Stem Cell and Regenerative Medicine Lab, Beijing Institute of Transfusion Medicine, Beijing, China.
South China Research Center for Stem Cell & Regenerative Medicine, AMMS, Guangzhou, China.
Hepatology. 2015 Sep;62(3):801-15. doi: 10.1002/hep.27887. Epub 2015 Jul 3.
Emerging evidence suggests that epithelial-mesenchymal transitions (EMTs) play important roles in tumor metastasis and recurrence. Understanding molecular mechanisms that regulate the EMT process is crucial for improving treatment of hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) play important roles in HCC; however, the mechanisms by which miRNAs target the EMT and their therapeutic potential remains largely unknown. To better explore the roles of miRNAs in the EMT process, we established an EMT model in HCC cells by transforming growth factor beta 1 treatment and found that several tumor-related miRNAs were significantly decreased. Among these miRNAs, miR-125b expression was most strongly suppressed. We also found down-regulation of miR-125b in most HCC cells and clinical specimens, which correlated with cellular differentiation in HCC patients. We then demonstrated that miR-125b overexpression attenuated EMT phenotype in HCC cancer cells, whereas knockdown of miR-125b promoted the EMT phenotype in vitro and in vivo. Moreover, we found that miR-125b attenuated EMT-associated traits, including chemoresistance, migration, and stemness in HCC cells, and negatively correlated with EMT and cancer stem cell (CSC) marker expressions in HCC specimens. miR-125b overexpression could inhibit CSC generation and decrease tumor incidence in the mouse xenograft model. Mechanistically, our data revealed that miR-125b suppressed EMT and EMT-associated traits of HCC cells by targeting small mothers against decapentaplegic (SMAD)2 and 4. Most important, the therapeutic delivery of synthetic miR-125b mimics decreased the target molecule of CSC and inhibited metastasis in the mice model. These findings suggest a potential therapeutic treatment of miR-125b for liver cancer.
miR-125b exerts inhibitory effects on EMT and EMT-associated traits in HCC by SMAD2 and 4. Ectopic expression of miR-125b provides a promising strategy to treat HCC.
新出现的证据表明上皮-间充质转化 (EMT) 在肿瘤转移和复发中起重要作用。了解调节 EMT 过程的分子机制对于改善肝细胞癌 (HCC) 的治疗至关重要。microRNAs (miRNAs) 在 HCC 中发挥重要作用；然而，miRNA 靶向 EMT 的机制及其治疗潜力在很大程度上仍是未知的。为了更好地探索 miRNAs 在 EMT 过程中的作用，我们通过转化生长因子β 1 处理建立了 HCC 细胞的 EMT 模型，发现几种肿瘤相关的 miRNAs 显著下调。在这些 miRNAs 中，miR-125b 的表达受抑制最强。我们还发现 miR-125b 在大多数 HCC 细胞和临床标本中下调，与 HCC 患者的细胞分化相关。我们随后证明 miR-125b 过表达可减弱 HCC 癌细胞的 EMT 表型，而 miR-125b 的敲低则促进了体外和体内 EMT 表型。此外，我们发现 miR-125b 减弱了 HCC 细胞的 EMT 相关特征，包括化学抗性、迁移和干性，并且与 HCC 标本中的 EMT 和癌症干细胞 (CSC) 标志物表达呈负相关。miR-125b 过表达可抑制 CSC 的生成并降低小鼠异种移植模型中的肿瘤发生率。从机制上讲，我们的数据表明，miR-125b 通过靶向小母 against decapentaplegic (SMAD)2 和 4 来抑制 HCC 细胞的 EMT 和 EMT 相关特征。最重要的是，合成 miR-125b 模拟物的治疗性传递降低了 CSC 的靶分子并抑制了小鼠模型中的转移。这些发现表明 miR-125b 可能成为治疗肝癌的一种潜在治疗方法。
miR-125b 通过 SMAD2 和 4 对 HCC 中的 EMT 和 EMT 相关特征发挥抑制作用。miR-125b 的异位表达为治疗 HCC 提供了一种很有前途的策略。
