Reprogramming of the tumour microenvironment by stromal PTEN-regulated miR-320

被引：224

作者：

Bronisz, A. ^{[1
,2
]}

Godlewski, J. ^{[3
,4
]}

Wallace, J. A. ^{[2
]}

Merchant, A. S. ^{[2
]}

Nowicki, M. O. ^{[3
,4
]}

Mathsyaraja, H. ^{[2
]}

Srinivasan, R. ^{[2
]}

Trimboli, A. J. ^{[5
,6
]}

Martin, C. K. ^{[2
]}

Li, F. ^{[2
,5
]}

Yu, L. ^{[7
]}

Fernandez, S. A. ^{[7
]}

Pecot, T. ^{[5
,6
,8
]}

Rosol, T. J. ^{[9
]}

Cory, S. ^{[10
,11
]}

Hallett, M. ^{[10
,11
]}

Park, M. ^{[11
,12
]}

Piper, M. G. ^{[13
]}

Marsh, C. B. ^{[13
]}

Yee, L. D. ^{[14
]}

Jimenez, R. E. ^{[15
]}

Nuovo, G. ^{[4
,16
]}

Lawler, S. E. ^{[3
,4
]}

Chiocca, E. A. ^{[3
,4
]}

Leone, G. ^{[1
,5
,6
]}

Ostrowski, M. C. ^{[1
,2
]}

机构：

[1] Ohio State Univ, Ctr Comprehens Canc, Tumor Microenvironm Program, Columbus, OH 43210 USA

[2] Ohio State Univ, Dept Mol & Cellular Biochem, Coll Med, Columbus, OH 43210 USA

[3] Ohio State Univ, Med Ctr, Dept Neurol Surg, Dardinger Lab Neurooncol & Neurosci, Columbus, OH 43210 USA

[4] James Comprehens Canc Ctr, Columbus, OH 43210 USA

[5] Ohio State Univ, Ctr Comprehens Canc, Dept Mol Genet, Coll Biol Sci, Columbus, OH 43210 USA

[6] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA

[7] Ohio State Univ, Ctr Biostat, Off Hlth Sci, Columbus, OH 43210 USA

[8] Ohio State Univ, Ohio State Univ Comp Sci & Engn, Ohio State Univ Biomed Informat, Columbus, OH 43210 USA

[9] Ohio State Univ, Coll Vet Med, Dept Vet Clin Sci, Columbus, OH 43210 USA

[10] McGill Univ, McGill Ctr Bioinformat, Montreal, PQ H3A0B1, Canada

[11] Rosalind & Morris Goodman Canc Ctr Univ, Dept Biochem, Montreal, PQ H3A0B, Canada

[12] McGill Univ, Dept Oncol, Montreal, PQ H3A 1A1, Canada

[13] Ohio State Univ, Divis Pulm Allergy Crit Care & Sleep Med, Dept Internal Med, Dorothy M Davis Heart & Lung Res Inst, Columbus, OH 43210 USA

[14] Ohio State Univ, Sch Med, Dept Surg, Columbus, OH 43210 USA

[15] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA

[16] Ohio State Univ, Med Ctr, Dept Pathol, Columbus, OH 43210 USA

来源：

NATURE CELL BIOLOGY | 2012年 / 14卷 / 02期

基金：

美国国家卫生研究院;

关键词：

EPITHELIAL-MESENCHYMAL TRANSITION; HUMAN BREAST-CANCER; IN-SITU DETECTION; GENE-EXPRESSION; MICRORNA EXPRESSION; MATURE MICRORNAS; FIBROBLASTS; IDENTIFICATION; PROGRESSION; SIGNATURES;

D O I：

10.1038/ncb2396

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

PTEN (Phosphatase and tensin homolog deleted on chromosome 10) expression in stromal fibroblasts suppresses epithelial mammary tumours, but the underlying molecular mechanisms remain unknown. Using proteomic and expression profiling, we show that Pten loss from mammary stromal fibroblasts activates an oncogenic secretome that orchestrates the transcriptional reprogramming of other cell types in the microenvironment. Downregulation of miR-320 and upregulation of one of its direct targets, ETS2 (v-ets erythroblastosis virus E26 oncogene homolog 2) are critical events in Pten-deleted stromal fibroblasts responsible for inducing this oncogenic secretome, which in turn promotes tumour angiogenesis and tumour-cell invasion. Expression of the Pten-miR-320-Ets2-regulated secretome distinguished human normal breast stroma from tumour stroma and robustly correlated with recurrence in breast cancer patients. This work reveals miR-320 as a critical component of the Pten tumour-suppressor axis that acts in stromal fibroblasts to reprogramme the tumour microenvironment and curtail tumour progression.

引用

页码：159 / 167

页数：9

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