212 LOSS OF LET-7 MICRORNA EXPRESSION UPREGULATES IL-6 IN MESENCHYMAL STEM CELLS AND TRIGGERS REACTIVE STROMAL RESPONSES TO PROSTATE CANCER

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research (I)1 Apr 2013212 LOSS OF LET-7 MICRORNA EXPRESSION UPREGULATES IL-6 IN MESENCHYMAL STEM CELLS AND TRIGGERS REACTIVE STROMAL RESPONSES TO PROSTATE CANCER Shian-Ying Sung, Chia-Hui Liao, Wen-Chi Hsiao, Sue-Hwa Lin, and Chia-Ling Hsieh Shian-Ying SungShian-Ying Sung Taichung, Taiwan More articles by this author , Chia-Hui LiaoChia-Hui Liao Taichung, Taiwan More articles by this author , Wen-Chi HsiaoWen-Chi Hsiao Taichung, Taiwan More articles by this author , Sue-Hwa LinSue-Hwa Lin Houston, TX More articles by this author , and Chia-Ling HsiehChia-Ling Hsieh Taichung, Taiwan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1592AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES It is widely accepted that bone marrow-derived mesenchymal stem cells (MSCs) are able to migrate and home to tumors, where they promote the tumorigenesis and cancer metastasis. However the molecular phenotype of the MSCs at the tumor microenvironment and the genetic programs underlying their property in cancer progression remains mainly unknown. We therefore intent to understand whether bone marrow-derived MSCs “co-evolve” with prostate cancer cells once they are recruited and incorporated into the tumor stroma. METHODS Matched pairs of human normal and cancer-associated MSC cell lines were generated using a three-dimensional rotary wall vessel coculture system, where MSCs grow alone or closely contacted with LNCaP, C4-2 or PC3 prostate cancer cell lines. The stemness of MSC derivatives was evaluated by the immunophenotypic expression, mesoderm differentiation, and expression of pluripotency-associated markers. Transwell migration/invasion assay and in vivo chimeric tumor model were used to assess pro-metastatic property of MSCs. Array analysis and functional validation was performed to identify the key cytokines and microRNAs involved in reactive phenotypes of MSCs. Transfection and luciferase assays were used to validate the microRNA targets. RESULTS Prostate cancer-associated MSCs acquired higher potential of adipogenic differentiation and exhibited stronger activity in promoting prostate cancer cell migration and invasion compared to normal MSCs both in vitro and in chimeric tumor models. This enhanced adipogenesis and pro-metastatic property is conferred by the high IL-6 secretion levels of cancer-associated MSCs and is reversible by functional inhibition of IL-6. In addition, IL-6 is a putative target gene for let-7 microRNA that was downregulated in cancer-associated MSCs. Overexpression of let-7 by transfection of let-7 precursors decreased IL-6 expression, adipogenic potential and metastasis-promoting activity of cancer-associated MSCs, which was consistent with inhibition of IL-6 3'UTR luciferase activity. Treatment of MSCs with let-7 inhibitors resulted in effects similar to those with IL-6. CONCLUSIONS Our data demonstrated that loss of let-7 upregulates IL-6 in cancer-associated MSCs that triggers adipogenesis and facilitates prostate cancer metastasis. These findings not only provide key insights into the molecular basis of tumor-stroma interactions, but also pave the way for new treatment, such as let-7 replacement and IL-6 blockade therapy against metastatic prostate cancer. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e87 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Shian-Ying Sung Taichung, Taiwan More articles by this author Chia-Hui Liao Taichung, Taiwan More articles by this author Wen-Chi Hsiao Taichung, Taiwan More articles by this author Sue-Hwa Lin Houston, TX More articles by this author Chia-Ling Hsieh Taichung, Taiwan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...