肿瘤细胞ER stress状态下pre-miRNA加工的调控研究

Tumorigenesis and cancer development are related to dysfunction of some cell organelles such as mitochondria, Golgi apparatus, and endoplasmic reticulum. Endoplasmic reticulum participates in protein translation, folding, and modification. Certain stimuli would lead to the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum, a phenomenon called ER stress. ER stress is buffered by the activation of the unfolded protein response (UPR). In another aspect, a great amount of studies have validated that microRNA is also closely related to tumorigenesis and cancer development. In our preliminary results, the processing of some microRNA precursors (pre-miRNAs) was altered in tumor cells under ER stress. We will further identify the protein factors involved in the regulation of pre-miRNA processing, as well as their relevancy with UPR in tumor cells. We will try to elucidate how UPR and these protein factors regulate the processing of pre-miRNAs, and what is the consequence of these regulations in tumorigenesis, tumor development, tumor cell growth, proliferation, and apoptosis. The related protein factors and miRNAs found from our research could facilitate future tumor diagnosis by serving as tumor markers, which hopefully will add biomedical significance to this project.

肿瘤的发生发展与细胞中一些重要细胞器(例如线粒体，高尔基体和内质网等)的功能异常相关。内质网参与蛋白质的翻译、折叠与修饰。当细胞受到某些外界刺激后将导致内质网中未折叠或错误折叠蛋白质的积累，会使细胞处于应激状态(内质网应激，ER stress)。细胞通过未折叠蛋白质反应(UPR)来适应这种内质网应激。大量研究证明，miRNA与肿瘤的发生和发展也密切相关。我们的前期实验发现肿瘤细胞在ER stress的状态下，一些pre-miRNA的加工调控发生变化。我们将进一步鉴定调控这些pre-miRNA加工的蛋白分子，及其与UPR之间的关联，以揭示肿瘤细胞ER stress状态下UPR与蛋白分子协同调控pre-miRNA加工的分子机理，以及这种调控与肿瘤的发生发展和肿瘤细胞的生长、增殖、或凋亡的关系。本研究中发现的相关蛋白分子和miRNA有可能成为肿瘤的诊断标记，具有一定的生物医学意义。

肿瘤的发生发展与细胞中一些重要细胞器(例如线粒体，高尔基体和内质网等)的功能异常相关。内质网参与蛋白质的翻译、折叠与修饰。当细胞受到某些外界刺激后将导致内质网中未折叠或错误折叠蛋白质的积累，会使细胞处于应激状态(内质网应激，ER stress)。细胞通过未折叠蛋白质反应(UPR)来适应这种内质网应激。大量研究证明，miRNA与肿瘤的发生和发展也密切相关。我们的实验发现肿瘤细胞在ER stress的状态下，一些pre-miRNA的加工调控发生变化。我们还对其中表达变化显著的miRNA进行了功能研究，鉴定了这些miRNA的靶基因，从而探讨这些miRNA在ER stress状态下可能发挥的生物学作用；最后我们还解析了ER stress中miRNA前体和成熟miRNA表达不一致的原因，可能是由于pri-miRNA的m6A甲基化修饰在ER stress状态下发生改变这一机理导致的。本研究中发现的相关蛋白分子和miRNA有可能成为肿瘤的诊断标记，具有一定的生物医学意义。