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EGFR 过表达肿瘤中 Aurora-A 的翻译上调。

Translational up-regulation of Aurora-A in EGFR-overexpressed cancer.

机构信息

Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

出版信息

J Cell Mol Med. 2010 Jun;14(6B):1520-31. doi: 10.1111/j.1582-4934.2009.00919.x. Epub 2009 Oct 3.

DOI:10.1111/j.1582-4934.2009.00919.x
PMID:19799648
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3829018/
Abstract

Abnormal expression of Aurora-A and epidermal growth factor receptor (EGFR) is observed in different kinds of cancer and associated with poor prognosis in cancer patients. However, the relationship between Aurora-A and EGFR in tumour development was not clear. In previous reports, we found that EGFR translocates to nucleus to activate Aurora-A expression after EGF treatment in EGFR-overexpressed cells. However, we also observed that not all the EGFR-overexpressed cells have the nuclear EGFR pathway to mediate the Aurora-A expression. In this study, we demonstrated that EGF signalling increased the Aurora-A protein expression in EGFR-overexpressed colorectal cancer cell lines via increasing the translational efficiency. In addition, the overexpression of EGFR was also associated with higher expression of Aurora-A in clinical colorectal samples. Activation of the PI3K/Akt/mTOR and MEK/ERK pathways mediated the effect of EGF-induced translational up-regulation. Besides, only the splicing variants containing exon 2 of Aurora-A mRNA showed increased interaction with the translational complex to synthesize Aurora-A protein under EGF stimulus. Besides, the exon 2 containing splicing variants were the major Aurora-A splicing forms expressed in human colorectal cancers. Taken together, our results propose a novel regulatory mechanism for the abnormal expression of Aurora-A in EGFR-overexpressed cancers, and highlight the importance of alternative 5'-UTR splicing variants in regulating Aurora-A expression. Furthermore, the specific expression of exon 2 containing splicing variants in cancer tissues may serve as a potential target for cancer therapy in the future.

摘要

Aurora-A 和表皮生长因子受体 (EGFR) 的异常表达在不同类型的癌症中观察到，并与癌症患者的预后不良相关。然而，Aurora-A 和 EGFR 在肿瘤发展中的关系尚不清楚。在之前的报告中，我们发现 EGFR 在 EGFR 过表达细胞中经 EGF 处理后转移到细胞核中激活 Aurora-A 的表达。然而，我们还观察到并非所有 EGFR 过表达的细胞都具有核 EGFR 途径来介导 Aurora-A 的表达。在这项研究中，我们证明 EGF 信号通过增加翻译效率增加 EGFR 过表达结直肠癌细胞系中的 Aurora-A 蛋白表达。此外，EGFR 的过表达也与临床结直肠样本中 Aurora-A 的高表达相关。PI3K/Akt/mTOR 和 MEK/ERK 通路的激活介导了 EGF 诱导的翻译上调的作用。此外，只有包含 Aurora-A mRNA 外显子 2 的剪接变体在 EGF 刺激下与翻译复合物相互作用增加，以合成 Aurora-A 蛋白。此外，在人类结直肠癌中，包含外显子 2 的剪接变体是表达的主要 Aurora-A 剪接形式。总之，我们的研究结果提出了一种新的调节机制，解释了 EGFR 过表达癌症中 Aurora-A 的异常表达，并强调了选择性 5'-UTR 剪接变体在调节 Aurora-A 表达中的重要性。此外，癌组织中包含外显子 2 的剪接变体的特异性表达可能成为未来癌症治疗的潜在靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2a32/3829018/89150443cd52/jcmm0014-1520-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2a32/3829018/3cf6c54a1854/jcmm0014-1520-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2a32/3829018/007d58748e92/jcmm0014-1520-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2a32/3829018/9f8b22b64be2/jcmm0014-1520-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2a32/3829018/f5cf7eae3d26/jcmm0014-1520-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2a32/3829018/524e696967bf/jcmm0014-1520-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2a32/3829018/89150443cd52/jcmm0014-1520-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2a32/3829018/3cf6c54a1854/jcmm0014-1520-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2a32/3829018/007d58748e92/jcmm0014-1520-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2a32/3829018/9f8b22b64be2/jcmm0014-1520-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2a32/3829018/f5cf7eae3d26/jcmm0014-1520-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2a32/3829018/524e696967bf/jcmm0014-1520-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2a32/3829018/89150443cd52/jcmm0014-1520-f6.jpg

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