旁分泌信号
癌症研究
转移
SMAD公司
肿瘤微环境
生物
自分泌信号
血管生成
奶油
上皮-间质转换
黑色素瘤
信号转导
癌症
细胞生物学
转录因子
细胞培养
基因
遗传学
受体
肿瘤细胞
作者
Shumin Ouyang,Shuo Shi,Wen Ding,Ge Yang,Yingxue Su,Jianshan Mo,Keren Peng,Qiyi Zhang,Liu Guang,Wei Xiao,Peibin Yue,Jin-Jian Lu,Li Wang,Xiao‐Feng Xiong,Xiaolei Zhang
标识
DOI:10.1002/advs.202407967
摘要
Abstract Uveal melanoma (UM), the predominant primary ocular malignancy, often progresses to liver metastasis with limited therapeutic options. The interplay of the tumor microenvironment, encompassing secreted soluble factors, plays a crucial role in facilitating liver metastasis. In this study, the role is elucidated of the neural growth factor‐inducible gene (VGF), a secreted neuropeptide precursor, in Gαq mutant UM. Employing a multiomics approach, encompassing transcriptomic and secretomic analyses, the intricate involvement of VGF in UM progression is unveiled. VGF is upregulated in Gαq mutant UM cells and associated with poor prognosis of UM patients. Targeting VGF significantly suppressed the growth of UM in vitro and in vivo. Further evidence shows that VGF is regulated by Gαq through MAPK/CREB pathway. Mechanistically, CREB modulates VGF expression by directly binding to consensus DNA response elements in the promoters of the VGF gene. Combined inhibition of Gαq and MEK remarkably reduces tumor burden in the UM xenograft model. Notably, VGF triggers liver metastatic colonization of UM and activates the fibrosis of hepatic stellate cells (HSCs), creating a favorable microenvironment, through an autocrine and paracrine loop. Furthermore, VGF directly binds to TGFBR2 and regulates TGF‐β‐SMAD signaling pathway, thereby regulating genes associated with endothelial‐mesenchymal transition (EMT) to promote metastasis. Taken together, these findings identify VGF as a pivotal driver in the progression and metastasis of Gαq mutant UM and confers a promising therapeutic target and strategy for UM patients.
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