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.
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This study was supported by start-up fund from Markey Cancer Center and funding support from AHA (12SDG8600000 to R. Xu), ACS (IRG 85-001-22 to R. Xu). This study was supported in part by NIH Grant Number P30GM110787 from the National Institute of General Medical Sciences, its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or the NIGMS.
Financial support: AHA (12SDG8600000 to R. Xu), ACS (IRG 85-001-22 to R. Xu), COBRE Pilot Award (201407231052 to R. Xu)
An editorial was written about this article:
Zhu, Jieqing; Xiong, Gaofeng; Fu, Hanjiang; Evers, B. Mark; Zhou, Binhua P.; and Xu, Ren, "Chaperone Hsp47 Drives Malignant Growth and Invasion by Modulating an ECM Gene Network" (2015). Markey Cancer Center Faculty Publications. 55.
Supplemental Table S1 - Supplemental Table S1. Expression of Hsp47 and ECM protein genes is correlated in mammary cell lines.
129597_4_supp_2802592_nhbmb4.tif (601 kB)
Supplemental Figure S1 - Supplemental Figure S1. Hsp47 expression is upregulated in various cancers, but the upregulation is not sufficient to induce transformation.
129597_4_supp_2802593_nhnmn4.tif (298 kB)
Supplemental Figure S2 - Supplemental Figure S2. MiR-29 is a potential regulator of multiple ECM network genes.
129597_4_supp_2802594_nhlml4.tif (803 kB)
Supplemental Figure S3 - Supplemental Figure S3. Hsp47 expression is associated with poor prognosis and contributes to the deposition of ECM proteins in breast cancer tissue.
129597_4_supp_2802595_nhymy4.tif (116 kB)
Supplemental Figure S4 - Supplemental Figure S4. Increased Hsp47 expression has been detected in ER negative cancer and is negatively associated with GATA3 levels.
129597_4_supp_0_nkclbm.docx (18 kB)
Supplemental Table and Figure Legends - Supplemental Table and Figure Legends. Legends for Supplemental Table S1 and Supplemental Figures S1-S4.