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.
authors: Uro-Oncology Research Program, Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: S
authors: S
authors: Josson
authors: Uro-Oncology Research Program, Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: M
authors: M
authors: Gururajan
authors: The Ph.D. program for Translational Medicine, Taipei Medical University, Taipei, Taiwan.
authors: S Y
authors: SY
authors: Sung
authors: Uro-Oncology Research Program, Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: P
authors: P
authors: Hu
authors: Uro-Oncology Research Program, Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: C
authors: C
authors: Shao
authors: Uro-Oncology Research Program, Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: H E
authors: HE
authors: Zhau
authors: Uro-Oncology Research Program, Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: C
authors: C
authors: Liu
authors: Uro-Oncology Research Program, Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: J
authors: J
authors: Lichterman
authors: Uro-Oncology Research Program, Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: P
authors: P
authors: Duan
authors: Biostatistics and Bioinformatics, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: Q
authors: Q
authors: Li
authors: Biostatistics and Bioinformatics, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: A
authors: A
authors: Rogatko
authors: Uro-Oncology Research Program, Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: E M
authors: EM
authors: Posadas
authors: The Scripps Research Institute, Jupiter, FL, USA.
authors: C L
authors: CL
authors: Haga
authors: Uro-Oncology Research Program, Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: L W K
authors: LW
authors: Chung
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005347:Fibroblasts / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D011467:Prostate / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D059016:Tumor Microenvironment / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: C572367:MIRN409 microRNA, human; D035683:MicroRNAs