Huang Tzu-Hsuan, Wu Fangting, Loeb Gabriel B, Hsu Ruby, Heidersbach Amy, Brincat Allison, Horiuchi Dai, Lebbink Robert J, Mo Yin-Yuan, Goga Andrei, McManus Michael T
Department of Microbiology and Immunology, University of California, San Francisco, California 94143, USA.
J Biol Chem. 2009 Jul 3;284(27):18515-24. doi: 10.1074/jbc.M109.006676. Epub 2009 May 6.
The cell surface receptor tyrosine kinase HER2/neu enhances tumor metastasis. Recent studies suggest that deregulated microRNA (miRNA) expression promotes invasion and metastasis of cancer cells; we therefore explored the possibility that HER2/neu signaling induces the expression of specific miRNAs involved in this process. We identified a putative oncogenic miRNA, miR-21, whose expression is correlated with HER2/neu up-regulation and is functionally involved in HER2/neu-induced cell invasion. We show that miR-21 is up-regulated via the MAPK (ERK1/2) pathway upon stimulation of HER2/neu signaling in breast cancer cells, and overexpression of other ERK1/2 activators such as RASV12 or ID-1 is sufficient to induce miR-21 up-regulation in HER2/neu-negative breast cancer cells. Furthermore, the metastasis suppressor protein PDCD4 (programmed cell death 4) is down-regulated by miR-21 in breast cancer cells expressing HER2/neu. Our data reveal a mechanism for HER2/neu-induced cancer cell invasion via miRNA deregulation. In addition, our results identify miR-21 as a potential therapeutic target for the prevention of breast cancer invasion and metastasis.
细胞表面受体酪氨酸激酶HER2/neu可促进肿瘤转移。最近的研究表明，失调的微小RNA（miRNA）表达会促进癌细胞的侵袭和转移；因此，我们探讨了HER2/neu信号传导诱导参与这一过程的特定miRNA表达的可能性。我们鉴定出一种假定的致癌miRNA，即miR-21，其表达与HER2/neu上调相关，并且在功能上参与HER2/neu诱导的细胞侵袭。我们发现，在乳腺癌细胞中刺激HER2/neu信号后，miR-21通过丝裂原活化蛋白激酶（MAPK，细胞外信号调节激酶1/2即ERK1/2）途径上调，并且其他ERK1/2激活剂（如RASV12或ID-1）的过表达足以在HER2/neu阴性乳腺癌细胞中诱导miR-21上调。此外，在表达HER2/neu的乳腺癌细胞中，转移抑制蛋白程序性细胞死亡4（PDCD4）被miR-21下调。我们的数据揭示了一种通过miRNA失调导致HER2/neu诱导癌细胞侵袭的机制。此外，我们的结果确定miR-21是预防乳腺癌侵袭和转移的潜在治疗靶点。
