Wu Jingjing, Wang Yuhong, Xu Xi, Cao Hui, Sahengbieke Sana, Sheng Hongqiang, Huang Qiong, Lai Maode
Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
Carcinogenesis. 2016 May;37(5):511-21. doi: 10.1093/carcin/bgw029. Epub 2016 Mar 10.
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.
结直肠癌（CRC）是全球癌症死亡的第二大主要原因，而转移是其预后不良的主要原因。高迁移率族蛋白A2（HMGA2）的过表达促进了结直肠癌的侵袭性。然而，其过表达的潜在分子机制仍不清楚。在本研究中，我们发现异位表达HMGA2可显著增强体外细胞迁移和侵袭能力，并促进体内肿瘤生长和远处转移。相反，沉默HMGA2在体外和体内均产生相反的效果。染色质免疫沉淀-PCR和荧光素酶分析显示，HMGA2直接结合到FN1和IL11的启动子上，并显著诱导它们的转录活性。此外，作为HMGA2的直接下游靶点，IL11通过pSTAT3依赖性信号通路调节细胞迁移和侵袭。此外，在122例结直肠癌组织中发现HMGA2与IL11表达呈强正相关。高IL11表达与结直肠癌患者的低分化、肿瘤体积大、淋巴结转移及总生存率低相关。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，并突出了靶向HMGA2和IL11治疗转移性结直肠癌患者的可能性。
