Hepatoblastoma modeling in mice places Nrf2 within a cancer field established by mutant β-catenin
Hepatoblastoma modeling in mice places Nrf2 within a cancer field established by mutant β-catenin
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DOI：
10.1172/jci.insight.88549
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发表时间：
2016-10-06
期刊：
影响因子：
8
通讯作者：
Hammer, Robert E.
中科院分区：
文献类型：
--
作者：
Comerford, Sarah A.;Hinnant, Elizabeth A.;Hammer, Robert E.
异常的 wnt/β-连环蛋白信号传导和 Myc 的扩增/过度表达与肝母细胞瘤 (HB) 相关，肝母细胞瘤是最常见的儿童肝癌类型。为了阐明它们在 HB 发病机制中的作用，我们培育了小鼠，其中 Myc 和突变型 β-catenin 靶向发育中小鼠肝脏的未成熟细胞。这两个基因在围产期的共表达促进了新生小鼠中 HBs 比其他肿瘤类型优先发展，所有这些肿瘤都与人类对应的肿瘤类型惊人相似。综合分析表明，肿瘤的出现是在全肝损伤、炎症和核因子（红细胞衍生2）样2/Nrf2依赖性抗氧化信号传导背景下Myc驱动的肝母细胞命运改变的结果，该信号与突变β-连环蛋白的表达特别相关，但与Myc无关。人类 HB 的免疫分析证实，大约 50% 的肿瘤表现出 Myc 或 Nfe2l2/Nrf2 的异常激活，而在具有 NFE2L2 基因扩增的人类 HB 衍生的细胞系中敲低 Nrf2 会降低肿瘤细胞的生长和活力。总而言之，这些数据表明，β-连环蛋白部分通过间接激活 Nrf2 创造了促肿瘤肝环境，并暗示氧化应激可能是儿童中一部分由 β-连环蛋白驱动的肝肿瘤的驱动力。
Aberrant wnt/beta-catenin signaling and amplification/overexpression of Myc are associated with hepatoblastoma (HB), the most prevalent type of childhood liver cancer. To address their roles in the pathogenesis of HB, we generated mice in which Myc and mutant beta-catenin were targeted to immature cells of the developing mouse liver. Perinatal coexpression of both genes promoted the preferential development of HBs over other tumor types in neonatal mice, all of which bore striking resemblance to their human counterparts. Integrated analysis indicated that tumors emerged as a consequence of Myc-driven alterations in hepatoblast fate in a background of pan-hepatic injury, inflammation, and nuclear factor (erythroid-derived 2)-like 2/Nrf2-dependent antioxidant signaling, which was specifically associated with expression of mutant beta-catenin but not Myc. Immunoprofiling of human HBs confirmed that approximately 50% of tumors demonstrated aberrant activation of either Myc or Nfe2l2/Nrf2, while knockdown of Nrf2 in a cell line-derived from a human HB with NFE2L2 gene amplification reduced tumor cell growth and viability. Taken together, these data indicate that beta-catenin creates a protumorigenic hepatic environment in part by indirectly activating Nrf2 and implicate oxidative stress as a possible driving force for a subset of beta-catenin-driven liver tumors in children.