去泛素化酶USP37调控GRP78介导的内质网应激性自噬在肝癌索拉非尼耐药中的作用和机制研究

索拉非尼耐药是导致肝癌预后差的主要原因，但机制尚不清楚。预实验发现：索拉非尼可诱导肝癌细胞发生具有细胞保护效应的内质网应激性自噬，并伴有去泛素化酶USP37和内质网应激分子GRP78表达上调；降低USP37可抑制GRP78介导的内质网应激性自噬，并增加耐药细胞对索拉非尼的敏感性；进一步探索发现USP37和GRP78相互结合，降低USP37可促进GRP78泛素化水平。结合既往我们研究证实GRP78在肝癌进展中扮演重要作用，我们推测去泛素化酶USP37通过抑制GRP78泛素化降解稳定其表达，从而促进肝癌细胞发生内质网应激性自噬，最终导致肝癌细胞对索拉非尼耐药。本研究拟利用体内外实验研究USP37在肝癌索拉非尼耐药中的作用，阐明USP37调控GRP78介导内质网应激性自噬导致索拉非尼耐药的机制，并明确USP37、GRP78可作为评估肝癌患者索拉非尼疗效的标记物，为逆转肝癌索拉非尼耐药提供新线索。

Sorafenib resistance is the main cause of poor prognosis of liver cancer, but the mechanism is still unclear. Pre-experiment found that sorafenib can induce endoplasmic reticulum stress autophagy with cytoprotective effect in liver cancer cells, accompanied by up-regulation of expression of deubiquitinase USP37 and endoplasmic reticulum stress molecule GRP78. Reducing USP37 can inhibit GRP78-mediated endoplasmic reticulum stress autophagy and increase the sensitivity of drug-resistant cells to sorafenib. Further exploration found that USP37 and GRP78 combine with each other, and reducing USP37 can promote the ubiquitination level of GRP78. In combination with previous studies, we have confirmed that GRP78 plays an important role in the progression of liver cancer. We speculate that USP37 can stabilize its expression by inhibiting the ubiquitination degradation of GRP78, thus promoting endoplasmic reticulum stress autophagy of liver cancer cells and eventually leading to sorafenib resistance of liver cancer cells. This research is intended to study the role of USP37 in sorafenib resistance of liver cancer in vitro and in vivo, to clarify the mechanism of USP37 regulating GRP78-mediated endoplasmic reticulum stress autophagy leading to sorafenib resistance, and to clarify that USP37 and GRP78 can be used as markers to evaluate the efficacy of sorafenib in liver cancer patients. It is hoped to provide new clues for reversing the sorafenib resistance of liver cancer.