1] Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng-Kung University, Tainan, Taiwan [2] Center for Infection Disease and Signal Transduction, National Cheng-Kung University, Tainan, Taiwan.
Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng-Kung University, Tainan, Taiwan.
Oncogene. 2015 Feb 12;34(7):826-37. doi: 10.1038/onc.2014.22. Epub 2014 Mar 17.
Nucleolin (NCL) participates in DNA transcription, ribosomal biogenesis and the regulation of RNA stability. However, the contribution of NCL to tumor development is still not clear. Herein, we found that NCL expression correlated with poor prognosis in lung cancer patients. Overexpressed NCL was predominantly cleaved to C-terminal truncated NCL (TNCL). In lung cancer formation, activation of the epidermal growth factor receptor pathway induced NCL expression, and also the expression of matrix metalloproteinase (MMP) 7, which then cleaved NCL at Asp255 to generate TNCL of 55 kDa. TNCL increased the expression of several oncogenes, including MMP9, anaplastic lymphoma kinase (ALK), HIF1a and CBLB, and decreased the expression of tumor suppressors including BRD4, PCM1, TFG and KLF6 by modulating mRNA stability through binding to the 3'-untranslated regions of their transcripts, thus ultimately enhancing metastasis activity. In conclusion, this study identified a novel role of the cleavage form of NCL generated by MMP7 in stabilizing MMP9 mRNA. We also provide a new insight that MMP7 not only cleaves the extracellular matrix to promote tumor invasion but also cleaves NCL, which augment oncogenesis. Blocking NCL cleavage may provide a useful new strategy for lung cancer therapy.
核仁素（NCL）参与 DNA 转录、核糖体生物发生和 RNA 稳定性的调节。然而，NCL 对肿瘤发展的贡献尚不清楚。在此，我们发现 NCL 的表达与肺癌患者的预后不良相关。过表达的 NCL 主要被切割为 C 端截断的 NCL（TNCL）。在肺癌形成过程中，表皮生长因子受体途径的激活诱导 NCL 的表达，以及基质金属蛋白酶（MMP）7 的表达，随后 MMP7 在 Asp255 处切割 NCL 产生 55kDa 的 TNCL。TNCL 通过与它们的转录物的 3'非翻译区结合来调节 mRNA 稳定性，从而增加几种癌基因的表达，包括 MMP9、间变性淋巴瘤激酶（ALK）、HIF1a 和 CBLB，以及降低肿瘤抑制因子的表达，包括 BRD4、PCM1、TFG 和 KLF6，从而最终增强转移活性。总之，本研究鉴定了 MMP7 生成的 NCL 切割形式在稳定 MMP9 mRNA 方面的新作用。我们还提供了一个新的见解，即 MMP7 不仅通过切割细胞外基质来促进肿瘤侵袭，而且还切割 NCL，从而增强致癌作用。阻断 NCL 切割可能为肺癌治疗提供一种有用的新策略。
