细胞自噬在CRM197逆转卵巢癌紫杉醇耐药机制中的作用研究

紫杉醇耐药是目前卵巢癌治疗的关键难题。我们的研究初步表明，交叉反应物质197（CRM197）可有效逆转卵巢癌紫杉醇耐药，该作用可能与NAC-1调控的自噬相关，并推测CRM197可能以NAC-1为靶点通过其下游HMGB1/MEK/ERK通路调控自噬，从而逆转卵巢癌紫杉醇耐药。为验证此推测，我们拟通过人卵巢癌耐药细胞、卵巢癌耐药细胞裸鼠移植瘤模型，采用real-time PCR、蛋白印迹、RNA干扰、活体荧光成像系统等方法，从分子、细胞、动物水平明确自噬在CRM197逆转耐药中的作用，揭示NAC-1在CRM197调控自噬逆转耐药的作用，探讨CRM197通过NAC-1下游HMGB1/MEK/ERK通路调控自噬的机制，从而进一步研究自噬在CRM197逆转卵巢癌紫杉醇耐药作用中的机制。本研究将从自噬这个新视点为解决CRM1197作用机制的核心问题奠定基础，并为卵巢癌紫杉醇耐药患者的治疗提供新的思路。

The resistance to paclitaxel has become a formidable problem in ovarian cancer. Our study showed that cross-reacting material 197 (CRM197) significantly reverses the resistance to paclitaxel in human paclitaxel-resistant ovarian carcinoma cells through autophagy, which is speculated to be regulated by nucleus accumbens-1(NAC-1) and its downstream HMGB1/MEK/ERK pathway.To prove the speculation that CRM197 contributes to paclitaxel resistance in ovarian cancer through the autophagy regulated by NAC-1 and HMGB1/MEK/ERK pathway，we establish the paclitaxel-resistant ovarian cancer cells and paclitaxel-resistant ovarian tumor xenograft in nude mice, and investigate the mechanism of the reversion of paclitaxel resistance in ovarian cancer by CRM197 via autophagy by ectopic expression and gene knockdown, using transfection、real-time PCR、western blot、in vivo bioluminescence imaging and so on. Thus, this study will provide evidence for solving the key problems on the mechanism of the effect of CRM197 and shed light on the chemotherapy options for paclitaxel-resistant ovarian cancer patients.