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RMP promotes venous metastases of hepatocellular carcinoma through promoting IL-6 transcription

Oncogene volume 34, pages 1575–1583 (2015)Cite this article

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Abstract

Hepatocellular carcinoma (HCC) is believed to arise from tumor-initiating cells (T-ICs), which are responsible for tumor relapse and metastases. Portal vein tumor thrombus (PVTT) is raised from HCC and strongly correlated to a poor prognosis. However, the mechanism underling the formation of PVTT is largely unknown. Herein, we provide evidence that RNA polymerase II subunit 5 (RPB5)-mediating protein (RMP) was progressively upregulated in PVTT and overexpressed RMP appeared to increase T-ICs self-renewal. Moreover, RMP promoted metastases of PVTT cells and HCC cells in vitro and in vivo. Knockdown of RMP attenuated T-ICs self-renewal and reversed epithelial–mesenchymal transition (EMT) in HCC and PVTT cells. The neutralizing assays suggested that interleukin-6 (IL-6) had an indispensable role in RMP regulating metastases and self-renewal of HCC cells. Furthermore, the transcription of IL-6 was verified to be modulated by RMP via interaction with p65 and RPB5, through which expanding the T-IC/cancer stem cell populations, as well as inducing EMT was promoted. These results suggested that RMP may promote PVTT formation by promoting IL-6 transcription. Thus, RMP serves as a potent factor contributed to develop PVTT and a promising therapeutic target for HCC patients.

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Acknowledgements

We thank Liang Tang, Dong-Ping Hu, Shan-Na Huang, Dan-Dan Huang, Shan-Hua Tang, Lin-Na Guo and Huan-Lin Sun for technical assistance. We thank Dr Xiao-Ni Kong for providing luciferase reporter constructs and Ad-caSTAT3 virus. This work was supported by grants from National Natural Science Foundation of China (81370066, 81372355, 81001075, 91229205, BWS11J036), the Funds for Creative Research Groups of China (81221061) and the State Key Project for Liver Cancer (2012ZX10002–009, 2013ZX10002–010), Stem Cell and Medicine Research Center’s Innovation Research Program of the Second Military Medical University (SCMRC1306).

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Author notes

  1. J Zhang, Y-F Pan and Z-W Ding: These authors contributed equally to this work.

Authors and Affiliations

  1. National Center for Liver Cancer, Shanghai, China

    J Zhang, Y-F Pan, Z-W Ding, G-Z Yang, Y-X Tan, C Yang, T-Y Jiang, L-J Liu, B Zhang, T Han, D Cao, L-W Dong & H-Y Wang

  2. International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai, China

    J Zhang, Y-F Pan, Z-W Ding, G-Z Yang, Y-X Tan, C Yang, T-Y Jiang, L-J Liu, B Zhang, T Han, D Cao, L-W Dong & H-Y Wang

  3. Department of Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China

    T Yang, N Yang & M-C Wu

  4. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

    H-Y Wang

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  1. J Zhang
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Correspondence to L-W Dong or H-Y Wang.

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Zhang, J., Pan, YF., Ding, ZW. et al. RMP promotes venous metastases of hepatocellular carcinoma through promoting IL-6 transcription. Oncogene 34, 1575–1583 (2015). https://doi.org/10.1038/onc.2014.84

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