Chaperone Hsp47 Drives Malignant Growth and Invasion by Modulating an ECM Gene Network.
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.
Markey Cancer Center, University of Kentucky, Lexington, Kentucky. Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky.
Jieqing
J
Zhu
Markey Cancer Center, University of Kentucky, Lexington, Kentucky. Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky.
Gaofeng
G
Xiong
Beijing Institute of Radiation Medicine, Beijing, People's Republic of China.
Hanjiang
H
Fu
Markey Cancer Center, University of Kentucky, Lexington, Kentucky. Department of Surgery, University of Kentucky, Lexington, Kentucky.
B Mark
BM
Evers
Markey Cancer Center, University of Kentucky, Lexington, Kentucky. Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky.
Binhua P
BP
Zhou
Markey Cancer Center, University of Kentucky, Lexington, Kentucky. Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky. ren.xu2010@uky.edu.
Ren
R
Xu
D000818:Animals; D049109:Cell Proliferation / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D005109:Extracellular Matrix / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks / Q000235:genetics*; D057809:HEK293 Cells; D050958:HSP47 Heat-Shock Proteins / Q000502:physiology*; D064593:Heterografts; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000502:physiology; D009361:Neoplasm Invasiveness / Q000235:genetics*; D009368:Neoplasm Transplantation; D014407:Tumor Cells, Cultured
D050958:HSP47 Heat-Shock Proteins; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; C494660:SERPINH1 protein, human