RMP promotes venous metastases of hepatocellular carcinoma through promoting IL-6 transcription.
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.
1] National Center for Liver Cancer, Shanghai, China [2] International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai, China.
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J
Zhang
1] National Center for Liver Cancer, Shanghai, China [2] International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai, China.
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YF
Pan
1] National Center for Liver Cancer, Shanghai, China [2] International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai, China.
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ZW
Ding
1] National Center for Liver Cancer, Shanghai, China [2] International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai, China.
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GZ
Yang
1] National Center for Liver Cancer, Shanghai, China [2] International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai, China.
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YX
Tan
1] National Center for Liver Cancer, Shanghai, China [2] International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai, China.
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C
Yang
1] National Center for Liver Cancer, Shanghai, China [2] International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai, China.
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TY
Jiang
1] National Center for Liver Cancer, Shanghai, China [2] International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai, China.
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LJ
Liu
1] National Center for Liver Cancer, Shanghai, China [2] International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai, China.
B
B
Zhang
1] National Center for Liver Cancer, Shanghai, China [2] International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai, China.
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T
Han
1] National Center for Liver Cancer, Shanghai, China [2] International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai, China.
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D
Cao
Department of Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.
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T
Yang
Department of Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.
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N
Yang
Department of Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.
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MC
Wu
1] National Center for Liver Cancer, Shanghai, China [2] International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai, China.
L-W
LW
Dong
1] National Center for Liver Cancer, Shanghai, China [2] International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai, China [3] State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
H-Y
HY
Wang
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D055785:Gene Knockdown Techniques; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism; D011169:Portal Vein / Q000378:metabolism / Q000473:pathology*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*
D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D012097:Repressor Proteins; C117184:URI1 protein, human; C485517:Uri1 protein, mouse; C577686:interleukin-6, mouse