Stromal fibroblast-derived miR-409 promotes epithelial-to-mesenchymal transition and prostate tumorigenesis

S. Josson, M. Gururajan, S. Y. Sung, P. Hu, C. Shao, H. E. Zhau, C. Liu, J. Lichterman, P. Duan, Q. Li, A. Rogatko, E. M. Posadas, C. L. Haga, L. W K Chung

Research output: Contribution to journalArticle

86 Citations (Scopus)

Abstract

Tumor-stromal interaction is a dynamic process that promotes tumor growth and metastasis via cell-cell interaction and extracellular vesicles. Recent studies demonstrate that stromal fibroblast-derived molecular signatures can be used to predict disease progression and drug resistance. To identify the epigenetic role of stromal noncoding RNAs in tumor-stromal interactions in the tumor microenvironment, we performed microRNA profiling of patient cancer-associated prostate stromal fibroblasts isolated by laser capture dissection microscopy and in bone-associated stromal models. We found specific upregulation of miR-409-3p and miR-409-5p located within the embryonically and developmentally regulated DLK1-DIO3 (delta-like 1 homolog-deiodinase, iodothyronine 3) cluster on human chromosome 14. The findings in cell lines were further validated in human prostate cancer tissues. Strikingly, ectopic expression of miR-409 in normal prostate fibroblasts conferred a cancer-associated stroma-like phenotype and led to the release of miR-409 via extracellular vesicles to promote tumor induction and epithelial-to-mesenchymal transition in vitro and in vivo. miR-409 promoted tumorigenesis through repression of tumor suppressor genes such as Ras suppressor 1 and stromal antigen 2. Thus, stromal fibroblasts derived miR-409-induced tumorigenesis, epithelial-to-mesenchymal transition and stemness of the epithelial cancer cells in vivo. Therefore, miR-409 appears to be an attractive therapeutic target to block the vicious cycle of tumor-stromal interactions that plagues prostate cancer patients.

Original languageEnglish
Pages (from-to)2690-2699
Number of pages10
JournalOncogene
Volume34
Issue number21
DOIs
Publication statusPublished - May 21 2015

Fingerprint

Epithelial-Mesenchymal Transition
Prostate
Carcinogenesis
Fibroblasts
Neoplasms
Prostatic Neoplasms
Chromosomes, Human, Pair 14
Iodide Peroxidase
Untranslated RNA
Disease Resistance
Tumor Microenvironment
Plague
Human Chromosomes
Tumor Suppressor Genes
MicroRNAs
Drug Resistance
Epigenomics
Cell Communication
Disease Progression
Dissection

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics
  • Medicine(all)

Cite this

Stromal fibroblast-derived miR-409 promotes epithelial-to-mesenchymal transition and prostate tumorigenesis. / Josson, S.; Gururajan, M.; Sung, S. Y.; Hu, P.; Shao, C.; Zhau, H. E.; Liu, C.; Lichterman, J.; Duan, P.; Li, Q.; Rogatko, A.; Posadas, E. M.; Haga, C. L.; Chung, L. W K.

In: Oncogene, Vol. 34, No. 21, 21.05.2015, p. 2690-2699.

Research output: Contribution to journalArticle

Josson, S, Gururajan, M, Sung, SY, Hu, P, Shao, C, Zhau, HE, Liu, C, Lichterman, J, Duan, P, Li, Q, Rogatko, A, Posadas, EM, Haga, CL & Chung, LWK 2015, 'Stromal fibroblast-derived miR-409 promotes epithelial-to-mesenchymal transition and prostate tumorigenesis', Oncogene, vol. 34, no. 21, pp. 2690-2699. https://doi.org/10.1038/onc.2014.212
Josson, S. ; Gururajan, M. ; Sung, S. Y. ; Hu, P. ; Shao, C. ; Zhau, H. E. ; Liu, C. ; Lichterman, J. ; Duan, P. ; Li, Q. ; Rogatko, A. ; Posadas, E. M. ; Haga, C. L. ; Chung, L. W K. / Stromal fibroblast-derived miR-409 promotes epithelial-to-mesenchymal transition and prostate tumorigenesis. In: Oncogene. 2015 ; Vol. 34, No. 21. pp. 2690-2699.
@article{fffb4e34bf5947f49dc78d462faebcb5,
title = "Stromal fibroblast-derived miR-409 promotes epithelial-to-mesenchymal transition and prostate tumorigenesis",
abstract = "Tumor-stromal interaction is a dynamic process that promotes tumor growth and metastasis via cell-cell interaction and extracellular vesicles. Recent studies demonstrate that stromal fibroblast-derived molecular signatures can be used to predict disease progression and drug resistance. To identify the epigenetic role of stromal noncoding RNAs in tumor-stromal interactions in the tumor microenvironment, we performed microRNA profiling of patient cancer-associated prostate stromal fibroblasts isolated by laser capture dissection microscopy and in bone-associated stromal models. We found specific upregulation of miR-409-3p and miR-409-5p located within the embryonically and developmentally regulated DLK1-DIO3 (delta-like 1 homolog-deiodinase, iodothyronine 3) cluster on human chromosome 14. The findings in cell lines were further validated in human prostate cancer tissues. Strikingly, ectopic expression of miR-409 in normal prostate fibroblasts conferred a cancer-associated stroma-like phenotype and led to the release of miR-409 via extracellular vesicles to promote tumor induction and epithelial-to-mesenchymal transition in vitro and in vivo. miR-409 promoted tumorigenesis through repression of tumor suppressor genes such as Ras suppressor 1 and stromal antigen 2. Thus, stromal fibroblasts derived miR-409-induced tumorigenesis, epithelial-to-mesenchymal transition and stemness of the epithelial cancer cells in vivo. Therefore, miR-409 appears to be an attractive therapeutic target to block the vicious cycle of tumor-stromal interactions that plagues prostate cancer patients.",
author = "S. Josson and M. Gururajan and Sung, {S. Y.} and P. Hu and C. Shao and Zhau, {H. E.} and C. Liu and J. Lichterman and P. Duan and Q. Li and A. Rogatko and Posadas, {E. M.} and Haga, {C. L.} and Chung, {L. W K}",
year = "2015",
month = "5",
day = "21",
doi = "10.1038/onc.2014.212",
language = "English",
volume = "34",
pages = "2690--2699",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "21",

}

TY - JOUR

T1 - Stromal fibroblast-derived miR-409 promotes epithelial-to-mesenchymal transition and prostate tumorigenesis

AU - Josson, S.

AU - Gururajan, M.

AU - Sung, S. Y.

AU - Hu, P.

AU - Shao, C.

AU - Zhau, H. E.

AU - Liu, C.

AU - Lichterman, J.

AU - Duan, P.

AU - Li, Q.

AU - Rogatko, A.

AU - Posadas, E. M.

AU - Haga, C. L.

AU - Chung, L. W K

PY - 2015/5/21

Y1 - 2015/5/21

N2 - Tumor-stromal interaction is a dynamic process that promotes tumor growth and metastasis via cell-cell interaction and extracellular vesicles. Recent studies demonstrate that stromal fibroblast-derived molecular signatures can be used to predict disease progression and drug resistance. To identify the epigenetic role of stromal noncoding RNAs in tumor-stromal interactions in the tumor microenvironment, we performed microRNA profiling of patient cancer-associated prostate stromal fibroblasts isolated by laser capture dissection microscopy and in bone-associated stromal models. We found specific upregulation of miR-409-3p and miR-409-5p located within the embryonically and developmentally regulated DLK1-DIO3 (delta-like 1 homolog-deiodinase, iodothyronine 3) cluster on human chromosome 14. The findings in cell lines were further validated in human prostate cancer tissues. Strikingly, ectopic expression of miR-409 in normal prostate fibroblasts conferred a cancer-associated stroma-like phenotype and led to the release of miR-409 via extracellular vesicles to promote tumor induction and epithelial-to-mesenchymal transition in vitro and in vivo. miR-409 promoted tumorigenesis through repression of tumor suppressor genes such as Ras suppressor 1 and stromal antigen 2. Thus, stromal fibroblasts derived miR-409-induced tumorigenesis, epithelial-to-mesenchymal transition and stemness of the epithelial cancer cells in vivo. Therefore, miR-409 appears to be an attractive therapeutic target to block the vicious cycle of tumor-stromal interactions that plagues prostate cancer patients.

AB - Tumor-stromal interaction is a dynamic process that promotes tumor growth and metastasis via cell-cell interaction and extracellular vesicles. Recent studies demonstrate that stromal fibroblast-derived molecular signatures can be used to predict disease progression and drug resistance. To identify the epigenetic role of stromal noncoding RNAs in tumor-stromal interactions in the tumor microenvironment, we performed microRNA profiling of patient cancer-associated prostate stromal fibroblasts isolated by laser capture dissection microscopy and in bone-associated stromal models. We found specific upregulation of miR-409-3p and miR-409-5p located within the embryonically and developmentally regulated DLK1-DIO3 (delta-like 1 homolog-deiodinase, iodothyronine 3) cluster on human chromosome 14. The findings in cell lines were further validated in human prostate cancer tissues. Strikingly, ectopic expression of miR-409 in normal prostate fibroblasts conferred a cancer-associated stroma-like phenotype and led to the release of miR-409 via extracellular vesicles to promote tumor induction and epithelial-to-mesenchymal transition in vitro and in vivo. miR-409 promoted tumorigenesis through repression of tumor suppressor genes such as Ras suppressor 1 and stromal antigen 2. Thus, stromal fibroblasts derived miR-409-induced tumorigenesis, epithelial-to-mesenchymal transition and stemness of the epithelial cancer cells in vivo. Therefore, miR-409 appears to be an attractive therapeutic target to block the vicious cycle of tumor-stromal interactions that plagues prostate cancer patients.

UR - http://www.scopus.com/inward/record.url?scp=84930274589&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84930274589&partnerID=8YFLogxK

U2 - 10.1038/onc.2014.212

DO - 10.1038/onc.2014.212

M3 - Article

C2 - 25065597

AN - SCOPUS:84930274589

VL - 34

SP - 2690

EP - 2699

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 21

ER -