Upregulation of MEK5 by Stat3 promotes breast cancer cell invasion and metastasis
Upregulation of MEK5 by Stat3 promotes breast cancer cell invasion and metastasis
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Stat3上调MEK5促进乳腺癌细胞侵袭和转移
DOI：
10.3892/or.2016.5256
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发表时间：
2017-01-01
期刊：
影响因子：
4.2
通讯作者：
Song, Hui
中科院分区：
文献类型：
--
作者：
Liu, Fang;Zhang, Hao;Song, Hui
丝裂原细胞外信号调节激酶激酶5（Mitogen extracellular-signal-regulated kinase kinase 5，MEK 5）在促进细胞增殖和肿瘤发生中起重要作用。已经报道了MEK 5在各种恶性疾病中的异常表达，包括乳腺癌、前列腺癌、肺癌、结肠直肠癌和脑癌。然而，MEK 5信号通路的功能和调节是不明确的，并且就其在各种癌症中的致癌作用而言仍然是难以捉摸的，特别是在调节癌症侵袭和转移的起始和进展方面。MEK 5的异位表达或通过基于细胞的体外模型的shRNA敲低MEK 5证实了MEK 5在调节上皮间质转化（EMT）和乳腺癌侵袭和转移中的作用。在这里，我们表明，MEK 5上调Stat 3促进乳腺癌细胞的侵袭通过EMT。进一步的研究表明Stat 3可以与MEK 5的启动子区结合，促进MEK 5的转录和表达。此外，MEK 5的磷酸化在乳腺癌细胞中显著增加，对应于乳腺癌细胞的转移能力。通过shRNA消耗MEK 5显著降低了乳腺癌的侵袭。MEK 5的异位表达可使非侵袭性乳腺癌细胞成为具有侵袭能力的细胞。此外，ERK 5的磷酸化，MEK 5调节的下游激酶，也上调与活性MEK 5的水平增加一致。我们的研究提供了一种分子机制的见解，通过这种机制，MEK 5转录上调Stat 3增强乳腺癌细胞EMT，从而增强癌细胞的侵袭和转移。这一发现可能表明Stat 3和MEK 5/Erk 5通路可能是抑制乳腺癌侵袭和转移的有效治疗靶点。
Mitogen extracellular-signal-regulated kinase kinase 5 (MEK5) plays an important role in promoting cell proliferation and tumorigenesis. The aberrant expression of MEK5 has been reported in various malignant diseases including cancers of breast, prostate, lung, colorectal and brain. However, the function and regulation of MEK5 signaling pathway are ambiguous and remain elusive with respect to its oncogenic roles in various cancers, especially in the regulation of the initiation and progression of cancer invasion and metastasis. Ectopic expression of MEK5 or knockdown of MEK5 by shRNA with in vitro cell based models demonstrated the role of MEK5 in regulation of epithelial mesenchymal transition (EMT) and breast cancer invasion and metastasis. Here, we show that MEK5 upregulated by Stat3 promotes breast cancer cell invasion through EMT. Further study demonstrated that Stat3 could bind to promoter region of MEK5 and enhanced MEK5 transcription and expression. In addition, the phosphorylation of MEK5 significantly increased in breast cancer cells corresponding to metastatic capability of breast cancer cells. The depletion of MEK5 by shRNA significantly decreased breast cancer invasion. Ectopic expression of MEK5 could confer non-invasive breast cancer cells to become invasion capable cells. Moreover, the phosphorylation of Erk5, a MEK5-regulated downstream kinase, was also upregulated consistent with the increased level of active MEK5. Our studies provide insights into a molecular mechanism by which MEK5 transcriptionally upregulated by Stat3 augments breast cancer cell EMT, which subsequently enhances cancer cell invasion and metastasis. This finding may suggest that Stat3 and MEK5/Erk5 pathways could be an effective therapeutic target for inhibition of breast cancer invasion and metastasis.