Cancer-secreted hsa-miR-940 induces an osteoblastic phenotype in the bone metastatic microenvironment via targeting ARHGAP1 and FAM134A
| Autor: | Shu Takeda, Kyoko Hashimoto, Yo Mabuchi, Satoko Sunamura, Hiroki Ochi, Mitsuru Futakuchi, Keisuke Ae, Kenta Yao, Toru Fukuda, Atsushi Okawa, Nobuyoshi Kosaka, Hiroaki Kanda, Takahiro Ochiya, Shingo Sato, Chihiro Akazawa |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Cell type Medical Sciences Bone Neoplasms Breast Neoplasms Biology Adenocarcinoma Bone remodeling 03 medical and health sciences Mice cancer-secreted microRNA Cell Line Tumor medicine Animals Humans exosome Tumor microenvironment Multidisciplinary Mesenchymal stem cell GTPase-Activating Proteins Cancer Bone metastasis Membrane Proteins Prostatic Neoplasms Mesenchymal Stem Cells Neoplasms Experimental Biological Sciences medicine.disease prostate cancer Microvesicles osteoblastic bone metastasis MicroRNAs 030104 developmental biology Cancer cell Bone Substitutes Cancer research Female bone microenvironment |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 |
| Popis: | Significance Prostate cancer is one of most common cancers in men worldwide, and osteoblastic bone metastasis is frequently observed in prostate cancer patients. However, the mechanisms responsible for the predominantly osteoblastic phenotype have not been fully elucidated. Cancer-secreted microRNAs (miRNAs) were recently shown to be significant in the modification of the tumor microenvironment. Here, hsa-miR-940, which was highly secreted by prostate cancer cells, promoted osteogenic differentiation of human mesenchymal stem cells in vitro, and induced extensive osteoblastic lesions in the bone metastatic microenvironment in vivo. Our study provides a demonstration that osteoblastic bone metastasis can be induced by miRNAs secreted by cancer cells in the bone microenvironment. Bone metastatic lesions are classified as osteoblastic or osteolytic lesions. Prostate and breast cancer patients frequently exhibit osteoblastic-type and osteolytic-type bone metastasis, respectively. In metastatic lesions, tumor cells interact with many different cell types, including osteoblasts, osteoclasts, and mesenchymal stem cells, resulting in an osteoblastic or osteolytic phenotype. However, the mechanisms responsible for the modification of bone remodeling have not been fully elucidated. MicroRNAs (miRNAs) are transferred between cells via exosomes and serve as intercellular communication tools, and numerous studies have demonstrated that cancer-secreted miRNAs are capable of modifying the tumor microenvironment. Thus, cancer-secreted miRNAs can induce an osteoblastic or osteolytic phenotype in the bone metastatic microenvironment. In this study, we performed a comprehensive expression analysis of exosomal miRNAs secreted by several human cancer cell lines and identified eight types of human miRNAs that were highly expressed in exosomes from osteoblastic phenotype-inducing prostate cancer cell lines. One of these miRNAs, hsa-miR-940, significantly promoted the osteogenic differentiation of human mesenchymal stem cells in vitro by targeting ARHGAP1 and FAM134A. Interestingly, although MDA-MB-231 breast cancer cells are commonly known as an osteolytic phenotype-inducing cancer cell line, the implantation of miR-940–overexpressing MDA-MB-231 cells induced extensive osteoblastic lesions in the resulting tumors by facilitating the osteogenic differentiation of host mesenchymal cells. Our results suggest that the phenotypes of bone metastases can be induced by miRNAs secreted by cancer cells in the bone microenvironment. |
| Databáze: | OpenAIRE |
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