MicroRNA-203 impacts on the growth, aggressiveness and prognosis of hepatocellular carcinoma by targeting MAT2A and MAT2B genes.
MicroRNA-203 impacts on the growth, aggressiveness and prognosis of hepatocellular carcinoma by targeting MAT2A and MAT2B genes.
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DOI：
10.18632/oncotarget.26838
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发表时间：
2019-04-19
期刊：
影响因子：
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通讯作者：
Pascale, Rosa M
中科院分区：
文献类型：
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作者：
Simile, Maria M;Peitta, Graziella;Pascale, Rosa M
肝细胞癌（HCC）的特征是肝脏特异性甲基腺苷转移酶1A（MAT1A）基因下调，该基因编码S - 腺苷甲硫氨酸合成同工酶MATI/III，以及广泛表达的甲基腺苷转移酶2A（MAT2A）上调，其编码MATII同工酶，还有甲基腺苷转移酶2B（MAT2B）上调，MAT2B编码一个无催化作用但可调节MATII酶活性的β亚基。不同的观察结果表明miR - 203对肝癌发生有抑制作用。我们发现肝细胞癌中miR - 203的表达与肝细胞癌增殖和侵袭性标志物以及MAT2A和MAT2B水平呈负相关。在HepG2和Huh7肝癌细胞中转染miR - 203可靶向MAT2A和MAT2B的3' - 非翻译区，抑制MAT2A和MAT2B的mRNA水平以及MATα2和MATβ2蛋白表达。这些分子事件伴随着S - 腺苷甲硫氨酸（SAM）含量的增加，并与生长抑制和细胞凋亡、细胞迁移和侵袭性抑制以及CD133和LIN28B干性标志物表达的抑制相关。相反，在相同细胞系中转染MAT2B导致MATβ2和MATα2表达均升高，与细胞生长、迁移、侵袭以及干性标志物和磷酸化蛋白激酶B（p - AKT）的过表达相关。总之，我们的结果表明miR - 203的抑癌活性可能至少部分取决于其对MAT2A和MAT2B的抑制作用，并首次表明MAT2B的致癌活性与AKT激活有关。
Hepatocellular carcinoma (HCC) is characterized by the down-regulation of the liver-specific methyladenosyltransferase 1A (MAT1A) gene, encoding the S-adenosylmethionine synthesizing isozymes MATI/III, and the up-regulation of the widely expressed methyladenosyltransferase 2A (MAT2A), encoding MATII isozyme, and methyladenosyltransferase 2B (MAT2B), encoding a beta-subunit without catalytic action that regulates MATII enzymatic activity. Different observations showed hepatocarcinogenesis inhibition by miR-203. We found that miR-203 expression in HCCs is inversely correlated with HCC proliferation and aggressiveness markers, and with MAT2A and MAT2B levels. MiR-203 transfection in HepG2 and Huh7 liver cancer cells targeted the 3'-UTR of MAT2A and MAT2B, inhibiting MAT2A and MAT2B mRNA levels and MATalpha2 and MATbeta2 protein expression. These molecular events were paralleled by an increase in SAM content and were associated with growth restraint and apoptosis, inhibition of cell migration and invasiveness, and suppression of the expression of CD133 and LIN28B stemness markers. In contrast, MAT2B transfection in the same cell lines led to a rise of both MATbeta2 and MATalpha2 expression, associated with increases in cell growth, migration, invasion and overexpression of stemness markers and p-AKT. Altogether, our results indicate that the miR-203 oncosuppressor activity may at least partially depend on its inhibition of MAT2A and MAT2B and show, for the first time, an oncogenic activity of MAT2B linked to AKT activation.