Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
Cancer Lett. 2017 Apr 1;390:67-76. doi: 10.1016/j.canlet.2016.12.042. Epub 2017 Jan 16.
The role of bone morphogenetic protein 4 (BMP4), a crucial epithelial-mesenchymal transition (EMT) mediator, in the progression of hepatocellular carcinoma (HCC) patients heretofore has not been elucidated. The present study analyzed BMP4 expression in tumors and paired non-tumorous liver tissue and its correlation with clinicopathological characteristics from two independent cohorts consisting of 420 HCC patients. Functional analysis of BMP4 was performed in Bel-7402 and HCCLM3 HCC cells, and in a murine HCC model. The downstream targets of BMP4 in HCC were screened and confirmed. The results indicated that BMP4 expression was significantly increased in HCC tissue and highly metastatic HCC cells. BMP4 expression was correlated with vein invasion, overall survival and recurrence-free survival of HCC. BMP4 promoted HCC EMT and metastasis in vitro, and consistently in vivo. BMP4 knockdown blocked EMT and tumor metastasis in nude mice. ID2 was up-regulated by recombinant human BMP4, resulting in HCC EMT. Knockdown of ID2 blocked BMP4-induced EMT. In conclusion, BMP4 promotes invasion and metastasis of HCC by an induction of EMT via up-regulating ID2. BMP4 may be a valuable prognostic factor and potential therapeutic target for HCC therapy.
骨形态发生蛋白 4（BMP4）是上皮-间质转化（EMT）的关键介质，其在肝细胞癌（HCC）患者进展中的作用迄今尚未阐明。本研究分析了来自两个独立队列的 420 名 HCC 患者的肿瘤和配对的非肿瘤性肝组织中 BMP4 的表达及其与临床病理特征的相关性。在 Bel-7402 和 HCCLM3 HCC 细胞以及小鼠 HCC 模型中进行了 BMP4 的功能分析。筛选和验证了 BMP4 在 HCC 中的下游靶标。结果表明，BMP4 在 HCC 组织和高转移性 HCC 细胞中表达显著增加。BMP4 表达与 HCC 的静脉侵犯、总生存率和无复发生存率相关。BMP4 在体外和体内均促进 HCC 的 EMT 和转移。BMP4 敲低可阻断裸鼠 EMT 和肿瘤转移。ID2 被重组人 BMP4 上调，导致 HCC EMT。ID2 敲低可阻断 BMP4 诱导的 EMT。总之，BMP4 通过上调 ID2 诱导 EMT 促进 HCC 的侵袭和转移。BMP4 可能是 HCC 治疗的一个有价值的预后因素和潜在的治疗靶点。
