JNCI:Ran表达或影响乳腺癌和肺癌患者的生存期

2013-04-01 echo1166 丁香园

体外试验证实,肿瘤细胞的生存需要Ras相关的核蛋白(Ran)的参与,同样在人体内的肿瘤出现进展时,也需要Ran的作用,但是Ran在其中所扮演的角色的分子学机制却还没有被揭示。为了找到上述问题的答案,来自英国Belfast Queen大学的Hiu-Fung Yuen等进行了相关研究,他们的研究结果发表在JNCI 3月的在线期刊上。 研究者采用蛋白质印迹法、染色质免疫沉淀法和荧光素酶序列评估V-my

体外试验证实,肿瘤细胞的生存需要Ras相关的核蛋白(Ran)的参与,同样在人体内的肿瘤出现进展时,也需要Ran的作用,但是Ran在其中所扮演的角色的分子学机制却还没有被揭示。为了找到上述问题的答案,来自英国Belfast Queen大学的Hiu-Fung Yuen等进行了相关研究,他们的研究结果发表在JNCI 3月的在线期刊上。

研究者采用蛋白质印迹法、染色质免疫沉淀法和荧光素酶序列评估V-myc骨髓细胞瘤病毒癌基因同源基因(Myc)对Ran表达的作用,采用软琼脂、细胞黏着和浸润序列评估Myc和Ran表达对肿瘤细胞的作用。研究者在包含了2430名患者的14个独立的患者队列中,分别应用Spearman等级相关、Kaplan-Meier曲线和Wilcoxon-Gehan测试评估了Myc和Ran之间存在的联系,以及其对患者生存期的影响。所有的统计检验都在双侧进行。

Myc与Ran上游序列结合,激活Ran启动子的活性。Myc过度表达会上调Ran的表达,而敲除Myc可下调Ran表达。在乳腺癌细胞中,Myc或Ran的过度表达与肿瘤的进展和转移相关。在乳腺癌细胞中,敲除Ran可逆转由Myc过度表达所造成的不良影响。对临床资料的分析发现,在288名乳腺癌患者和102名肺癌患者中,Myc和Ran表达呈正相关。此外,在Myc过度表达的乳腺癌和肺癌患者中,Ran表达水平影响到患者的生存期。

本研究的结果提示,在乳腺癌和肺癌患者中,若存在Myc所导致的肿瘤进展,那么Ran是潜在的治疗靶点。

doi: 10.1093/jnci/djt028
PMC:
PMID:

RanGTPase: A Candidate for Myc-Mediated Cancer Progression

Yuen HF Gunasekharan VK Chan KK Zhang SD Platt-Higgins A Gately K O'Byrne K Fennell DA Johnston PG Rudland

Ras-related nuclear protein (Ran) is required for cancer cell survival in vitro and human cancer progression, but the molecular mechanisms are largely unknown.MethodsWe investigated the effect of the v-myc myelocytomatosis viral oncogene homolog (Myc) on Ran expression by Western blot, chromatin immunoprecipitation, and luciferase reporter assays and the effects of Myc and Ran expression in cancer cells by soft-agar, cell adhesion, and invasion assays. The correlation between Myc and Ran and the association with patient survival were investigated in 14 independent patient cohorts (n = 2430) and analyzed with Spearman's rank correlation and Kaplan-Meier plots coupled with Wilcoxon-Gehan tests, respectively. All statistical tests were two-sided.ResultsMyc binds to the upstream sequence of Ran and transactivates Ran promoter activity. Overexpression of Myc upregulates Ran expression, whereas knockdown of Myc downregulates Ran expression. Myc or Ran overexpression in breast cancer cells is associated with cancer progression and metastasis. Knockdown of Ran reverses the effect induced by Myc overexpression in breast cancer cells. In clinical data, a positive association between Myc and Ran expression was revealed in 288 breast cancer and 102 lung cancer specimens. Moreover, Ran expression levels differentiate better or poorer survival in Myc overexpressing breast (χ(2) = 24.1; relative risk [RR] = 9.1, 95% confidence interval [CI] = 3.3 to 24.7, P < .001) and lung (χ(2) = 6.04; RR = 2.8, 95% CI = 1.2 to 6.3; P = .01) cancer cohorts.ConclusionsOur results suggest that Ran is required for and is a potential therapeutic target of Myc-driven cancer progression in both breast and lung cancers.

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