Serra Marina, Pal Rajesh, Puliga Elisabetta, Sulas Pia, Cabras Lavinia, Cusano Roberto, Giordano Silvia, Perra Andrea, Columbano Amedeo, Kowalik Marta Anna
Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy.
Department of Oncology, University of Turin, Turin, Italy.
Front Oncol. 2022 Sep 20;12:941552. doi: 10.3389/fonc.2022.941552. eCollection 2022.
Thyroid hormones (THs) inhibit hepatocellular carcinoma (HCC) through different mechanisms. However, whether microRNAs play a role in the antitumorigenic effect of THs remains unknown.
By next generation sequencing (NGS) we performed a comprehensive comparative miRNomic and transcriptomic analysis of rat hepatic preneoplastic lesions exposed or not to a short-term treatment with triiodothyronine (T3). The expression of the most deregulated miRs was also investigated in rat HCCs, and in human hepatoma cell lines, treated or not with T3.
Among miRs down-regulated in preneoplastic nodules following T3, co-expression networks revealed those targeting thyroid hormone receptor-β (Thrβ) and deiodinase1, and Oxidative Phosphorylation. On the other hand, miRs targeting members of the Nrf2 Oxidative Pathway, Glycolysis, Pentose Phosphate Pathway and Proline biosynthesis - all involved in the metabolic reprogramming displayed by preneoplastic lesions- were up-regulated. Notably, while the expression of most miRs deregulated in preneoplastic lesions was not altered in HCC or in hepatoma cells, miR-182, a miR known to target and mitochondrial complexes, was down-deregulated by T3 treatment at all stages of hepatocarcinogenesis and in hepatocarcinoma cell lines. In support to the possible critical role of miR-182 in hepatocarcinogenesis, exogenous expression of this miR significantly impaired the inhibitory effect of T3 on the clonogenic growth capacity of human HCC cells.
This work identified several miRNAs, so far never associated to T3. In addition, the precise definition of the miRNA-mRNA networks elicited by T3 treatment gained in this study may provide a better understanding of the key regulatory events underlying the inhibitory effect of T3 on HCC development. In this context, T3-induced down-regulation of miR-182 appears as a promising tool.
甲状腺激素（THs）通过不同机制抑制肝细胞癌（HCC）。然而，微小RNA是否在THs的抗肿瘤作用中发挥作用仍不清楚。
通过下一代测序（NGS），我们对接受或未接受短期三碘甲状腺原氨酸（T3）治疗的大鼠肝前病变进行了全面的比较微小RNA组学和转录组学分析。还研究了在接受或未接受T3治疗的大鼠肝癌以及人肝癌细胞系中，调控最为明显的微小RNA的表达情况。
在T3处理后的癌前结节中下调的微小RNA中，共表达网络揭示了那些靶向甲状腺激素受体-β（Thrβ）和脱碘酶1以及氧化磷酸化的微小RNA。另一方面，靶向Nrf2氧化途径、糖酵解、磷酸戊糖途径和脯氨酸生物合成成员的微小RNA均上调，这些途径都参与了癌前病变所表现出的代谢重编程。值得注意的是，虽然在癌前病变中调控最为明显的大多数微小RNA在肝癌或肝癌细胞中表达未改变，但已知靶向线粒体复合物的微小RNA-182在肝癌发生的各个阶段以及肝癌细胞系中均被T3处理下调。为支持微小RNA-182在肝癌发生中可能的关键作用，该微小RNA的外源性表达显著削弱了T3对人肝癌细胞克隆生长能力的抑制作用。
这项研究鉴定了几种迄今从未与T3相关联的微小RNA。此外，本研究中获得的T3处理引发的微小RNA-信使核糖核酸网络的精确定义，可能有助于更好地理解T3对肝癌发展抑制作用背后的关键调控事件。在此背景下，T3诱导的微小RNA-182下调似乎是一种有前景的工具。
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