PDF(Pubmed)
Abstract：
Patients with pancreatic neuroendocrine tumors (pNETs) have limited access to effective targeted agents and invariably succumb to progressive disease. MUC1-C is a druggable oncogenic protein linked to driving pan-cancers. There is no known involvement of MUC1-C in pNET progression. The present work was performed to determine if MUC1-C represents a potential target for advancing pNET treatment. We demonstrate that the MUC1 gene is upregulated in primary pNETs that progress with metastatic disease. In pNET cells, MUC1-C drives E2F- and MYC-signaling pathways necessary for survival. Targeting MUC1-C genetically and pharmacologically also inhibits self-renewal capacity and tumorigenicity. Studies of primary pNET tissues further demonstrate that MUC1-C expression is associated with (i) an advanced NET grade and pathological stage, (ii) metastatic disease, and (iii) decreased disease-free survival. These findings demonstrate that MUC1-C is necessary for pNET progression and is a novel target for treating these rare cancers with anti-MUC1-C agents under clinical development.
摘要：
胰腺神经内分泌肿瘤（pNETs）患者获得有效靶向药物的途径有限，并且总是屈服于进行性疾病。MUC1-C是一种与驱动泛癌症相关的药物致癌蛋白。已知MUC1-C不参与pNET进展。进行本工作以确定MUC1-C是否代表推进pNET治疗的潜在靶标。我们证明MUC1基因在转移性疾病进展的原发性pNETs中上调。在pNET单元格中，MUC1-C驱动生存所必需的E2F-和MYC-信号通路。在遗传和药理学上靶向MUC1-C还抑制自我更新能力和致瘤性。原发性pNET组织的研究进一步证明MUC1-C的表达与（i）高级NET等级和病理阶段有关，(ii)转移性疾病，和（iii）减少无病生存率。这些发现表明MUC1-C是pNET进展所必需的，并且是临床开发中使用抗MUC1-C药物治疗这些罕见癌症的新靶标。
