Chaperone Hsp47 Drives Malignant Growth and Invasion by Modulating an ECM Gene Network

Cancer Res. 2015 Apr 15;75(8):1580-91. doi: 10.1158/0008-5472.CAN-14-1027. Epub 2015 Mar 5.

Abstract

The extracellular matrix (ECM) is a determining factor in the tumor microenvironment that restrains or promotes malignant growth. In this report, we show how the molecular chaperone protein Hsp47 functions as a nodal hub in regulating an ECM gene transcription network. A transcription network analysis showed that Hsp47 expression was activated during breast cancer development and progression. Hsp47 silencing reprogrammed human breast cancer cells to form growth-arrested and/or noninvasive structures in 3D cultures, and to limit tumor growth in xenograft assays by reducing deposition of collagen and fibronectin. Coexpression network analysis also showed that levels of microRNA(miR)-29b and -29c were inversely correlated with expression of Hsp47 and ECM network genes in human breast cancer tissues. We found that miR-29 repressed expression of Hsp47 along with multiple ECM network genes. Ectopic expression of miR-29b suppressed malignant phenotypes of breast cancer cells in 3D culture. Clinically, increased expression of Hsp47 and reduced levels of miR-29b and -29c were associated with poor survival outcomes in breast cancer patients. Our results show that Hsp47 is regulated by miR-29 during breast cancer development and progression, and that increased Hsp47 expression promotes cancer progression in part by enhancing deposition of ECM proteins.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation / genetics*
  • Cell Transformation, Neoplastic / genetics*
  • Extracellular Matrix / genetics*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Regulatory Networks / genetics*
  • HEK293 Cells
  • HSP47 Heat-Shock Proteins / physiology*
  • Heterografts
  • Humans
  • Mice
  • Mice, SCID
  • MicroRNAs / physiology
  • Neoplasm Invasiveness / genetics*
  • Neoplasm Transplantation
  • Tumor Cells, Cultured

Substances

  • HSP47 Heat-Shock Proteins
  • MIRN29a microRNA, human
  • MicroRNAs
  • SERPINH1 protein, human