血管生成
生物
癌症研究
Wnt信号通路
肝细胞癌
基因敲除
旁分泌信号
连环素
连环蛋白
蛋白激酶B
细胞培养
信号转导
细胞生物学
六氯环己烷
受体
生物化学
遗传学
作者
Pengyi Guo,Yi Wang,Dai Chun-xiu,Chonglin Tao,Fang Wu,Xiaozai Xie,Haitao Yu,Qiandong Zhu,Junjian Li,Long‐Yun Ye,Fuxiang Yu,Yunfeng Shan,Zhengping Yu,Renumathy Dhanasekaran,Rong-Yuan Zheng,Gang Chen
出处
期刊:Oncogene
[Springer Nature]
日期:2017-12-15
卷期号:37 (9): 1220-1236
被引量:53
标识
DOI:10.1038/s41388-017-0017-y
摘要
Ribosomal protein s15a (RPS15A) plays a promotive role in the mRNA/ribosome interactions during early translation. Our previous study has found that inhibiting RPS15A expression can decrease proliferation and induce cell cycle arrest in hepatocellular carcinoma (HCC) cell lines. However, the mechanism underlying the involvement of RPS15A in HCC pathogenesis and the clinical significance of RPS15A expression remain unclear. In this study, an evaluation of RPS15A expression in 110 surgically resected HCCs and matched tumor-adjacent normal tissues revealed an overexpression of RPS15A in HCC, which was correlated with worse survival. In addition, tumor tissue with higher RPS15A expression demonstrated a higher microvascular density (MVD). Subsequently, two HCC cell lines, Huh7 (low-level constitutive RPS15A expression) and HepG2 (high RPS15A expression) were used to further evaluate the role of RPS15A in angiogenesis. The co-culture experiment of HCC cells with endothelial cells revealed that the induced overexpression of RPS15A in Huh7 cells increased the angiogenic potential of HUVEC in a paracrine fashion; conversely, knockdown of RPS15A in HepG2 cells showed an opposite effect. Further analysis indicated that RPS15A modulated FGF signaling by enhancing Wnt/beta-catenin-mediated FGF18 expression in HCC cells. FGF18, in turn, through binding to its FGFR3 receptor on endothelial cells, can activate the AKT and ERK pathway and promotes angiogenesis in a tumor microenvironment. Our in vivo experiment further confirmed that inhibition of RPS15A expression in HCC xenografts dramatically hindered tumor growth and inhibited tumor angiogenesis. Together, our findings suggest that RPS15A promotes angiogenesis in HCCs by enhancing Wnt/beta-catenin induced FGF18 expression. The RPS15A/FGF18 pathway may be a rational target for anti-angiogenic therapy of HCC.
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