Liver Cancer Laboratory, Xiangya Hospital, Central South University, Hunan, China.
Hepatology. 2013 Jul;58(1):205-17. doi: 10.1002/hep.26315. Epub 2013 May 14.
By comparing the expression profiles of microRNAs (miRNAs) in different hepatocellular carcinoma (HCC) subtypes, we identified miR-140-5p as an HCC-related miRNA. We found that miR-140-5p was significantly decreased in HCC tissues and all of six liver cancer cell lines examined and its expression levels were correlated with multiple nodules, vein invasion, capsular formation, and differentiation, as well as overall and disease-free survival of HCC. We also found that miR-140-5p suppressed HCC cell proliferation and HCC metastasis. Multipathway reporter arrays suggested that miR-140-5p inhibited transforming growth factor β (TGF-β) and mitogen-activated protein kinase / extracellular signal-regulated kinase (MAPK/ERK) signaling. TGFB receptor 1 (TGFBR1) and fibroblast growth factor 9 (FGF9) were then characterized as the direct targets for miR-140-5p after it was found that ectopic miR-140-5p expression suppressed TGFBR1 and FGF9 expression. Silencing TGFBR1 and FGF9 by small interfering RNA (siRNA) resembled the phenotype resulting from ectopic miR-140-5p expression, while overexpression of TGFBR1 and FGF9 attenuated the effect of miR-140-5p on HCC growth and metastasis.
These data elucidated a tumor suppressor role for miR-140-5p in HCC development and progression with therapeutic potential. Our correlation studies in clinical HCC samples further suggest that miR-140-5p could be a valuable biomarker for HCC prognosis.
通过比较不同肝细胞癌（HCC）亚型中 microRNAs（miRNAs）的表达谱，我们鉴定出 miR-140-5p 是一种与 HCC 相关的 miRNA。我们发现 miR-140-5p 在 HCC 组织和我们检查的六种肝癌细胞系中均显著下调，其表达水平与多个结节、静脉侵犯、包膜形成和分化以及 HCC 的总生存和无病生存相关。我们还发现 miR-140-5p 抑制 HCC 细胞增殖和 HCC 转移。多通路报告基因分析表明，miR-140-5p 抑制转化生长因子 β（TGF-β）和丝裂原活化蛋白激酶/细胞外信号调节激酶（MAPK/ERK）信号通路。随后发现外源性 miR-140-5p 表达抑制 TGFBR1 和 FGF9 的表达，表明 TGFB 受体 1（TGFBR1）和成纤维细胞生长因子 9（FGF9）是 miR-140-5p 的直接靶基因。用小干扰 RNA（siRNA）沉默 TGFBR1 和 FGF9 类似于外源性 miR-140-5p 表达产生的表型，而过表达 TGFBR1 和 FGF9 则减弱了 miR-140-5p 对 HCC 生长和转移的作用。
这些数据阐明了 miR-140-5p 在 HCC 发展和进展中的肿瘤抑制作用，具有治疗潜力。我们在临床 HCC 样本中的相关性研究进一步表明，miR-140-5p 可能是 HCC 预后的有价值的生物标志物。
