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首页> 外文期刊>BMC Cancer >The peroxidase PRDX1 inhibits the activated phenotype in mammary fibroblasts through regulating c-Jun N-terminal kinases
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The peroxidase PRDX1 inhibits the activated phenotype in mammary fibroblasts through regulating c-Jun N-terminal kinases

机译:过氧化物酶PRDX1通过调节c-Jun N端激酶抑制乳腺成纤维细胞的活化表型

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摘要

Reactive oxygen species (ROS), including hydrogen peroxide, drive differentiation of normal fibroblasts into activated fibroblasts, which can generate high amounts of hydrogen peroxide themselves, thereby increasing oxidative stress in the microenvironment. This way, activated fibroblasts can transition into cancer-associated fibroblasts (CAFs). Mammary fibroblasts from either female 8?weeks old PRDX1 knockout and wildtype mice or Balb/c mice were studied for characteristic protein expression using immunofluorescence and immunoblotting. Cancer-associated fibroblasts was examined by transwell migration and invasion assays. The binding of PRDX1 to JNK1 was assessed by co-immuneprecipitation and JNK regulation of CAF phenotypes was examined using the JNK inhibitor SP600125. Extracellular hydrogen peroxide levels were measured by chemiluminescence via the reaction between hypochlorite and luminol. Statistical analyses were done using Students t-test. We show here PRDX1 activity as an essential switch in regulating the activated phenotype as loss of PRDX1 results in the development of a CAF-like phenotype in mammary fibroblasts. We also show that PRDX1 regulates JNK kinase signaling thereby inhibiting CAF-like markers and CAF invasion. Inhibition of JNK activity reduced these behaviors. These data suggest that PRDX1 repressed the activated phenotype of fibroblasts in part through JNK inhibition which may present a novel therapeutic option for CAF-enriched cancers such as breast cancer.
机译:包括过氧化氢在内的活性氧(ROS)驱使正常的成纤维细胞分化为活化的成纤维细胞,活化的成纤维细胞自身会产生大量的过氧化氢,从而增加了微环境中的氧化应激。这样,活化的成纤维细胞可以转变为癌症相关的成纤维细胞(CAF)。使用免疫荧光和免疫印迹研究了8周龄PRDX1雌性基因敲除的野生型小鼠或Balb / c小鼠的乳腺成纤维细胞的特征性蛋白表达。通过transwell迁移和侵袭测定法检查了与癌症相关的成纤维细胞。通过共免疫沉淀评估PRDX1与JNK1的结合,并使用JNK抑制剂SP600125检查CAF表型的JNK调节。通过次氯酸盐与鲁米诺之间的化学发光测定细胞外过氧化氢水平。使用学生t检验进行统计分析。我们在这里显示PRDX1活性作为调节激活表型的必要开关,因为PRDX1的丢失导致乳腺成纤维细胞中CAF样表型的发展。我们还显示PRDX1调节JNK激酶信号传导,从而抑制CAF样标记和CAF入侵。 JNK活性的抑制减少了这些行为。这些数据表明PRDX1部分通过JNK抑制抑制了成纤维细胞的活化表型,这可能为富含CAF的癌症(如乳腺癌)提供了一种新的治疗选择。

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