转录因子BRF2出核介导内质网应激调控肺癌侵袭转移的机制研究

Lung cancer is the most common cancer in terms of both incidence and mortality throughout the world. Metastasis is one of the reasons of high mortality of patients suffered from lung cancer. Our former researches showed that BRF2 was high expressed in lung cancer and BRF2 was involved with invasion and migration. However, it remain unknown how BRF2 promote metastasis. We found highly expressed BRF2 was related to smoking by analysis on TCGA data base, and we thought inflammation induced by smoking played an important role in highly expressed BRF2. Besides, we found that BRF2 could be exported from nucleus and promote ER stress on our previous studies. In this study, we aim to focus on inflammation to investigate the mechanism of BRF2 high expression, and ER stress induced by BRF2 exported from nucleus to investigate the effect of BRF2 on metastasis. The current study will provide evidence for further understanding of the role of highly expressed BRF2 in metastasis, and shed new insight on the mechanism and intervention for lung cancer progression.

肺癌是最常见的恶性肿瘤之一，其发病率和死亡率均居癌症首位。侵袭转移是肺癌患者低存活率的重要原因之一。我们的前期研究证实转录因子BRF2在肺癌中高表达，且与肺癌侵袭转移相关，但具体的分子机制尚不清楚。我们通过TCGA数据库进行大样本分析，发现BRF2与吸烟相关，并进一步推断炎症参与BRF2上调。预实验结果证实BRF2可出核诱导内质网应激。本课题旨在前期研究基础上探究吸烟介导的炎症上调BRF2表达的机制。同时，进一步深入探讨BRF2在肺癌侵袭转移过程中的作用方式和调控分子机制，通过对BRF2的核外定位的相关研究明确BRF2出核诱导内质网应激参与调控EMT等相关机制。本研究有助于明确BRF2高表达的原因和调控肺癌侵袭转移的机制，为肺癌的发生发展机制的研究提供新思路。

我们的前期研究证实转录因子BRF2在肺癌中高表达，且与肺癌侵袭转移相关，但具体的分子机制尚不清楚。我们通过TCGA数据库进行大样本分析，发现BRF2表达水平与吸烟相关，并进一步推断炎症参与BRF2上调。我们研究证实炎症可介导BRF2表达上调，干扰BRF2可逆转尼古丁类似物的促侵袭转移作用，以上结果说明BRF2是吸烟诱导的炎症促进肺癌细胞侵袭转移的关键分子。进一步的实验探讨了BRF2的出核机制并明确核外定位的BRF2可通过诱导内质网应激介导EMT进而调控肺癌侵袭转移。动物实验和临床标本均佐证了上述实验结论。最后我们发现micro RNA Let-7b-3p可靶向BRF2介导的MAPK/ERK通路调控肺癌侵袭转移。本课题在前期研究基础上进一步深入探讨BRF2在肺癌侵袭转移过程中的作用方式和调控分子机制，为肺癌的发生发展机制的研究提供新思路，为肺癌的治疗提供一个新靶点。