APOBEC3C介导的NF-κB激活促进透明细胞肾细胞癌的进展

APOBEC3C-mediated NF-κB activation enhances clear cell renal cell carcinoma progression

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Molecular Oncology

影响因子:4.5

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

DOI: 10.1002/1878-0261.13721

摘要

以其特定表达谱和显著的免疫细胞浸润，透明细胞肾细胞癌（ccRCC）被誉为肾癌的主要类型，表现出对免疫疗法的敏感性。尽管如此，有效治疗转移性ccRCC仍然是一大挑战，亟需深入理解其进展的分子机制。在本研究中，我们揭示了RNA结合蛋白DNA dC→dU编辑酶APOBEC-3C（APOBEC3C，亦称A3C）在ccRCC组织及其衍生细胞系中表达增强，促进肿瘤生长的作用，主要通过增强核因子κB（NF-κB）活性实现。通过在ccRCC细胞系中应用RNA测序和细胞实验，我们确定A3C是一个应激反应因子，并且对细胞存活至关重要。此外，我们发现A3C可以结合并可能稳定编码NF-κB通路正调控因子的mRNA。在A3C耗竭后，NF-κB家族的关键亚基异常地滞留在细胞质中，导致NF-κB靶基因的调控失常。本研究阐明了A3C在促进ccRCC肿瘤发展中的关键作用，并将其定位为未来治疗策略的潜在靶点。

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.