TGF-β1 accelerates the hepatitis B virus X-induced malignant transformation of hepatic progenitor cells by upregulating miR-199a-3p
TGF-β1 accelerates the hepatitis B virus X-induced malignant transformation of hepatic progenitor cells by upregulating miR-199a-3p
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DOI：
10.1038/s41388-019-1107-9
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发表时间：
2020-02-01
期刊：
影响因子：
8
通讯作者：
Dong, Han-hua
中科院分区：
文献类型：
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作者：
Dong, Ke-shuai;Chen, Yan;Dong, Han-hua
越来越多的证据表明肝癌部分源自转化的肝祖细胞（HPC）。然而，人们对 HPC 转型的详细机制知之甚少。在这项研究中，我们提供了乙型肝炎病毒X蛋白（HBx）和转化生长因子β1（TGF-β1）与miR-199a-3p在HPC恶性转化中共存的证据。肝癌标本检查发现HBx、TGF-β1表达与上皮细胞粘附分子(EpCAM)、分化簇90(CD90)呈正相关。重要的是，高 HBx 和高 TGF-β 1 表达的标本中 EpCAM 和 CD90 的表达远高于高 HBx 或高 TGF-β 1 和双低表达组。 HBx和TGF-β1双高表达与原发性肝癌不良预后显着相关。我们还发现，HBx 和 TGF-β 1 诱导 HPC 转化为肝癌干细胞，并促进上皮间质转化，同时暴露 HBx 和 TGF-β 1 进一步增强这种转化。此外，c-Jun N末端激酶（JNK）/c-Jun通路的激活参与了HPC的恶性转化。在暴露于 HBx 和 TGF-β 1 后，miR-199a-3p 被鉴定为 HPC 中显着上调的 microRNA，其通过 c-Jun 介导的激活促进 miR-199a-3p 表达。最后，我们发现miR-199a-3p负责HPC的恶性转化。总之，我们的结果提供了证据，证明 TGF-β1 与 HBx 合作通过 JNK/c-Jun/miR-199a-3p 依赖性途径促进 HPC 的恶性转化。这可能为针对肝癌恶性转化的治疗干预开辟新途径。
Increasing evidence has suggested that liver cancer arises partially from transformed hepatic progenitor cells (HPCs). However, the detailed mechanisms underlying HPC transformation are poorly understood. In this study, we provide evidence linking the coexistence of hepatitis B virus X protein (HBx) and transforming growth factor beta 1 (TGF-beta 1) with miR-199a-3p in the malignant transformation of HPCs. The examination of liver cancer specimens demonstrated that HBx and TGF-beta 1 expression was positively correlated with epithelial cell adhesion molecule (EpCAM) and cluster of differentiation 90 (CD90). Importantly, EpCAM and CD90 expression was much higher in the specimens expressing both high HBx and high TGF-beta 1 than in those with high HBx or high TGF-beta 1 and the double-low-expression group. HBx and TGF-beta 1 double-high expression was significantly associated with poor prognosis in primary liver cancer. We also found that HBx and TGF-beta 1 induced the transformation of HPCs into hepatic cancer stem cells and promoted epithelial-mesenchymal transformation, which was further enhanced by concomitant HBx and TGF-beta 1 exposure. Moreover, activation of the c-Jun N-terminal kinase (JNK)/c-Jun pathway was involved in the malignant transformation of HPCs. miR-199a-3p was identified as a significantly upregulated microRNA in HPCs upon HBx and TGF-beta 1 exposure, which were shown to promote miR-199a-3p expression via c-Jun-mediated activation. Finally, we found that miR-199a-3p was responsible for the malignant transformation of HPCs. In conclusion, our results provide evidence that TGF-beta 1 cooperates with HBx to promote the malignant transformation of HPCs through a JNK/c-Jun/miR-199a-3p-dependent pathway. This may open new avenues for therapeutic interventions targeting the malignant transformation of HPCs in treating liver cancer.