Identification of a TGF-beta-miR-195 positive feedback loop in hepatocytes and its deregulation in hepatoma cells.
Identification of a TGF-beta-miR-195 positive feedback loop in hepatocytes and its deregulation in hepatoma cells.
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肝细胞中 TGF-β-miR-195 正反馈环的鉴定及其在肝癌细胞中的失调。
DOI：
10.1096/fj.201701199r
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
Zhuang Shi-Mei
中科院分区：
文献类型：
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作者：
Wang Ruizhi;Fu Tao;You Kai;Li Siwen;Zhao Na;Yang Jine;Zhuang Shi-Mei
对TGF-β诱导的生长抑制的抗性在各种癌细胞中普遍存在，但潜在的机制仍不清楚。在这项研究中，我们发现TGF-β信号的激活导致Sma和Mad相关家族（Smad）2和Smad 3直接与miR-195的启动子区域结合，然后激活正常肝细胞中miR-195的转录。相反，miR-195通过结合其3′-UTR抑制Smad 7的表达，从而加强TGF-β-Smad信号传导。这些数据确定了正常肝细胞中新的TGF-β-miR-195正调控回路。进一步的研究表明，HDAC 1是一种在肝细胞癌中异常过表达的组蛋白去乙酰化酶，可以通过Smad 3与miR-195启动子结合，并导致肝癌细胞中与miR-195启动子相关的组蛋白低乙酰化。这导致了miR-195的转录抑制，随后破坏了TGF-β-miR-195调控环，并逃避了TGF-β介导的生长抑制。此外，肝癌细胞中HDAC 1的沉默恢复了TGF-β介导的生长抑制，但如果miR-195表达降低，这种作用就会减弱。这些发现表明，HDACL诱导的miR-195下调是肿瘤细胞抵抗TGF-β细胞生长抑制活性的重要机制，并强调了TGF-β-Smad 2/3-miR-195-Smad 7电路在防止不受控制的细胞增殖中的重要性。王，R.，傅，T.，你K Li，S.，赵，N.，杨杰，庄S-M肝细胞中TGF-β-miR-195正反馈环的鉴定及其在肝癌细胞中的失调FASEB J. 32，3936-3945（2018）。www.fasebj.org
Resistance to TGF‐β‐induced growth repression is prevalent in various cancer cells, but the underlying mechanisms remain unclear. In this study, we showed that activation of TGF‐β signaling caused Sma‐ and Mad‐related family (Smad) 2 and Smad3 to bind directly to the promoter region of miR‐195, and then activated miR‐195 transcription in normal hepatocytes. Conversely, miR‐195 inhibited the expression of Smad7 by binding to its 3′‐UTR, thereby strengthening TGF‐β‐Smad signaling. These data identify a novel TGF‐β‐miR‐195 positive regulatory circuitry in normal hepatocytes. Further investigation revealed that HDAC1, a histone deacetylase that was abnormally overexpressed in hepatocellular carcinoma, could bind to the miR‐195 promoterviaSmad3 and cause hypoacetylation in the histones associated with the miR‐195 promoter in hepatoma cells. This resulted in transcriptional repression of miR‐195 and, subsequently, disruption of the TGF‐β‐miR‐195 regulatory loop and evasion of TGF‐β‐mediated growth inhibition. Moreover, silencing HDAC1 in hepatoma cells restored TGF‐β‐mediated growth suppression, but this effect was attenuated if miR‐195 expression decreased. These findings suggest that HDACL‐induced miR‐195 down‐regulation is an important mechanism for tumor cells to resist the cytostatic activity of TGF‐β, and highlight the importance of TGF‐β‐Smad2/3‐miR‐195‐Smad7 circuitry in preventing uncontrolled cell proliferation.—Wang, R., Fu, T., You, K., Li, S., Zhao, N., Yang, J., Zhuang, S.‐M. Identification of a TGF‐β‐miR‐195 positive feedback loop in hepatocytes and its deregulation in hepatoma cells. FASEB J. 32, 3936–3945 (2018). www.fasebj.org