MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer. Mus musculus

Hepatocellular carcinoma is generally refractory to clinical treatment. Here, we report that inactivation of the MYC oncogene is sufficient to induce sustained regression of invasive liver cancers. MYC inactivation resulted en masse in tumour cells differentiating into hepatocytes and biliary cells forming bile duct structures, and this was associated with rapid loss of expression of the tumour marker alpha-fetoprotein, the increase in expression of liver cell markers cytokeratin 8 and carcinoembryonic antigen, and in some cells the liver stem cell marker cytokeratin 19. Using in vivo bioluminescence imaging we found that many of these tumour cells remained dormant as long as MYC remain inactivated; however, MYC reactivation immediately restored their neoplastic features. Using array comparative genomic hybridization we confirmed that these dormant liver cells and the restored tumour retained the identical molecular signature and hence were clonally derived from the tumour cells. Our results show how oncogene inactivation may reverse tumorigenesis in the most clinically difficult cancers. Oncogene inactivation uncovers the pluripotent capacity of tumours to differentiate into normal cellular lineages and tissue structures, while retaining their latent potential to become cancerous, and hence existing in a state of tumour dormancy. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Keywords: Logical Set Overall design: Using regression correlation

肝细胞癌（Hepatocellular carcinoma）通常对临床治疗具有难治性。本研究证实，失活MYC癌基因（MYC oncogene）即可诱导侵袭性肝癌发生持续消退。MYC失活可促使大量肿瘤细胞分化为肝细胞与胆管细胞并形成胆管结构；这一过程伴随肿瘤标志物甲胎蛋白（alpha-fetoprotein）表达快速下调，肝细胞标志物细胞角蛋白8（cytokeratin 8）与癌胚抗原（carcinoembryonic antigen）表达上调，且部分细胞表达肝干细胞标志物细胞角蛋白19（cytokeratin 19）。通过活体生物发光成像（in vivo bioluminescence imaging）我们发现，在MYC持续失活的情况下，多数此类肿瘤细胞会保持休眠状态；而当MYC重新激活时，这些细胞的肿瘤表型会立即恢复。借助阵列比较基因组杂交（array comparative genomic hybridization）技术，我们证实这些休眠肝细胞与恢复生长的肿瘤细胞具有完全一致的分子特征，因此二者均克隆源自原始肿瘤细胞。本研究结果揭示了癌基因失活如何逆转临床最难治癌症中的肿瘤发生过程。癌基因失活可揭示肿瘤向正常细胞谱系与组织结构分化的多能性潜能，同时保留其恶变为肿瘤的潜伏能力，从而使肿瘤处于休眠状态。按共享生物学背景（如生物物种、肿瘤类型、生物学过程等）组织的阵列数据集。关键词：逻辑集合（Logical Set） 整体设计：采用回归相关分析