Sox8促进胰腺癌细胞干性功能与化疗耐药的机制研究

Cancer stem cells are closely associated with chemotherapy resistance in pancreatic cancer. In the previous study, we discovered that stem cell transcription factor, Sox8, is highly expressed in pancreatic cancer, and participated in the promotion of stemness maintenance and gemcitabine resistance. However, the mechanism of Sox8 expression and function still remains to be elucidated, especially under the characteristic hypoxia microenvironment of pancreatic cancer. Based on our previous results, we aim to explore the expression and function of Sox8 from clinical level, cellular level and animal model level, to analyze its correlation with relapse rate in patients of early stages and chemo-resistance rate in patients of late stages, to elucidate the mechanism of Sox8 on stemness maintenance and chemo-resistance, and also its expression under hypoxia microenvironment. We also use nude mice and patient-derived xenograft model to further discuss the function and mechanism of HIF-1α/Sox8 pathway on stemness maintenance and chemo-resistance. In conclusion, the study of the function and regulatory mechanism of Sox8 in pancreatic cancer would expect to understand more on cancer stem cell, and provide novel mechanism for chemotherapy resistance.

肿瘤干细胞与胰腺癌的化疗耐药密切相关。我们在前期研究中发现，胰腺癌细胞高表达干性转录因子Sox8。它参与了肿瘤细胞干性特征的维持，并与吉西他滨的耐药有关。然而，在以乏氧为特征的胰腺癌微环境下，Sox8的表达调控模式及其影响细胞干性与化疗耐药的分子机制仍需进一步探讨。本课题在前期工作基础上，拟从临床水平、细胞水平以及动物水平分别分析Sox8表达水平与早期患者术后复发，及晚期患者化疗耐药的相关性；揭示Sox8促进胰腺癌细胞干性及化疗耐药的分子机制，阐明胰腺癌特征性乏氧微环境影响Sox8表达与功能的分子基础和调控方式，并利用裸鼠移植瘤和PDX (Patient-derived Xenograft)模型深入讨论HIF-1α/Sox8通路对胰腺癌肿瘤干细胞及化疗耐药的影响及其作用机制。针对Sox8功能及表达机制的研究将丰富我们对胰腺癌干细胞的认知，为逆转胰腺癌耐药提供新的思路。

SOX8是SOX基因家族的一员，该基因家族编码产物为转录调节因子, 并且编码产物在决定性别决定及胚胎发育和过程中起着及其重要的作用。但有越来越多研究证明, SOX8 基因的表达异常与肿瘤的发生发展有密切的联系。因此，本课题探讨了SOX8在胰腺导管腺癌的表达变化及其变化对胰腺癌治疗的意义，发现SOX8蛋白的表达水平在胰腺导管腺癌中存在差异，其高表达提示胰腺导管腺癌患者的预后不良。SOX8表达与胰腺癌细胞中β-catenin及其下游的Cyclin D1、C-myc表达水平呈正相关，SOX8低表达的胰腺癌细胞接受白蛋白结合型紫杉醇处理后更多的集聚于G2期，而SOX8高表达的肿瘤细胞对白蛋白结合型紫杉醇反应降低。通过进一步研究我们发现，EZH2的启动子区域存在SOX8转录调控结合的靶序列，胰腺癌细胞SOX8蛋白可以直接结合到EZH2的启动子区域的特定靶序列，激活EZH2转录，进而上调EZH2及下游β-catenin的表达。在此基础上，我们构建了人胰腺癌原代细胞胰腺癌皮下成瘤的裸鼠模型，给予白蛋白结合型紫杉醇药物治疗。治疗后，我们发现SOX8高表达组对肿瘤的白蛋白结合型紫杉醇抑制作用较低表达组减弱，而给予EZH2抑制剂后对肿瘤抑制作用改善。因此，本研究发现SOX8可以预测胰腺癌患者对白蛋白结合型紫杉醇的药物治疗效果，有望成为的白蛋白结合型紫杉醇治疗效果的筛选标记。