胞存活至关重要。此外，我们还发现 A3C 可以结合编码 NF-κB 通路正调节因子的信使 RNA (mRNA)，并可能稳定该信使 RNA (mRNA)。 A3C 耗尽后，NF-κB 家族的重要亚基在细胞质中受到异常抑制，导致 NF-κB 靶基因失调。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。© 2024 作者。约翰·威利出版的《分子肿瘤学》

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.© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.