Tuppurainen Hanna, Nätynki Marjut, Laurila Niina, Pylkäs Katri, Winqvist Robert, Peltoketo Hellevi
Laboratory of Cancer Genetics and Tumor Biology, Translational Medicine Research Unit, Biocenter Oulu and Faculty of Medicine, Medical Research Center Oulu, University of Oulu, FI-90220 Oulu, Finland.
Laboratory of Cancer Genetics and Tumor Biology, Translational Medicine Research Unit, Biocenter Oulu and Faculty of Medicine, Medical Research Center Oulu, University of Oulu, FI-90220 Oulu, Finland; Northern Finland Laboratory Centre, Oulu, Finland.
Biochem Biophys Res Commun. 2025 Sep 8;778:152402. doi: 10.1016/j.bbrc.2025.152402. Epub 2025 Jul 24.
High-risk genes, heterozygous pathogenic mutations of which predispose to familial breast cancers, typically encode factors securing a proper DNA damage response. PALB2 is one such major cellular factor that is needed for alleviation of genomic, replicative, and oxidative stresses. Thus, it has a crucial role in maintaining genomic integrity and protecting cells against cancer. While the malfunctions in DNA damage repair of PALB2-mutated cells have extensively been documented, our research continues to explore cells' other pro-tumorigenic characteristics, focusing particularly on the early stages of malignancy development. Recently, we generated biallelically and monoallelically PALB2-mutated cell lines in a non-malignant background and reported that also their migratory capacity had enhanced together with changes in their transcriptomes and formation of three-dimensionally grown spheroids. Here we demonstrate that JAM3 and PARVB are among the top up-regulated genes in PALB2-mutated cells and that knockdown of the genes reduce migration of the cells and morphological abnormalities of PALB2-mutated spheroids. Macropinocytosis that cancer cells utilize to advance their viability, has also enhanced in PALB2-mutated cells in a β-parvin-dependent manner. Knocking down PALB2 or increased DNA damage did not trigger JAM3 and PARVB expression in control cells, suggesting the need for long-term changes in cell fate and/or cellular conditions. However, DNA damage boosted the nuclear accumulation of a macropinosome marker dextran, indicating that PALB2-mutated cells may use the system to replenish nucleotide stocks for DNA repair. Altogether, several mechanisms can increase the oncogenic potential of PALB2-mutated cells and may offer new approaches to treat PALB2-associated cancers.
高风险基因的杂合致病突变易引发家族性乳腺癌，这些基因通常编码确保适当DNA损伤反应的因子。PALB2就是这样一种主要的细胞因子，它是缓解基因组、复制和氧化应激所必需的。因此，它在维持基因组完整性和保护细胞免受癌症侵害方面起着至关重要的作用。虽然PALB2突变细胞在DNA损伤修复方面的功能障碍已被广泛记录，但我们的研究继续探索细胞的其他促肿瘤特征，尤其关注恶性肿瘤发展的早期阶段。最近，我们在非恶性背景下生成了双等位基因和单等位基因PALB2突变的细胞系，并报告称它们的迁移能力增强，同时转录组发生变化，且形成了三维生长的球体。在这里，我们证明JAM3和PARVB是PALB2突变细胞中上调最明显的基因之一，敲低这些基因会减少细胞的迁移以及PALB2突变球体的形态异常。癌细胞用于提高其生存能力的巨胞饮作用，在PALB2突变细胞中也以β-帕文依赖的方式增强。敲低PALB2或增加DNA损伤不会在对照细胞中触发JAM3和PARVB的表达，这表明需要细胞命运和/或细胞条件的长期变化。然而，DNA损伤促进了巨胞饮体标记物葡聚糖的核积累，表明PALB2突变细胞可能利用该系统补充用于DNA修复的核苷酸储备。总之，几种机制可以增加PALB2突变细胞的致癌潜力，并可能为治疗PALB2相关癌症提供新方法。
