CUL4B promotes gastric cancer invasion and metastasis-involvement of upregulation of HER2
CUL4B promotes gastric cancer invasion and metastasis-involvement of upregulation of HER2
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CUL4B促进胃癌侵袭转移——HER2上调参与
DOI：
10.1038/onc.2017.380
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发表时间：
2018-02-22
期刊：
影响因子：
8
通讯作者：
Han, B.
中科院分区：
文献类型：
--
作者：
Qi, M.;Jiao, M.;Han, B.
Cullin 4 B（CUL 4 B）是在几种实体恶性肿瘤中过表达的支架蛋白。已知通过转录后方式沉默肿瘤抑制因子。然而，其在胃癌（GC）中的临床意义和潜在的分子机制仍不清楚。在本研究中，我们发现CUL 4 B在胃癌组织中显著过表达，其过表达与淋巴结转移和预后不良相关。通过功能获得和丧失实验，我们发现CUL 4 B在体外促进GC细胞侵袭和上皮-间质转化（EMT），以及在体内促进肿瘤生长和转移。从机制上讲，我们确定HER 2为GC中CUL 4 B的下游靶基因。CUL 4 B通过转录抑制miR-125 a而不调节HER 2表达。有趣的是，HER 2抑制剂在体外显著逆转了CUL 4 B诱导的EMT，并部分阻断了CUL 4 B过表达的肿瘤异种移植物中的GC转移。最后，我们认为PI 3 K/AKT通路参与了CUL 4 B诱导的胃癌中HER 2的上调。总之，我们提出了一个CUL 4 B-miR-125 a-HER 2癌蛋白轴的模型，这为HER 2如何被激活并促进GC进展和转移提供了新的见解。
Cullin 4B (CUL4B) is a scaffold protein overexpressed in several solid malignancies. It is known to silence tumor suppressor through post-transcriptional manner. However, its clinical significance and underlying molecular mechanisms in gastric cancer (GC) remain largely unknown. In this study, we found that CUL4B was significantly overexpressed in GC tissues and its overexpression was correlated with lymph node metastasis and poor prognosis. Through gain-and loss-of-function experiments, we showed that CUL4B promotes GC cell invasion and epithelial–mesenchymal transition (EMT) in vitro, as well as tumor growth and metastasis in vivo. Mechanistically, we identified HER2 as a downstream target gene of CUL4B in GC. CUL4B unregulated HER2 expression via transcriptionally repressing miR-125a. Intriguingly, HER2 inhibitors significantly reversed CUL4B-induced EMT in vitro and partially blocked GC metastasis in tumor xenografts with CUL4B overexpression. Finally, we suggested the involvement of the PI3K/AKT pathway in CUL4B-induced HER2 upregulation in GC. In all, we proposed a model for a CUL4B-miR-125a-HER2 oncoprotein axis, which provided novel insight into how HER2 was activated and contributed to GC progression and metastasis.