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首页> 外文期刊>Cell Reports >Chromosomal Instability Triggered by Rrm2b Loss Leads to IL-6 Secretion and Plasmacytic Neoplasms
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Chromosomal Instability Triggered by Rrm2b Loss Leads to IL-6 Secretion and Plasmacytic Neoplasms

机译：Rrm2b丢失引发的染色体不稳定导致IL-6分泌和浆细胞性肿瘤。

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Chronic inflammation has a tight cause-and-effect relationship with DNA damage by inflicting tissue damage and increasing cancer risk. Rrm2b, a key enzyme in de novo deoxyribonucleotide synthesis, is involved in DNA damage repair, but its role in cancer development has yet to be demonstrated. In this work, Rrm2b gene loss led to severe numerical and structural chromosome abnormalities that caused ATM activation, inducing p-Ser85 IKK@c/NEMO and I@kB kinase (IKK). NF-@kB consequently induced by IKK triggered sustained IL-6 expression that constitutively activated STAT3 in Rrm2b-deficient cells. High plasma interleukin-6 (IL-6) and associated hematologic disorders were observed in Rrm2b^-^/^- mice, and 30%-40% of aged Rrm2b heterozygous knockout mice developed plasma cell neoplasms and suffered from progressive splenomegaly and ascites. The genetic ablation of IL-6 suppressed STAT3 induction and delayed disease onset in Rrm2b^-^/^- mice, extending their lifespan. Thus, Rrm2b plays a crucial role in maintaining chromosomal stability and preventing chronic-inflammation-associated tumorigenesis.
机译：慢性炎症通过造成组织损伤和增加癌症风险，与DNA损伤具有紧密的因果关系。 Rrm2b是新生脱氧核糖核苷酸合成中的关键酶，参与DNA损伤修复，但其在癌症发展中的作用尚未得到证实。在这项工作中，Rrm2b基因缺失导致严重的数字和结构染色体异常，导致ATM激活，从而诱导p-Ser85 IKK @ c / NEMO和I @ kB激酶（IKK）。因此，IKK诱导的NF-kB触发了持续的IL-6表达，该表达在Rrm2b缺陷细胞中组成性激活STAT3。在Rrm2b ^-^ / ^-小鼠中观察到高血浆白细胞介素6（IL-6）和相关的血液系统疾病，并且30％-40％的老年Rrm2b杂合敲除小鼠发展出浆细胞瘤，并患有进行性脾肿大和腹水。 IL-6的遗传消融抑制了Rrm2b ^-^ / ^-小鼠中STAT3的诱导并延缓了疾病的发作，延长了它们的寿命。因此，Rrm2b在维持染色体稳定性和预防慢性炎症相关的肿瘤发生中起着至关重要的作用。

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