MYC-Dependent Regulation and Prognostic Role of CIP2A in Gastric Cancer
MYC-Dependent Regulation and Prognostic Role of CIP2A in Gastric Cancer
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DOI：
10.1093/jnci/djp103
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发表时间：
2009-06-02
影响因子：
10.3
通讯作者：
Ristimaki, Ari
中科院分区：
文献类型：
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作者：
Khanna, Anchit;Bockelman, Camilla;Ristimaki, Ari
蛋白磷酸酶2A （CIP2A）的癌性抑制剂是最近发现的一种稳定c-Myc （MYC）蛋白的人类癌蛋白。然而，CIP2A与人类癌症的临床相关性尚未得到证实，其调控机制及其在癌症中的临床作用也完全未知。采用免疫组化技术对223个胃腺癌标本组成的组织微阵列进行CIP2A的检测，并采用Kaplan-Meier分析评估CIP2A表达与生存的关系。利用对CIP2A和MYC的小干扰rna和免疫印迹技术，在几种胃癌细胞系中研究了MYC和CIP2A相互表达和对细胞增殖的影响。为了进一步评估MYC在CIP2A调控中的作用，我们使用了MYC二聚化抑制剂10058-F4和诱导型MycER模型。在肿瘤小于等于5厘米的胃癌患者中，CIP2A蛋白的表达与总生存率降低相关，CIP2A免疫阳性组的10年总生存率为8.1%，而CIP2A免疫阴性组的10年总生存率为37.6%（差异= 29.5%，95%可信区间= 12.5% ~ 46.5%,P = 0.001）。在胃癌细胞系中，CIP2A缺失导致细胞增殖和非锚定生长下降，MYC蛋白的稳定性和表达降低。有趣的是，MYC缺失导致CIP2A mRNA和蛋白的表达降低。此外，MYC抑制剂和激活剂的实验表明，MYC直接促进CIP2A基因的表达。最后，胃癌标本中CIP2A和MYC免疫阳性相关（P = 0.021）。CIP2A免疫阳性是某些亚组胃癌患者生存的预测因子。CIP2A和MYC似乎在一个正反馈回路中受到调节，其中它们促进彼此的表达和胃癌细胞的增殖。
Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently identified human oncoprotein that stabilizes the c-Myc (MYC) protein. However, the clinical relevance of CIP2A to human cancers had not been demonstrated, but the mechanism of its regulation and its clinical role in cancer were completely unknown.Tissue microarrays consisting of 223 gastric adenocarcinoma specimens were evaluated for the presence of CIP2A using immunohistochemistry, and the association of CIP2A expression with survival was assessed using Kaplan-Meier analysis. The effects of MYC and CIP2A on each other's expression and on cell proliferation were investigated in several gastric cancer cell lines using small interfering RNAs to CIP2A and MYC and immunoblotting. To further evaluate the role of MYC in CIP2A regulation, an inhibitor of MYC dimerization, 10058-F4, and an inducible MycER model were used.Expression of CIP2A protein was associated with reduced overall survival for gastric cancer patients with tumors 5 cm or smaller, with a 10-year overall survival in the CIP2A-immunopositive group of 8.1% as compared with 37.6% in the CIP2A-negative group (difference = 29.5%, 95% confidence interval = 12.5% to 46.5%, P = .001). In gastric cancer cell lines, CIP2A depletion led to decreased proliferation and anchorage-independent growth of the cells, as well as to reduced stability and expression of MYC protein. Interestingly, MYC depletion led to reduced expression of CIP2A mRNA and protein. Moreover, experiments with an MYC inhibitor and activator suggested that MYC directly promotes CIP2A gene expression. Finally, CIP2A and MYC immunopositivities were associated in gastric cancer specimens (P = .021).CIP2A immunopositivity is a predictor of survival for some subgroups of gastric cancer patients. CIP2A and MYC appear to be regulated in a positive feedback loop, wherein they promote each other's expression and gastric cancer cell proliferation.