Association of AMP-activated protein kinase with risk and progression of non-Hodgkin lymphoma.
Association of AMP-activated protein kinase with risk and progression of non-Hodgkin lymphoma.
复制标题
DOI：
10.1158/1055-9965.epi-12-1014
复制
发表时间：
2013-04
期刊：
影响因子：
--
通讯作者：
Zhu Y
中科院分区：
文献类型：
--
作者：
Hoffman AE;Demanelis K;Fu A;Zheng T;Zhu Y
新陈代谢失调已被确认为癌症的一个“新兴标志”。异三聚体AMP激活的蛋白激酶(AMPK)复合体是代谢系统的中枢调节因子，也是mTOR途径和P53轴的重要组成部分，使其具有独特的地位，通过其在代谢领域的规范功能，以及通过更传统的机制，如调节细胞凋亡和血管生成，影响肿瘤的发生。我们进行了一项基于人群的遗传关联研究，以检查AMPK亚单位基因突变对非霍奇金淋巴瘤(NHL)风险的影响。我们还分析了公共微阵列数据，以确定AMPK在NHL细胞中的表达，并评估AMPK表达对NHL患者总体生存的影响。在没有癌症家族史的女性中，我们发现AMPK亚基单倍型与非霍奇金淋巴瘤显著相关(OR=5.44，95%CI：2.15-13.75)。PRKAA2和PRKAG3这两个亚基的单倍型在名义上分别与滤泡性和弥漫性大B细胞淋巴瘤的组织学亚型相关，尽管经过多次比较校正后，这些相关性不再具有统计学意义。此外，这两个亚基在一种或多种淋巴瘤细胞类型中都有不同的表达(p<0.05)，并且两个版本的ampk-β亚基的高表达与非霍奇金淋巴瘤患者的5年生存率的增加显著相关(p=0.001和p=0.021)。这些结果为AMPK参与NHL的发生发展提供了证据。这些发现可能导致对NHL治疗和化学预防的新的研究领域。
Metabolic dysregulation has been identified as an “emerging hallmark” of cancer. The heterotrimeric AMP-activated protein kinase (AMPK) complex is a central regulator of the metabolic system and an important component of the mTOR pathway and the p53 axis, making it uniquely positioned to influence carcinogenesis through its canonical functions in the metabolic arena, as well as through more traditional mechanisms such as regulation of apoptosis and angiogenesis. We conducted a population-based genetic association study to examine the impact of mutations in AMPK subunit genes on risk of non-Hodgkin’s lymphoma (NHL). We also analyzed public microarray data to determine the expression of AMPK in NHL cells and to assess the influence of AMPK expression on overall survival in NHL patients. We identified an AMPK subunit haplotype which was significantly associated with NHL (OR=5.44, 95%CI: 2.15–13.75) in women with no family history of cancer. Haplotypes in two subunits, PRKAA2 and PRKAG3, were nominally associated with the follicular and diffuse large B cell lymphoma histologic subtypes, respectively, although these associations did not retain statistical significance after correction for multiple comparisons. Further, both of these subunits were differentially expressed (p<0.05) in one or more lymphoma cell type, and higher expression of two versions of the AMPK-β subunit were significantly associated with increased five-year survival among NHL patients (p=0.001 and p=0.021). These results provide evidence for AMPK involvement in the pathogenesis and progression of NHL. These findings may lead to a novel area of research into NHL treatment and chemoprevention.