Transcriptional activation of FN1 and IL11 by HMGA2 promotes the malignant behavior of colorectal cancer
Transcriptional activation of FN1 and IL11 by HMGA2 promotes the malignant behavior of colorectal cancer
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HMGA2转录激活FN1和IL11促进结直肠癌的恶性行为
DOI：
10.1093/carcin/bgw029
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发表时间：
2016-05-01
期刊：
影响因子：
4.7
通讯作者：
Lai, Maode
中科院分区：
文献类型：
--
作者：
Wu, Jingjing;Wang, Yuhong;Lai, Maode
高迁移率族基因A2(HMGA2)在结直肠癌中的致癌作用是通过直接与IL11和FN1启动子结合，转录激活它们的表达，通过依赖pSTAT3的途径诱导上皮-间充质转化来实现的。HMGA2和IL11可预测结直肠癌的预后不良，结直肠癌是全球第二大癌症死亡原因，转移是其预后不良的主要原因。高迁移率族基因A2(HMGA2)的过度表达与结直肠癌的侵袭性有关。然而，其过度表达的潜在分子机制仍不清楚。在这项研究中，我们发现HMGA2的异位表达在体外显著促进了细胞的迁移和侵袭，在体内促进了肿瘤的生长和远处转移。相比之下，在体外和体内，沉默HMGA2产生了相反的效果。染色质免疫沉淀-聚合酶链式反应和荧光素酶分析表明，HMGA2直接与FN1和IL11的启动子结合，并显著诱导其转录活性。此外，作为HMGA2的直接下游靶点，IL11通过依赖pSTAT3的信号通路调控细胞的迁移和侵袭。此外，122例大肠癌组织中HMGA2和IL11的表达呈显著正相关。在结直肠癌患者中，IL11的高表达与分化差、肿瘤体积大、淋巴结转移和总生存率低有关。总之，我们的数据揭示了HMGA2介导的结直肠癌转移的分子机制的新见解，并强调了靶向HMGA2和IL11用于治疗有转移的结直肠癌患者的可能性。
The oncogenic properties of high-mobility gene group A2 (HMGA2) in colorectal cancer (CRC) were mediated through directly binding to the promoters of IL11 and FN1, transcriptionally activating their expressions and inducing epithelial-mesenchymal transition through a pSTAT3-dependent pathway. HMGA2 and IL11 may predict worse prognosis of CRC.Colorectal cancer (CRC) is the second leading cause of cancer deaths worldwide, and metastasis is the principle reason for its poor prognosis. Overexpression of high-mobility gene group A2 (HMGA2) contributes to the aggressiveness of CRC. However, the underlying molecular mechanism of its overexpression is still elusive. In this study, we showed that ectopic expression of HMGA2 significantly enhanced cell migration and invasion in vitro and promoted tumor growth and distant metastasis in vivo. In contrast, the silencing of HMGA2 produced the opposite effects in vitro and in vivo. Chromatin immunoprecipitation-PCR and luciferase assays revealed that HMGA2 bound directly to the promoters of FN1 and IL11 and significantly induced their transcriptional activities. Moreover, as the direct downstream target of HMGA2, IL11 modulated cell migration and invasion through a pSTAT3-dependent signaling pathway. Furthermore, a strong positive correlation between HMGA2 and IL11 expression was identified in 122 CRC tissues. High IL11 expression was associated with poor differentiation, a large tumor size, lymph node metastasis and low overall survival in CRC patients. Collectively, our data reveal novel insights into the molecular mechanisms underlying HMGA2-mediated CRC metastasis and highlight the possibility of targeting HMGA2 and IL11 for treating CRC patients with metastasis.