Pleiotrophin, a target of miR-384, promotes proliferation, metastasis and lipogenesis in HBV-related hepatocellular carcinoma

J Cell Mol Med. 2017 Nov;21(11):3023-3043. doi: 10.1111/jcmm.13213. Epub 2017 May 30.

Abstract

Hepatitis B virus (HBV) infection plays a crucial role and is a major cause of hepatocellular carcinoma (HCC) in China. microRNAs (miRNAs) have emerged as key players in hepatic steatosis and carcinogenesis. We found that down-regulation of miR-384 expression was a common event in HCC, especially HBV-related HCC. However, the possible function of miR-384 in HBV-related HCC remains unclear. The oncogene pleiotrophin (PTN) was a target of miR-384. HBx inhibited miR-384, increasing PTN expression. The PTN receptor N-syndecan was highly expressed in HCC. PTN induced by HBx acted as a growth factor via N-syndecan on hepatocytes and further promoted cell proliferation, metastasis and lipogenesis. PTN up-regulated sterol regulatory element-binding protein 1c (SREBP-1c) through the N-syndecan/PI3K/Akt/mTORC1 pathway and the expression of lipogenic genes, including fatty acid synthesis (FAS). PTN-mediated de novo lipid synthesis played an important role in HCC proliferation and metastasis. PI3K/AKT and an mTORC1 inhibitor diminished PTN-induced proliferation, metastasis and lipogenesis. Taken together, these data strongly suggest that the dysregulation of miR-384 could play a crucial role in HBV related to HCC, and the target gene of miR-384, PTN, represents a new potential therapeutic target for the prevention of hepatic steatosis and further progression to HCC after chronic HBV infection.

Keywords: hepatitis B virus; hepatocellular carcinoma; lipogenesis; metastasis; miR-384; pleiotrophin.

MeSH terms

  • Adult
  • Carcinoma, Hepatocellular / etiology
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Cell Proliferation
  • Chromones / pharmacology
  • Cytokines / genetics*
  • Cytokines / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Hep G2 Cells
  • Hepatitis B / complications
  • Hepatitis B / genetics*
  • Hepatitis B / metabolism
  • Hepatitis B / pathology
  • Hepatitis B virus / pathogenicity
  • Hepatitis B virus / physiology
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Host-Pathogen Interactions*
  • Humans
  • Lipogenesis / drug effects
  • Lipogenesis / genetics
  • Liver Neoplasms / etiology
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Lymphatic Metastasis
  • Male
  • Mechanistic Target of Rapamycin Complex 1 / antagonists & inhibitors
  • Mechanistic Target of Rapamycin Complex 1 / genetics
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Middle Aged
  • Morpholines / pharmacology
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction
  • Sirolimus / pharmacology
  • Sterol Regulatory Element Binding Protein 1 / genetics
  • Sterol Regulatory Element Binding Protein 1 / metabolism
  • Syndecan-3 / genetics
  • Syndecan-3 / metabolism
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Trans-Activators / pharmacology
  • Viral Regulatory and Accessory Proteins
  • fas Receptor / genetics
  • fas Receptor / metabolism

Substances

  • Carrier Proteins
  • Chromones
  • Cytokines
  • FAS protein, human
  • MIRN384 microRNA, human
  • MicroRNAs
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Sterol Regulatory Element Binding Protein 1
  • Syndecan-3
  • Trans-Activators
  • Viral Regulatory and Accessory Proteins
  • fas Receptor
  • hepatitis B virus X protein
  • pleiotrophin
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Mechanistic Target of Rapamycin Complex 1
  • Proto-Oncogene Proteins c-akt
  • Sirolimus