GSK-3β调控NF-κB的分子机制及其在胰腺炎和胰腺癌变进程中的作用

Pancreatic ductal adenocarcinoma (PDAC) carries one of the most dismal prognoses among human malignancies and is a challenging world issue. Recent research in genetically engineered mouse (GEM) models has provided compelling evidence that oncogenic K-Ras (G12D) alone can initiate pancreatic intraepithelial neoplasia (PanIN) lesions, but not PDAC. Therefore, the identification of additional factors capable of cooperating with oncogenic KRAS to drive PDAC development is a critical area of research. One of the main risk factors for developing human PDAC is chronic pancreatitis, which can dramatically accelerate KRas(G12D)-induced PanIN and progression to PDAC. Significantly, NF-κB is a key inflammatory factor contributing to the pathogenic process of pancreatitis. Inflammation and NF-κB signaling can further enhance oncogenic KRas activity via a positive feedback loop highlighting the importance of this cross-regulation in connecting pancreatitis to pancreatic tumorigenesis. GSK-3β is a pleotropic kinase involved in numerous cellular pathways and is best known for its regulation of β-catenin. We have previously shown that GSK-3β is aberrantly overexpressed in human PDAC and contributes to cell proliferation and survival, at least in part, via regulation of NF-κB. More recent work indicates that GSK-3 isoforms differentially affect p65 and p50 chromatin binding, cofactor recruitment and selectively affect a subset of NF-κB anti-apoptotic genes. Our proposed research will be the first to directly address the role and molecular mechanism(s) underlying GSK-3β regulation of the NF-κB target network in the setting of pancreatitis and its impact on PanIN and PDAC development. Given the highly druggable nature of GSK-3, elucidating the mechanism of GSK-3β ?signaling axis in conjunction with NF-κB and oncogenic KRas will provide not only novel mechanistic insight, but also therapeutic and/or prophylactic strategies for pancreatitis/PDAC.

胰腺癌死亡率极高，其诊治为世界公认难题。迄今导致胰腺癌的早期事件，如KRAS突变后，与其它易感因素相互作用引发癌变的信号转导及表观遗传学调控机制仍不清楚。而慢性胰腺炎作为胰腺癌的主要易感因素, 能极大促进Kras（G12D）诱导的癌变进程。NF-κB是已知胰腺炎发生及发展进程中激活的主要转录因子，可以通过正反馈弧提高KRAS致瘤活性。我们的前期工作显示，GSK-3β在胰腺癌中高表达并参与调节癌细胞的增殖，存活，其中涉及对NF-κB的激活作用。GSK-3能差异影响 p65和p50与染色体DNA及辅助转录因子的结合，并藉此选择性影响NF-κB某些抗凋亡基因的表达。本课题利用独特的遗传工程小鼠模型探讨GSK-3β在胰腺炎，及胰腺炎促进Kras（G12D）诱导的癌前和癌症过程中的作用, 并采用RNA及ChIP-DNA测序结合先进的分子生物学手段研究GSK-3β对NF-κB靶基因网络调控及分子机制。

胰腺癌死亡率极高，其诊治为世界公认难题。迄今导致胰腺癌的早期事件，如KRAS 突变后，与其它易感因素相互作用引发癌变的信号转导及表观遗传学调控机制仍不清楚。而慢性胰腺炎作为胰腺癌的主要易感因素, 能极大促进 Kras（ G12D）诱导的癌变进程。我们的前期工作显示， GSK-3β在胰腺癌中高表达并参与调节癌细胞的增殖。本课题利用独特的遗传工程小鼠模型探讨 GSK-3β在胰腺炎，及胰腺炎促进 Kras（ G12D）诱导的癌前和癌症过程中的作用。结果显示，GSK-3β在维持炎症诱导的ADM表型及KRas驱动的ADM向PanIN（及PDAC的发展过程中起重要作用。在胰腺癌进程中，GSK-3β主要通过影响mTOR下游的S6K激酶活性而影响KRas 促进的导管化细胞增殖。我们还证明GSK3的小分子抑制剂可在一定程度上抑制KrasG12D突变和胰腺炎症诱导的胰腺癌变进程和胰腺ADM细胞的增殖，为临床治疗胰腺癌提供了新方向，新靶点。