Macrophages-induced long noncoding RNA H19 up-regulation triggers and activates the miR-193b/MAPK1 axis and promotes cell aggressiveness in hepatocellular carcinoma
Macrophages-induced long noncoding RNA H19 up-regulation triggers and activates the miR-193b/MAPK1 axis and promotes cell aggressiveness in hepatocellular carcinoma
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巨噬细胞诱导的长链非编码 RNA H19 上调触发并激活 miR-193b/MAPK1 轴并促进肝细胞癌的细胞侵袭性
DOI：
10.1016/j.canlet.2019.11.001
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发表时间：
2020-01-01
期刊：
影响因子：
9.7
通讯作者：
Yu, Jinpu
中科院分区：
文献类型：
--
作者：
Ye, Yingnan;Guo, Jincheng;Yu, Jinpu
长非编码RNA(LncRNA)H19的异常调控与肝细胞癌有关，但具体的调控机制尚缺乏研究。我们从TCGA和TJMUCH队列中挖掘了457例肝癌样本的基因表达谱，并在FFPE肝癌组织中进一步验证。LncRNAH19原位过表达与肝细胞癌患者的不良预后显著相关，在体外可诱导肝细胞癌发生EMT，增强细胞的侵袭性，加速细胞的侵袭。共表达网络分析表明，lncRNA H19与miR-193B呈负相关，与MAPK1基因呈正相关，提示lncRNA H19作为海绵分子劫持miR-193B，保护MAPK1。H19的强制过表达减弱了miR-193B对多个癌基因(EGFR、KRAS、PTEN和IGF1R)和MAPK1基因的抑制，从而触发了肝细胞癌的EMT和干细胞转化。LncRNAH19与CD68(+)TAMS原位检测呈正相关。TAMS诱导的lncRNA H19通过触发和激活miR-193B/MAPK1轴促进肝癌的侵袭性，介导肝癌与免疫微环境之间的串扰，导致不良的临床结局。LncRNAH19是一种有价值的预测肝癌的生物标志物和潜在的治疗靶点。
Dysregulation of long noncoding RNA (lncRNA) H19 has been implicated in hepatocellular carcinoma (HCC), but the concrete regulatory mechanism is lack of research. We mined gene expression profiles of 457 HCC samples from TCGA and TJMUCH cohorts and further validated in 64 FFPE HCC tissues. LncRNA H19 overexpression in situ was significantly correlated with poor prognosis of HCC patients, which induced EMT, promoted sternness and accelerated invasion of HCC cells in vitro. Co-expression network analysis indicated lncRNA H19 negatively correlated with miR-193b and positively correlated with MAPK1 gene, which implicated that lncRNA H19 served as a sponge molecule to hijack miR-193b and protect MAPK1. Forced overexpression of H19 attenuated miR-193b-mediated inhibition on multiple driver oncogenes (EGFR, KRAS, PTEN and IGF1R) and MAPK1 gene, thus triggered EMT and stem cell transformation in HCC. LncRNA H19 positively correlated with CD68 (+) TAMs in situ. TAMs-induced lncRNA H19 promotes HCC aggressiveness via triggering and activating the miR-193b/MAPK1 axis, mediates the crosstalk between HCC and immunological microenvironment, and causes poor clinical outcomes. LncRNA H19 is a valuable predictive biomarker and potential therapeutic target in HCC.