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Ribosomal protein S15a promotes tumor angiogenesis via enhancing Wnt/β-catenin-induced FGF18 expression in hepatocellular carcinoma

Oncogene volume 37, pages 1220–1236 (2018)Cite this article

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Abstract

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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Acknowledgements

This work was supported by the grants from the Natural Science Foundation of Zhejiang Province (LY17H160047), the National Natural Science Foundation of China (81201953), the Research Found for the Doctoral Fund of Ministry of Education of China (20113321120003).

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    Authors and Affiliations

    1. Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China

      Pengyi Guo, Chonglin Tao, Xiaozai Xie, Haitao Yu, Qiandong Zhu, Junjian Li, Longyun Ye, Fuxiang Yu, Yunfeng Shan, Zhengping Yu & Gang Chen

    2. Research Center of Evidence-based Medicine and Clinical Epidemiology, School of Public Health and management, Wenzhou Medical University, Wenzhou, Zhejiang, China

      Yi Wang

    3. Department of Traditional Chinese Medicine, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China

      Chunxiu Dai

    4. Department of Gastroenterology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China

      Fang Wu

    5. Division of Gastroenterology and Hepatology, Stanford University, Palo Alto, CA, USA

      Renumathy Dhanasekaran

    6. Department of Neurology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China

      Rongyuan Zheng

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    Guo, P., Wang, Y., Dai, C. et al. Ribosomal protein S15a promotes tumor angiogenesis via enhancing Wnt/β-catenin-induced FGF18 expression in hepatocellular carcinoma. Oncogene 37, 1220–1236 (2018). https://doi.org/10.1038/s41388-017-0017-y

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