High-Mobility Group Box 1 Promotes Hepatocellular Carcinoma Progression through miR-21-Mediated Matrix Metalloproteinase Activity.
High-Mobility Group Box 1 Promotes Hepatocellular Carcinoma Progression through miR-21-Mediated Matrix Metalloproteinase Activity.
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高迁移率 Group Box 1 通过 miR-21 介导的基质金属蛋白酶活性促进肝细胞癌进展。
DOI：
10.1158/0008-5472.can-14-2147
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发表时间：
2015-04-15
期刊：
影响因子：
11.2
通讯作者：
Tsung A
中科院分区：
文献类型：
--
作者：
Chen M;Liu Y;Varley P;Chang Y;He XX;Huang H;Tang D;Lotze MT;Lin J;Tsung A
肝脏炎症在肝细胞癌（HCC）病因学中起着关键作用。损伤相关分子模式（DAMP），如高迁移率族蛋白1（HMGB 1）和参与炎症疾病状态的失调miRNA，如miR-21，可能参与炎症和癌症之间的联系。我们试图确定HMGB 1信号在HCC肿瘤进展中的作用。我们首先记录了HCC细胞系和原发性HCC肿瘤样品中HMGB 1和miR-21的一致表达增加，随后显示HMGB 1刺激导致miR-21的过表达。发现这些变化依赖于IL 6/STAT 3信号传导轴。体外HCC细胞的侵袭和迁移被STAT 3和miR-21拮抗剂抑制，表明该途径在HCC肿瘤进展中的作用。我们验证了HMGB 1诱导的HCC中miR-21的表达提供了对基质金属蛋白酶（MMP）抑制剂RECK和TIMP 3的转录后抑制，已知这两种抑制剂会影响HCC的进展和转移。最后，我们发现，在小鼠HMGB 1过表达的HCC异种移植物中抑制miR-21，通过释放对miR-21靶点RECK和TIMP 3的抑制，导致肿瘤MMP活性降低，最终阻碍肿瘤进展。原型DAMP，HMGB 1，在肝脏炎症期间释放，并为HCC生长提供有利的环境。HMGB 1信号通过RECK和TIMP 3增加miR-21的表达来介导MMPs活性的增强。这些发现为HMGB 1通过IL 6/Stat 3-miR-21轴介导的HCC进展提供了新的机制。
Liver inflammation plays a critical role in hepatocellular carcinoma (HCC) etiology. Damage-associated molecular patterns (DAMP), such as high-mobility group box 1 (HMGB1), and dysregulated miRNAs involved in inflammatory disease states, such as miR-21, may participate in the link between inflammation and cancer. We sought to determine the role of HMGB1 signaling in HCC tumor progression. We first document the concordant expression increase of HMGB1 and miR-21 in HCC cell lines and primary HCC tumor samples and subsequently show that HMGB1 stimulation results in overexpression of miR-21. These changes were found to be dependent on the IL6/STAT3 signaling axis. Invasion and migration of HCC cells in vitro were inhibited by both STAT3 and miR-21 antagonists, suggesting a role for this pathway in HCC tumor progression. We verified that HMGB1-induced expression of miR-21 in HCC provides a posttranscriptional repression of the matrix metalloproteinase (MMP) inhibitors RECK and TIMP3, which are known to impact HCC progression and metastases. Finally, we found that inhibition of miR-21 in murine HMGB1-overexpressing HCC xenografts led to reduced tumor MMP activity through released repression of the miR-21 targets RECK and TIMP3, which ultimately impeded tumor progression. The prototypical DAMP, HMGB1, is released during liver inflammation and provides a favorable environment for HCC growth. HMGB1 signaling increases miR-21 expression to mediate the enhanced activity of MMPs through RECK and TIMP3. These findings provide a novel mechanism for HMGB1-mediated HCC progression through the IL6/Stat3-miR-21 axis.