The Insulin-Like Growth Factor 2 mRNA Binding Protein IMP2/IGF2BP2 is Overexpressed and Correlates with Poor Survival in Pancreatic Cancer
The Insulin-Like Growth Factor 2 mRNA Binding Protein IMP2/IGF2BP2 is Overexpressed and Correlates with Poor Survival in Pancreatic Cancer
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DOI：
10.3390/ijms20133204
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发表时间：
2019-07-01
影响因子：
5.6
通讯作者：
Kessler, Sonja M.
中科院分区：
文献类型：
--
作者：
Dahlem, Charlotte;Barghash, Ahmad;Kessler, Sonja M.
胰岛素样生长因子2（IGF 2）mRNA结合蛋白IMP 2（IGF 2BP 2）是一种致癌蛋白，已知在不同肿瘤类型中过表达。胰腺癌是一种非常致命的癌症，需要早期诊断和新的治疗方案。本研究的目的是探讨IMP 2在胰腺导管腺癌（PDAC）发生和发展中的作用。IMP 2在人类前体（PanIN）病变中显著过表达，表明IMP 2是PDAC早期阶段的标志物。在匹配的正常和肿瘤样品的PDAC队列中，与正常胰腺组织相比，IMP 2在肿瘤组织中显示过表达。严格相关分析（阈值R-2 > 0.75）显示22个基因与IMP 2高度正相关，9个基因与IMP 2高度负相关。除了参与细胞凋亡抑制的基因（Bcl-XL）外，尤其是参与泛素化的因子与IMP 2表达密切相关：SMURF 1和FBXO 45。此外，蛋白激酶C（PKC）信号通路明显受到影响：编码PKC iota的DXS 1179 E、PKC底物PLEK 2和三磷酸肌醇受体IP 3R 3与IMP 2表达呈正相关。除了肿瘤起始，IMP 2似乎也对肿瘤进展有影响。TGF-β处理Panc-1胰腺癌细胞以诱导上皮-间充质转化（EMT）伴随着增加的IMP 2表达。EMT对于癌细胞获得迁移和侵袭潜力是重要的，这对于转移是必不可少的。一致地，与来自肿瘤来源的正常组织和正常血液细胞相比，循环肿瘤细胞显示出更高的IMP 2水平。因此，IMP 2蛋白水平与较差的存活率相关。总之，由于IMP 2似乎促进了PDAC的肿瘤进展，因此它可能是一个有趣的诊断和预后标志物以及治疗PDAC的新靶点。
The insulin-like growth factor 2 (IGF2) mRNA binding protein IMP2 (IGF2BP2) is an oncogenic protein known to be overexpressed in different tumor types. Pancreatic cancer is a very lethal cancer that requires early diagnosis and new treatment options. The aim of our study was to investigate the role of IMP2 in the initiation and progression of pancreatic ductal adenocarcinoma (PDAC). IMP2 was significantly overexpressed in a human precursor (PanIN) lesions suggesting IMP2 as a marker for early stages of PDAC. In a PDAC cohort of matched normal and tumor samples IMP2 showed overexpression in tumor tissues compared with normal pancreatic tissue. Strict correlation analysis (threshold R-2 > 0.75) revealed 22 genes highly positively and 9 genes highly negatively correlating with IMP2. Besides genes involved in the inhibition of apoptosis (Bcl-XL), especially factors involved in ubiquitination were strongly correlated with IMP2 expression: SMURF1 and FBXO45. Moreover, protein kinase C (PKC) signaling pathway was distinctly affected: DXS1179E encoding PKC iota, PKC substrate PLEK2, and inositol triphosphate receptor IP3R3 were positively correlated with IMP2 expression. Besides tumor initiation, IMP2 also seemed to have an impact on tumor progression. TGF-beta treatment of Panc-1 pancreatic cancer cells to induce epithelial-mesenchymal transition (EMT) was accompanied by increased IMP2 expression. EMT is important for cancer cells to gain migratory and invasive potential, which is essential for metastasis. Concordantly, circulating tumor cells showed higher IMP2 levels as compared with normal tissue from tumor origin and with normal hematological cells. Accordingly, IMP2 protein levels correlated with poor survival. In conclusion, as IMP2 seems to promote tumor progression of PDAC, it might be an interesting diagnostic and prognostic marker as well as a novel target for the treatment of PDAC.