Long non-coding RNA HULC promotes tumor angiogenesis in liver cancer by up-regulating sphingosine kinase 1 (SPHK1)

Oncotarget. 2016 Jan 5;7(1):241-54. doi: 10.18632/oncotarget.6280.


Highly up-regulated in liver cancer (HULC) is a long non-coding RNA (lncRNA). We found that HULC up-regulated sphingosine kinase 1 (SPHK1), which is involved in tumor angiogenesis. Levels of HULC were positively correlated with levels of SPHK1 and its product, sphingosine-1-phosphate (S1P), in patients HCC samples. HULC increased SPHK1 in hepatoma cells. Chicken chorioallantoic membrane (CAM) assays revealed that si-SPHK1 remarkably blocked the HULC-enhanced angiogenesis. Mechanistically, HULC activated the promoter of SPHK1 in hepatoma cells through the transcription factor E2F1. Chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assay (EMSA) further showed that E2F1 was capable of binding to the E2F1 element in the SPHK1 promoter. HULC increased the expression of E2F1 in hepatoma cells and levels of HULC were positively correlated with those of E2F1 in HCC tissues. Intriguingly, HULC sequestered miR-107, which targeted E2F1 mRNA 3'UTR, by complementary base pairing. Functionally, si-SPHK1 remarkably abolished the HULC-enhanced tumor angiogenesis in vitro and in vivo. Taken together, we conclude that HULC promotes tumor angiogenesis in liver cancer through miR-107/E2F1/SPHK1 signaling. Our finding provides new insights into the mechanism of tumor angiogenesis.

Keywords: E2F1; HCC; HULC; SPHK1; angiogenesis; miR-107.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • Adult
  • Aged
  • Animals
  • Blotting, Western
  • Chick Embryo
  • E2F1 Transcription Factor / genetics
  • E2F1 Transcription Factor / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Hep G2 Cells
  • Humans
  • Liver Neoplasms / blood supply
  • Liver Neoplasms / genetics*
  • Male
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / genetics
  • Middle Aged
  • Neovascularization, Pathologic / genetics*
  • Neovascularization, Physiologic / genetics
  • Phosphotransferases (Alcohol Group Acceptor) / genetics*
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • RNA Interference
  • RNA, Long Noncoding / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transplantation, Heterologous
  • Up-Regulation / genetics


  • 3' Untranslated Regions
  • E2F1 Transcription Factor
  • E2F1 protein, human
  • HULC long non-coding RNA, human
  • MIRN107 microRNA, human
  • MicroRNAs
  • RNA, Long Noncoding
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase