Lieberman Rachel, Pan Jing, Zhang Qi, You Ming
Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA.
Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.
Oncotarget. 2017 May 23;8(21):34032-34044. doi: 10.18632/oncotarget.16371.
RAD52 is involved in homologous recombination and DNA repair. This study focuses on lung cancer progression and how the DNA repair gene, Rad52, enables tumor cells to have sufficient genome integrity, i.e., the ability to repair lethal DNA damage, to avoid cell death. In this report, we analyze the phenotypic differences between wild type and Rad52-/- in inhibition of tumor phenotypes including cell growth, viability, cytolysis, and immune profiling. We demonstrated that loss of Rad52 not only increases the death of cells undergoing carcinogen-induced transformation in vivo, but that Rad52 loss also augments in vivo antitumor activity through an enhanced capacity for direct killing of LLC tumor cells by stimulated Rad52-/- NK and CD8+ T cells. We hypothesize that upon DNA damage, wild type cells attempt to repair DNA lesions, but those cells that survive will continue to divide with damage and a high likelihood of progressing to malignancy. Loss of Rad52, however, appears to increase genomic instability beyond a manageable threshold, acceding the damaged cells to death before they are able to become tumor cells. Our results suggest a key role for the complex interplay between the DNA damage response and host immunity in determining risk for Squamous Cell Lung Carcinoma.
RAD52参与同源重组和DNA修复。本研究聚焦于肺癌进展以及DNA修复基因Rad52如何使肿瘤细胞具备足够的基因组完整性，即修复致死性DNA损伤以避免细胞死亡的能力。在本报告中，我们分析了野生型和Rad52基因敲除型在抑制肿瘤表型（包括细胞生长、活力、细胞溶解和免疫谱分析）方面的表型差异。我们证明，Rad52的缺失不仅会增加体内经历致癌物诱导转化的细胞死亡，而且Rad52缺失还会通过增强Rad52基因敲除型自然杀伤细胞（NK）和CD8 + T细胞直接杀伤LLC肿瘤细胞的能力来增强体内抗肿瘤活性。我们推测，在DNA损伤时，野生型细胞试图修复DNA损伤，但那些存活下来的细胞会带着损伤继续分裂，并有很高的概率发展为恶性肿瘤。然而，Rad52的缺失似乎会使基因组不稳定性增加到超出可控阈值，导致受损细胞在能够成为肿瘤细胞之前就死亡。我们的结果表明，DNA损伤反应与宿主免疫之间的复杂相互作用在决定鳞状细胞肺癌风险方面起着关键作用。
