High mobility group Box-1 inhibits cancer cell motility and metastasis by suppressing activation of transcription factor CREB and nWASP expression.
High mobility group Box-1 inhibits cancer cell motility and metastasis by suppressing activation of transcription factor CREB and nWASP expression.
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DOI：
10.18632/oncotarget.2150
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发表时间：
2014-09-15
期刊：
影响因子：
--
通讯作者：
Huang C
中科院分区：
文献类型：
--
作者：
Zuo Z;Che X;Wang Y;Li B;Li J;Dai W;Lin CP;Huang C
转移能力是恶性肿瘤的一个标志，而转移是癌症患者死亡的主要原因。高迁移率基团盒-1 （HMGB1）是一种多功能蛋白，既作为染色质蛋白又作为细胞外信号分子。我们目前的研究揭示了HMGB1调控癌细胞肌动蛋白聚合、细胞骨架形成、癌细胞运动和转移的新机制。我们发现，在人肺癌A549细胞中，敲低HMGB1可显著增加细胞β-肌动蛋白聚合、细胞骨架形成、体外癌细胞迁移侵袭和体内转移。用重组人HMGB1处理HMGB1敲除细胞可抑制这种增加。进一步研究发现，HMGB1通过抑制PKA催化亚基的核易位，抑制磷酸化、核易位和CREB活化。这降低了nWASP mRNA的转录和表达，进一步损害了癌细胞的运动性。我们关于HMGB1抗肿瘤转移作用的新机制的发现，为了解HMGB1在癌症侵袭和转移中的本质提供了重要的见解，进一步为利用HMGB1及其调控的下游成分作为癌症治疗的新靶点提供了关键信息。
The ability to metastasize is a hallmark of malignant tumors, and metastasis is the principal cause of death of cancer patients. The High Mobility Group Box-1 (HMGB1) is a multifunction protein that serves as both a chromatin protein and an extracellular signaling molecule. Our current study demonstrated a novel mechanism of HMGB1 in the regulation of cancer cell actin polymerization, cell skeleton formation, cancer cell motility and metastasis. We found that knockdown of HMGB1 in human lung cancer A549 cells significantly increased cell β-actin polymerization, cell skeleton formation, cancer cell migration and invasion in vitro, as well as metastasis in vivo. And this increase could be inhibited by treatment of HMGB1 knockdown cells with recombinant human HMGB1. Further studies discovered that HMGB1 suppressed phosphorylation, nuclear translocation, and activation of CREB, by inhibiting nuclear translocation of PKA catalytic subunit. This reduces nWASP mRNA transcription and expression, further impairing cancer cell motility. Our findings on the novel mechanism underlying the HMGB1 anti-metastatic effect on cancer provides significant insight into the understanding of the nature of HMGB1 in cancer invasion and metastasis, further serving as key information for utilization of HMGB1 and its regulated downstream components as new targets for cancer therapy.