癌基因AGK诱导乳腺癌淋巴结转移的分子机制

Lymphatic metastasis is critical for early cancer metastasis. Thus idenifying key molecular factor in lymphatic metastasis process would be of great value for early diagnosis and therapy. We previously reported that Acylglycerol kinase (AGK) was upregulated in breast cancer, and significantly correlated with N and M classification (Molecular Cancer). However, the biological role and mechanism of AGK in breast cancer lymphatic metastasis remain unclear. And recently, we found that upregulation of AGK induced lymphangiogenesis, enhanced breast cancer invasive and migratory abilities, leading to lymphatic metastasis in vivo. Thus, our results suggest that AGK plays an important role in breast cancer lyphmtic metastasis both in vitro and in vivo. Combining different molecular biology methods, we identified that AGK significantly activated the NF-κB and Wnt/β-catenin signaling, and upregulated VEGF-C, Snail and MMP7 expression. In the current project, we will combine in vivo and in vitro experimental systems with data from clinical samples, in order to investigate the multi-dimensional mechanisms of AGK-induced breast cancer lymphatic metastasis. Our work may help identify novel diagnostic markers and therapeutic targets for breast metastasis.

淋巴结转移是肿瘤转移的早期关键事件。寻找促肿瘤淋巴结转移的关键分子对肿瘤的早期诊断和治疗具有重要的意义。前期我们发表文章证明酰基甘油激酶（Acylglycerol kinase，AGK）在乳腺癌中高表达，并且与乳腺癌 N、M 分期显著相关（Molecular Cancer）。然而AGK在乳腺癌淋巴结转移中的功能及分子机制仍不清楚。进一步体内体外预实验结果显示：上调 AGK表达可①诱导淋巴管新生，②增强乳腺癌细胞侵袭能力，③诱导乳腺癌细胞发生淋巴结转移。这些结果表明AGK在乳腺癌淋巴结转移过程中具有重要的生物学功能。结合免疫共沉淀等多种方法，我们发现：AGK明显激活NF-κB和Wnt/β-catenin信号通路，上调VEGF-C，Snail和MMP7等的表达水平。本研究将承前启后，深层次解析癌基因AGK诱导乳腺癌转移的分子机制，并与临床相结合，为乳腺癌转移提供新的诊断标记物及治疗靶位点。

我们前期研究发现AGK可促进乳腺癌远处转移和肿瘤生长。本项目根据既往关于AGK促进乳腺癌转移的研究基础上，进一步深入探究AGK促进乳腺癌远处转移和肿瘤生长的相关分子机制。我们获得以下研究成果：AGK可转录调控CGI-99和E2F8进而促进乳腺癌远处转移和肿瘤生长。（1）. CGI-99在发生转移的患者组织中显著高表达，并且CGI-99的表达水平与患者发生远处转移的风险呈显著正相关。CGI-99可增强乳腺癌细胞的肿瘤干细胞特性，从而促使肿瘤细胞在远处脏器定植成瘤。CGI-99高表达与STAT3信号通路的激活相关，它可通过募集RNA聚合酶II和p300辅助因子而上调IL-6表达，并促进其在肿瘤细胞中的自分泌进而激活IL-6/STAT3信号通路。本研究为乳腺癌转移提供了新的分子机制（Oncogene；通讯作者）。（2）. E2F8高表达与肿瘤复发和远处转移显著相关。E2F8可通过促进细胞周期G1/S过渡从而诱导乳腺癌细胞增殖和肿瘤形成，而干扰EF28的表达可使抑制肿瘤细胞的增殖和体内成瘤。E2F8的表达上调可转录上调细胞周期素E1/E2进而促进细胞周期的过渡，E2F8是通过结合细胞周期素E1/E2编码基因上的转录启动子而发挥转录上调的作用。本研究发现了促进乳腺癌肿瘤进展的关键分子，为肿瘤治疗提供了新的预后指标和治疗靶点。项目研究期间共发表SCI论文2篇，其中通讯作者论文发表在Oncogene杂志上。项目资助培养博士后1名，博士毕业生1名。