Inflammation-induced cell proliferation potentiates DNA damage-induced mutations in vivo.
Inflammation-induced cell proliferation potentiates DNA damage-induced mutations in vivo.
复制标题
DOI：
10.1371/journal.pgen.1004901
复制
发表时间：
2015-02
期刊：
影响因子：
4.5
通讯作者：
Engelward BP
中科院分区：
文献类型：
--
作者：
Kiraly O;Gong G;Olipitz W;Muthupalani S;Engelward BP
突变是癌症发生的关键驱动因素。虽然广泛的研究集中在暴露诱导的突变上，但很少有研究探讨组织生理学作为体内突变易感性调节剂的重要性。特别令人感兴趣的是炎症，这是一种与慢性炎症性疾病和病原体引起的炎症相关的已知癌症危险因素。在这里，我们使用带有报告基因的荧光黄色直接重复序列（FYDR）小鼠来检测同源重组（HR）过程中的错位，这是一类重要的突变。 FYDR 小鼠暴露于雨蛙素（一种有效的胰腺炎症诱导剂）。我们发现炎症会诱导 DSB（γH2AX 病灶），并且几天后细胞增殖会增加。虽然孤立的炎症发作不会诱导 HR，但炎症诱导的 DNA 损伤和炎症诱导的细胞增殖之间的重叠显着诱导 HR。为了研究外源性诱导的 DNA 损伤，动物被暴露于甲基亚硝基脲，这是一种模型烷化剂，可产生与环境暴露和癌症化疗相关的 DNA 损伤。我们发现，烷基化损伤会诱导 HR，重要的是，炎症诱导的细胞增殖和烷基化以协同方式诱导 HR。总而言之，这些结果表明，在急性炎症发作期间，存在一个将 DNA 损伤与细胞增殖分开的动力学屏障，可防止突变，并且炎症诱导的细胞增殖极大地增强了暴露诱导的突变。这些研究证明了一种基本机制，通过这种机制，炎症可以与 DNA 损伤协同作用，从而诱导导致癌症和癌症复发的突变。患有慢性炎症的人患癌症的风险显着增加。此外，许多癌症具有促进肿瘤生长的炎症微环境。在这里，我们发现炎症浸润与组织再生协同作用，诱导体内 DNA 序列重排。因此，不断再生的慢性炎症问题发生突变和恶性转化的风险增加。此外，在炎症微环境中快速分裂的肿瘤细胞也可能获得突变，这已被证明有助于耐药性和疾病复发。最后，炎症诱导的组织再生使组织对 DNA 损伤的环境暴露和化疗变得敏感。因此，这里描述的工作增加了我们对炎症如何导致导致癌症形成和复发的基因变化的理解。
Mutations are a critical driver of cancer initiation. While extensive studies have focused on exposure-induced mutations, few studies have explored the importance of tissue physiology as a modulator of mutation susceptibility in vivo. Of particular interest is inflammation, a known cancer risk factor relevant to chronic inflammatory diseases and pathogen-induced inflammation. Here, we used the fluorescent yellow direct repeat (FYDR) mice that harbor a reporter to detect misalignments during homologous recombination (HR), an important class of mutations. FYDR mice were exposed to cerulein, a potent inducer of pancreatic inflammation. We show that inflammation induces DSBs (γH2AX foci) and that several days later there is an increase in cell proliferation. While isolated bouts of inflammation did not induce HR, overlap between inflammation-induced DNA damage and inflammation-induced cell proliferation induced HR significantly. To study exogenously-induced DNA damage, animals were exposed to methylnitrosourea, a model alkylating agent that creates DNA lesions relevant to both environmental exposures and cancer chemotherapy. We found that exposure to alkylation damage induces HR, and importantly, that inflammation-induced cell proliferation and alkylation induce HR in a synergistic fashion. Taken together, these results show that, during an acute bout of inflammation, there is a kinetic barrier separating DNA damage from cell proliferation that protects against mutations, and that inflammation-induced cell proliferation greatly potentiates exposure-induced mutations. These studies demonstrate a fundamental mechanism by which inflammation can act synergistically with DNA damage to induce mutations that drive cancer and cancer recurrence. People with chronic inflammatory conditions have a markedly increased risk for cancer. In addition, many cancers have an inflammatory microenvironment that promotes tumor growth. Here, we show that inflammatory infiltration synergizes with tissue regeneration to induce DNA sequence rearrangements in vivo. Chronically inflamed issues that are continuously regenerating are thus at an increased risk for mutagenesis and malignant transformation. Further, rapidly dividing tumor cells in an inflammatory microenvironment can also acquire mutations, which have been shown to contribute to drug resistance and disease recurrence. Finally, inflammation-induced tissue regeneration sensitizes tissues to DNA damaging environmental exposures and chemotherapeutics. The work described here thus increases our understanding of how inflammation leads to genetic changes that drive cancer formation and recurrence.
登录
查看更多内容
影响因子：
3.6
作者：
Biederbick, A;Elsässer, HP
通讯作者：
Elsässer, HP
DOI：
10.1016/j.mrfmmm.2003.07.002
发表时间：
2003-10-29
影响因子：
2.3
作者：
Bjelland, S;Seeberg, E
通讯作者：
Seeberg, E
影响因子：
16
作者：
Davies, AA;Masson, JY;West, SC
通讯作者：
West, SC
影响因子：
4.8
作者：
Dou, H;Mitra, S;Hazra, TK
通讯作者：
Hazra, TK
影响因子：
2.7
作者：
Fung, KY;Douglas, GR;Krewski, D
通讯作者：
Krewski, D