内质网应激关键蛋白GRP78调控内质网自噬介导肝细胞癌凋亡抵抗的机制研究

肿瘤细胞在各种应激条件下产生的保护性自噬是导致肿瘤治疗效果不佳的重要因素之一。目前，关于非选择性自噬的研究取得了较大的进展，而有关选择性之内质网自噬的研究进展有限。我们前期研究中发现：GRP78在内质网应激条件下不但能够激活肝细胞癌的非选择性自噬，同时还能够激活内质网自噬。Nature最新研究显示内质网自噬特异性受体蛋白FAM134B是调控内质网自噬的潜在靶点，与我们前期研究中发现的GRP78可以通过FAM134B调控内质网自噬的现象相似，同时我们发现mTOR参与了此调控过程。本研究将通过体内体外实验深入研究GRP78-FAM134B轴的精确调控机制，探讨mTOR及我们通过蛋白互作网络预测的UBC蛋白与该调控轴的作用关系及机制，同时探索其他潜在的靶蛋白。为揭示GRP78-FAM134B轴在肝细胞癌中介导的内质网自噬对抗凋亡的机制，并为肝细胞癌潜在的调控靶点及精准治疗提供理论依据。

Cancer cells will survive under various stress status through initiating protective autophagy, which is one of the common factors impairing the anti-cancer therapy. Currently, great progress had been made in the non-selective autophagy, but less in the selective autophagy of the endoplasmic reticulum (ER-phagy). Our previous research revealed that GRP78, under the status of endoplasmic reticulum stress (ER-stress), not only activated non-selective autophagy in HCC cells, but also ER-phagy. Latest researches in Nature reported that: FAM134B, a specific ER-phagy receptor, had been proved to be a potential target for ER-phagy regulation. These findings were similar to our results: GRP78 was able to regulate ER-phagy through influencing FAM134B expression levels. Simultaneously, we also found that mTOR may be a key part in such regulation axis. Further, our study tends to figure out the explicit mechanisms of GRP78-FAM134B axis both in vitro and in vivo. We will focus on the exact role of mTOR and explore other candidate targets, such as UBC (derived from protein-protein interaction analysis). Altogether, our work may be conducive to the clarification of GRP78-FAM134B-mediated anti-apoptotic effect, providing promising targets in HCC and empirical evidences for precision medicine.