ERK8表观遗传调控EP3促进肺癌细胞迁移的作用及分子机制研究

ERK8 is the latest discovered member of the MAPK family and has limited knowledge of its biological functions and downstream signaling cascades. Our previous study found that ERK8 is associated with lymph node metastasis in human lung cancer tissues, and EP3 promotes lung cancer cell migration. In addition, EP3 mRNA level was decreased after the knockdown of ERK8 in lung cancer cells, and further investigation revealed that ERK8 regulates the transcription of EP3 involving histone modifications. We hypothesize that ERK8 promotes the migration of lung cancer cells by participating in the epigenetic regulation of EP3 transcription. In order to verify the hypothesis, the role of epigenetic regulation of EP3 by ERK8 and the underlying molecular mechanism will be examined at cellular, animal and human lung cancer tissue levels. The findings will certainly help to understand the biological function of ERK8 more comprehensively and further clarify the signal transduction network mediated by ERK8.

ERK8是最晚发现的MAPK家族成员，对其生物学功能以及下游信号分子认识有限。我们的前期研究发现，ERK8在人肺癌组织中与淋巴结转移相关，且EP3能促进肺癌细胞迁移。此外，在肺癌细胞中敲降ERK8后EP3的转录水平下降，进一步研究发现ERK8通过参与组蛋白修饰而调控EP3的转录。因此，我们推测ERK8通过参与表观遗传调控EP3的转录而促进肺癌的迁移。为了验证假设，本课题拟从肺癌细胞、动物模型、肺癌组织等多层次多角度研究ERK8表观遗传调控EP3的作用以及分子机制。本课题的研究有助于更全面的认识ERK8的生物学功能，进一步明确ERK8介导的信号转导网络。

肺癌是死亡率最高的恶性肿瘤，由于缺乏有效的早期诊断标志物，肺癌被确诊时往往处于中晚期。ERK8作为最新发现的非典型丝裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK），与其相关的研究相对较少，探索其对肿瘤进展/患者预后的影响，及其对下游基因的潜在转录调控等，对恶性肿瘤的诊断、预后和潜在的肿瘤治疗具有很高的价值。在本项目中，我们发现ERK8与肺腺癌患者的淋巴结转移呈正相关。通过细胞水平和动物水平研究发现，敲降ERK8后，EP3表达下调，细胞迁移/转移能力下降。在分子机制方面，我们首次证实ERK8与p50相互作用并促使其进入细胞核，p50与EP3启动子结合并转录调节EP3。我们上述研究表明，ERK8和p50的相互作用调控EP3的转录，促进肺腺癌细胞迁移，此外我们还发现ERK8通过p300/CBP表观遗传调控EP3的表达。

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