Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan.
Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan; Cancer Progression Research Center, National Yang-Ming University, Taipei, Taiwan.
Am J Pathol. 2018 Nov;188(11):2688-2702. doi: 10.1016/j.ajpath.2018.07.019. Epub 2018 Aug 27.
This study aimed to shed light on the molecular and cellular mechanisms responsible for initiation and progression of liver malignancies by examining the role of phosphatase and tensin homolog on chromosome 10 (Pten) in liver tumor progression in miR-122a (Mir122a)-null mice. We generated and monitored liver tumor initiation in Mir122a-null Pten heterozygous (Mir122a;Pten and Mir122a;Alb-Cre;Pten) mice and compared the results with those in Mir122a mice. Both Mir122a;Pten and Mir122a;Alb-Cre;Pten mice developed visible liver tumor nodules at 6 months of age. In premalignant livers of Mir122a;Pten mice, decreased PTEN and increased phosphorylated AKT were specifically observed in periportal cells, associated with inflammatory and fibrotic microenvironments. Furthermore, IL-1β and tumor necrosis factor-α levels significantly increased in Mir122a;Pten premalignant livers at 6 months of age. Oval cells expressing A6, epithelial cell adhesion molecule, keratin (K) 8, K19, and SRY (sex determining region Y)-box 9 (SOX9) were present in both Mir122a and Mir122a;Pten livers. Interestingly, a hybrid hepatocyte-like population with intermediate levels of K8, HNF4α, and SOX9 was located proximally to the oval cells in Mir122a;Pten livers. Lineage-tracing experiments revealed that these intermediate levels of K8 hepatocyte-like cells may be the cells of origin for Mir122a;Pten liver tumors. These findings suggest that inflammatory microenvironments in the periportal area of Mir122a-null mice may locally cause Pten down-regulation and expand tumor-initiating cells, causing hepatocellular carcinoma.
本研究旨在通过研究磷酸酶和张力蛋白同源物 10 号染色体（PTEN）在 miR-122a（Mir122a）缺失小鼠肝脏肿瘤进展中的作用，阐明肝脏恶性肿瘤发生和进展的分子和细胞机制。我们生成并监测了 Mir122a 缺失的 Pten 杂合（Mir122a；Pten 和 Mir122a；Alb-Cre；Pten）小鼠肝脏肿瘤的起始，并将结果与 Mir122a 小鼠进行了比较。Mir122a；Pten 和 Mir122a；Alb-Cre；Pten 小鼠在 6 月龄时均可见明显的肝脏肿瘤结节。在 Mir122a；Pten 小鼠的癌前肝脏中，门脉周围细胞中特异性观察到 PTEN 减少和磷酸化 AKT 增加，与炎症和纤维化微环境相关。此外，Mir122a；Pten 癌前肝脏中 IL-1β 和肿瘤坏死因子-α水平在 6 月龄时显著升高。在 Mir122a 和 Mir122a；Pten 肝脏中均存在表达 A6、上皮细胞黏附分子、角蛋白（K）8、K19 和性别决定区 Y 框 9（SOX9）的卵圆细胞。有趣的是，在 Mir122a；Pten 肝脏中，与卵圆细胞相邻的位置存在具有中等水平 K8、HNF4α 和 SOX9 的混合肝细胞样群体。谱系追踪实验表明，这些中等水平 K8 肝细胞样细胞可能是 Mir122a；Pten 肝脏肿瘤的细胞起源。这些发现表明，Mir122a 缺失小鼠门脉周围区的炎症微环境可能局部导致 Pten 下调并扩大肿瘤起始细胞，导致肝细胞癌。
