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

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

Author information

1
Markey Cancer Center, University of Kentucky, Lexington, Kentucky. Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky.
2
Beijing Institute of Radiation Medicine, Beijing, People's Republic of China.
3
Markey Cancer Center, University of Kentucky, Lexington, Kentucky. Department of Surgery, University of Kentucky, Lexington, Kentucky.
4
Markey Cancer Center, University of Kentucky, Lexington, Kentucky. Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky.
5
Markey Cancer Center, University of Kentucky, Lexington, Kentucky. Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky. ren.xu2010@uky.edu.

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.

PMID:
25744716
PMCID:
PMC4401637
DOI:
10.1158/0008-5472.CAN-14-1027
[Indexed for MEDLINE]
Free PMC Article

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