HDAC7/HSF1通路调控内质网应激驱动肺腺癌恶性进展的研究

组蛋白去乙酰化酶7（HDAC7）是重要的促增殖因子，在肿瘤恶性进展中起重要作用。最新文献和我们研究表明HDAC7在肺腺癌组织中高表达，但其作用及机制尚未阐明。前期结果显示HDAC7过表达可显著促进肺腺癌细胞增殖和移植瘤生长，并发现内质网应激（ERS）信号通路相关分子表达下调和热休克蛋白（HSPs）表达上调。鉴于热休克因子1（HSF1）去乙酰化后上调HSPs在维持内质网稳态中发挥重要作用，我们推测HDAC7在肺腺癌中可能通过去乙酰化HSF1调控ERS发挥促肿瘤进展作用。为此，本项目拟从临床标本、裸鼠荷瘤模型、细胞与分子水平，进一步明确HDAC7高表达促进肺腺癌进展的作用；阐明HSF1/HSPs通路在介导HDAC7调控ERS促肺腺癌进展的具体机制；结合临床资料和标本综合分析这些因子表达水平与临床预后的相关性。本研究的完成将为开发靶向HDAC7-HSF1信号通路抗肺腺癌的方法或药物奠定理论基础。

Histone deacetylase 7 (HDAC7), a proliferation-related endogenous factor, involves in the progression of various tumors. The recent study and our research results documented HDAC7 is overexpressed in the lung adenocarcinoma tissues, but the mechanisms remain unclear. Recently, our preliminary experiments documented HDAC7 overexpression promoted the proliferation in lung adenocarcinoma cells and nude mice-bearing tumors, and significantly inhibited the expression of ERS-related signaling pathways and partially upregulated the expression of heat shock proteins (HSPs). Considering deacylated heat shock factor 1 (HSF1) promotes the HSPs expression, which contributes to the regulation of ERS signaling and maintenance of endoplasmic reticulum homeostasis, we put forward the scientific hypothesis that ERS is regulated by the HDAC7-induced HSF1 deacylation then promoting the lung adenocarcinoma progression. On the above bases, lung adenocarcinoma cell lines and nude bearding mice models will be used to investigate the underlining mechanisms of HDAC7-HSF1/HSPs signaling in regulating ERS pathways thus promoting lung adenocarcinoma progression both in vivo and in vitro. In the meantime, we will comprehensively analyze the correlation between these signaling and clinical prognosis using lung adenocarcinoma patient’s tissues. Above all, this study will provide new anti-cancer method and theoretical basis for targeting HDAC7-HSF1 signaling pathway during lung adenocarcinoma treatment.