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Cell Rep & EMBO Rep:有益分子NF-κB是癌细胞保镖?

来源:生物谷 2014-10-14 10:27

2014年10月14日 讯 /生物谷BIOON/ --近日,来自俄亥俄州立大学癌症研究中心的研究人员通过研究发现,一种特殊的分子可以帮助癌细胞躲避细胞的程序化自我摧毁过程,其或许也可以帮助恶性细胞来躲避机体免疫系统的攻击,相关研究发表在国际杂志Cell ReportsEMBO Reports上。

研究者Richard J. Solove教授说道,这种名为核因子κB(NF-κB)的分子可以通过抑制免疫系统检测杀灭癌细胞的能力来帮助癌细胞躲避免疫系统的杀伤作用;NF-κB分子可以调节那些抑制免疫系统监督机制的基因,包括产生抑制免疫反应的细胞等。如果同抑制NF-κB的药物相结合,那么一般的免疫疗法在治疗癌症上将更加有效,与此同时研究人员还揭示了癌细胞和非癌性细胞在帮助肿瘤细胞生长上的相互作用。

“我们一直都知道NF-κB可以通过推翻细胞凋亡来促进肿瘤发育,而我们的研究则发现,NF-κB分子可以协调免疫抑制基因的网络,而该基因网络的产物记忆促进肿瘤细胞躲避机体的获得性免疫力”,Denis Guttridge博士说,因此抑制NF-κB就会使得肿瘤细胞对免疫系统更加敏感。

早在2009年本文的研究者就发现,NF-κB可以帮助正常细胞进行DNA修复,这可以抑制机体的细胞损伤;然而为何NF-κB分子在癌细胞中可以扮演不同的角色,至今研究者并不清楚。本文中研究者指出,在NF-κB激活的癌细胞中,关闭TGF-β的表达会移除其对癌细胞的免疫抑制效应,进而延缓肿瘤生长,因此TGF-β是受NF-κB调节的促进肿瘤发育的关键基因。

最后研究者表示,总的来讲本文研究阐明了NF-κB在促进癌细胞躲避机体先天及后天免疫系统监控上所扮演的重要角色。(生物谷Bioon.com)

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NF-κB Functions in Tumor Initiation by Suppressing the Surveillance of Both Innate and Adaptive Immune Cells

David J. Wang, Nivedita M. Ratnam, John C. Byrd, Denis C. Guttridge

NF-κB is considered a major contributor to tumor development, but how this factor functions in the initial stages of oncogenesis is not clear. In a model of Ras-induced transformation, we probed NF-κB function as preneoplastic cells formed tumors in mice. As previously shown, the p65 subunit of NF-κB acts as a tumor suppressor in normal cells by sustaining senescence following DNA damage. Our current data reveal that, following immortalization, p65 switches to an oncogene by counteracting the surveillance properties of immune cells. NF-κB exerts this effect by protecting transformed cells against macrophage-derived proapoptotic factors, tumor necrosis factor, and nitric oxide. Additionally, NF-κB acts through transforming growth factor beta (TGF-β) to mitigate T cell cytotoxicity and other factors to expand myeloid-derived suppressor cells. Together, these data suggest that NF-κB functions in the early stages of transformation by suppressing immune surveillance of both innate and adaptive immune cells, information that may be useful for targeted immunotherapies.

RelA/p65 functions to maintain cellular senescence by regulating genomic stability and DNA repair

Jingxin Wang, Naduparambil K Jacob, Katherine J Ladner, Amer Beg, James D Perko, Stephan M Tanner, Sandya Liyanarachchi, Richard Fishel, Denis C Guttridge

Nuclear factor (NF)‐κB is a positive regulator of tumour development and progression, but how it functions in normal cells leading to oncogenesis is not clear. As cellular senescence has proven to be an intrinsic tumour suppressor mechanism that cells must overcome to establish deregulated growth, we used primary fibroblasts to follow NF‐κB function in cells transitioning from senescence to subsequent immortalization. Our findings show that RelA/p65−/− murine fibroblasts immortalize at considerably faster rates than RelA/p65+/+ cells. The ability of RelA/p65−/− fibroblasts to escape senescence earlier is due to their genomic instability, characterized by high frequencies of DNA mutations, gene deletions and gross chromosomal translocations. This increase in genomic instability is closely related to a compromised DNA repair that occurs in both murine RelA/p65−/− fibroblasts and tissues. Significantly, these results can also be duplicated in human fibroblasts lacking NF‐κB. Altogether, our findings present a fresh perspective on the role of NF‐κB as a tumour suppressor, which acts in pre‐neoplastic cells to maintain cellular senescence by promoting DNA repair and genomic stability.

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