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Cell Res:广州医科大学唐道林课题组发现新的胰腺肿瘤抑癌基因

摘要 : 2017年4月4日,国际学术权威刊物自然出版集团旗下子刊《Cell Research》杂志在线发表了广州医科大学蛋白质修饰与降解实验室唐道林博士课题组的一篇研究论文,研究报道了内源性的高迁移率族蛋白1(HMGB1)是胰腺肿瘤的新型抑癌基因。

2017年4月4日,国际学术权威刊物自然出版集团旗下子刊《Cell Research》杂志在线发表了广州医科大学蛋白质修饰与降解实验室唐道林博士课题组的一篇研究论文,研究报道了内源性的高迁移率族蛋白1(HMGB1)是胰腺肿瘤的新型抑癌基因

胰腺癌是一种恶性程度很高,诊断和治疗都很困难的消化道恶性肿瘤,其发病率和死亡率近年来明显上升,是预后最差的恶性肿瘤,被称为“癌中之王”。因此,揭示胰腺癌的发病机制,寻找新的治疗干预靶点,对于防治胰腺癌具有十分重要的意义。

HMGB1是一种非组蛋白染色体结合蛋白,它的功能涉及基因转录、DNA损伤修复、细胞死亡、代谢重组、蛋白降解等多种生物学过程;除此之外,细胞应激可以促进核HMGB1移位和释放到细胞外,从而成为一种重要的炎症免疫介质。

唐道林博士课题组利用位点特异性重组酶可诱导系统,制备了世界上第一个HMGB1胰腺条件基因敲除小鼠,并发现HMGB1基因缺失可以显著加速K-RAS癌基因介导的胰腺肿瘤的发生。分子机制上证明K-RAS可以促进HMGB1从细胞核释放到细胞外。丢失内源性HMGB1能够促进染色质不稳定性,核小体释放以及炎性微环境形成。此外,通过药物甘草酸抑制核HMGB1移位和释放能够防止小鼠胰腺肿瘤发生。上述研究揭示HMGB1在肿瘤的作用新机制,为寻找胰腺癌治疗药物和检测手段提供新的思路与实验线索,具有重要的科学意义和潜在的应用前景。

原文链接:

Intracellular HMGB1 as a novel tumor suppressor of pancreatic cancer

原文摘要:

Pancreatic ductal adenocarcinoma (PDAC) driven by oncogenic K-Ras remains among the most lethal human cancers despite recent advances in modern medicine. The pathogenesis of PDAC is partly attributable to intrinsic chromosome instability and extrinsic inflammation activation. However, the molecular link between these two events in pancreatic tumorigenesis has not yet been fully established. Here, we show that intracellular high mobility group box 1 (HMGB1) remarkably suppresses oncogenic K-Ras-driven pancreatic tumorigenesis by inhibiting chromosome instability-mediated pro-inflammatory nucleosome release. Conditional genetic ablation of either single or both alleles of HMGB1 in the pancreas renders mice extremely sensitive to oncogenic K-Ras-driven initiation of precursor lesions at birth, including pancreatic intraepithelial neoplasms, intraductal papillary mucinous neoplasms, and mucinous cystic neoplasms. Loss of HMGB1 in the pancreas is associated with oxidative DNA damage and chromosomal instability characterized by chromosome rearrangements and telomere abnormalities. These lead to inflammatory nucleosome release and propagate K-Ras-driven pancreatic tumorigenesis. Extracellular nucleosomes promote interleukin 6 (IL-6) secretion by infiltrating macrophages/neutrophils and enhance oncogenic K-Ras signaling activation in pancreatic lesions. Neutralizing antibodies to IL-6 or histone H3 or knockout of the receptor for advanced glycation end products all limit K-Ras signaling activation, prevent cancer development and metastasis/invasion, and prolong animal survival in Pdx1-Cre;K-RasG12D/+;Hmgb1−/− mice. Pharmacological inhibition of HMGB1 loss by glycyrrhizin limits oncogenic K-Ras-driven tumorigenesis in mice under inflammatory conditions. Diminished nuclear and total cellular expression of HMGB1 in PDAC patients correlates with poor overall survival, supporting intracellular HMGB1 as a novel tumor suppressor with prognostic and therapeutic relevance in PDAC.

来源: Cell Research 浏览次数:0

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