MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis
MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis
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DOI：
10.1172/jci63455
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发表时间：
2012-08-01
影响因子：
15.9
通讯作者：
Tsou, Ann-Ping
中科院分区：
文献类型：
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作者：
Tsai, Wei-Chih;Hsu, Sheng-Da;Tsou, Ann-Ping
MicroRNA-122(miR-122)在肝脏中起着举足轻重的作用，占肝脏总miRNAs的70%。然而，其内在的生理作用在很大程度上仍未确定。我们证明，缺乏miR-122a(Mir122a)编码基因的小鼠是存活的，但会发展成时间可控的脂肪性肝炎、纤维化和肝细胞癌(HCC)。这些小鼠在基于性别的肝癌发病率上表现出显著的差异，男女比例为3.9：1，这概括了人类的发病率。微粒体甘油三酯转移蛋白(MTTP)的表达受损导致脂肪变性，这种脂肪变性可通过体内MTTP表达的恢复而逆转。我们发现肝纤维化的发生可以部分归因于miR-122a靶标KLF6转录本的作用。此外，Mir122a(-/-)肝脏在一系列途径上表现出破坏，其中许多与人类肝细胞癌中发现的破坏非常相似。重要的是，miR-122a的重新表达减少了Mir122a(-/-)小鼠的疾病表现和肿瘤发生率。这项研究表明，Mir122a基因定向缺失的小鼠具有几种关键的人类肝病表型，这为开发治疗慢性肝病和肝细胞癌的独特疗法提供了理论基础。
MicroRNA-122 (miR-122), which accounts for 70% of the liver's total miRNAs, plays a pivotal role in the liver. However, its intrinsic physiological roles remain largely undetermined. We demonstrated that mice lacking the gene encoding miR-122a (Mir122a) are viable but develop temporally controlled steatohepatitis, fibrosis, and hepatocellular carcinoma (HCC). These mice exhibited a striking disparity in HCC incidence based on sex, with a male-to-female ratio of 3.9:1, which recapitulates the disease incidence in humans. Impaired expression of microsomal triglyceride transfer protein (MTTP) contributed to steatosis, which was reversed by in vivo restoration of Mttp expression. We found that hepatic fibrosis onset can be partially attributed to the action of a miR-122a target, the Klf6 transcript. In addition, Mir122a(-/-) livers exhibited disruptions in a range of pathways, many of which closely resemble the disruptions found in human HCC. Importantly, the reexpression of miR-122a reduced disease manifestation and tumor incidence in Mir122a(-/-) mice. This study demonstrates that mice with a targeted deletion of the Mir122a gene possess several key phenotypes of human liver diseases, which provides a rationale for the development of a unique therapy for the treatment of chronic liver disease and HCC.