title: Loss of let-7 microRNA upregulates IL-6 in bone marrow-derived mesenchymal stem cells triggering a reactive stromal response to prostate cancer.
abstract: Bone marrow-derived mesenchymal stem cells (MSCs) are able to migrate to tumors, where they promote tumorigenesis and cancer metastasis. However, the molecular phenotype of the recruited MSCs at the tumor microenvironment and the genetic programs underlying their role in cancer progression remains largely unknown. By using a three-dimensional rotary wall vessel coculture system in which human MSCs were grown alone or in close contact with LNCaP, C4-2 or PC3 prostate cancer cell lines, we established in vitro matched pairs of normal and cancer-associated MSC derivatives to study the stromal response of MSCs to prostate cancer. We observed that prostate cancer-associated MSCs acquired a higher potential for adipogenic differentiation and exhibited a stronger ability to promote prostate cancer cell migration and invasion compared with normal MSCs both in vitro and in experimental animal models. The enhanced adipogenesis and the pro-metastatic properties were conferred by the high levels of IL-6 secretion by cancer-associated MSCs and were reversible by functionally inhibiting of IL-6. We also found that IL-6 is a direct target gene for the let-7 microRNA, which was downregulated in cancer-associated MSCs. The overexpression of let-7 via the transfection of let-7 precursors decreased IL-6 expression and repressed the adipogenic potential and metastasis-promoting activity of cancer-associated MSCs, which was consistent with the inhibition of IL-6 3'UTR luciferase activity. Conversely, the treatment of normal MSCs with let-7 inhibitors resulted in effects similar to those seen with IL-6. Taken together, our data demonstrated that MSCs co-evolve with prostate cancer cells in the tumor microenvironment, and the downregulation of let-7 by cancer-associated MSCs upregulates IL-6 expression. This upregulation triggers adipogenesis and facilitates prostate cancer progression. These findings not only provide key insights into the molecular basis of tumor-stroma interactions but also pave the way for new treatments for metastatic prostate cancer.
authors: Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan ; Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan ; The Institute for Translational Medicine, Taipei Medical University, Taipei, Taiwan.
authors: Shian-Ying
authors: SY
authors: Sung
authors: Chia-Hui
authors: CH
authors: Liao
authors: Hsun-Pai
authors: HP
authors: Wu
authors: Wan-Chi
authors: WC
authors: Hsiao
authors: I-Hui
authors: IH
authors: Wu
authors: Jinpu
authors: Yu
authors: Sue-Hwa
authors: SH
authors: Lin
authors: Chia-Ling
authors: CL
authors: Hsieh
mesh_terms: D000818:Animals; D019149:Bioreactors; D001854:Bone Marrow Cells / Q000473:pathology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D019070:Cell Lineage; D049109:Cell Proliferation; D018920:Coculture Techniques; D018450:Disease Progression; D057809:HEK293 Cells; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D017154:Stromal Cells / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D035683:MicroRNAs; C487931:mirnlet7 microRNA, human
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