HSP47 Promotes Glioblastoma Stemlike Cell Survival by Modulating Tumor Microenvironment Extracellular Matrix through TGF-β Pathway

ACS Chem Neurosci. 2017 Jan 18;8(1):128-134. doi: 10.1021/acschemneuro.6b00253. Epub 2016 Oct 12.


Grade IV glioblastoma multiforme (GBM) is the most malignant form of gliomas. HSP47, encoded by SERPINH1 gene, is a serpin which serves as a human chaperone protein for collagen. We have shown that HSP47 is significantly overexpressed in GBM and associated with tumor grade. However, the role of HSP47 on GBM progression and stemlike property remains unclear. The stable overexpression of HSP47 in primary GBM cells was established by lentivirus infection. The effects of HSP47 overexpression on tumor growth and the effects of blocking the TGF-β pathway on tumor regression were investigated by animal study. The expression of HSP47 was examined by real time qRT-PCR and immunohistochemistry. The stemlike property was investigated by sphere formation and CD44 cell population analysis using flow cytometry. We found that overexpression of HSP47 promotes primary glioma cell tumor formation, invasion, angiogenesis, and stemlike properties. The overexpression of HSP47 was correlated and promoted extracellular matrix (ECM) related genes through the TGF-β pathway in GBM. Blocking TGF-β pathway overcomes HSP47 induced tumorigenesis and stemness. This study demonstrated that HSP47 promotes GBM stemlike cell survival by modulating tumor microenvironment ECM through TGF-β pathway. Blocking the TGF-β pathway provides a promising therapeutic potential for HSP47 overexpressed GBM.

Keywords: Glioblastoma; HSP47; TGF-β; extracellular matrix; glioma stem cell; inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / pathology
  • Cell Survival / drug effects
  • Computational Biology
  • Disease Models, Animal
  • Extracellular Matrix / genetics
  • Extracellular Matrix / metabolism*
  • Flow Cytometry
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / physiology*
  • Glioblastoma / drug therapy
  • Glioblastoma / pathology
  • HSP47 Heat-Shock Proteins / genetics
  • HSP47 Heat-Shock Proteins / metabolism*
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplastic Stem Cells / metabolism*
  • Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
  • Pyrazoles / pharmacology
  • Pyrroles / pharmacology
  • RNA, Messenger
  • Transforming Growth Factor beta / antagonists & inhibitors
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*
  • Tumor Cells, Cultured
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / physiology*
  • Xenograft Model Antitumor Assays


  • HSP47 Heat-Shock Proteins
  • LY2109761
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Pyrazoles
  • Pyrroles
  • RNA, Messenger
  • Transforming Growth Factor beta