Stromal fibroblast-derived miR-409 promotes epithelial-to-mesenchymal transition and prostate tumorigenesis
Stromal fibroblast-derived miR-409 promotes epithelial-to-mesenchymal transition and prostate tumorigenesis
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DOI：
10.1038/onc.2014.212
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发表时间：
2015-05-21
期刊：
影响因子：
8
通讯作者：
Chung, L. W. K.
中科院分区：
文献类型：
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作者：
Josson, S.;Gururajan, M.;Chung, L. W. K.
肿瘤-基质相互作用是一个动态过程，通过细胞-细胞相互作用和细胞外囊泡促进肿瘤生长和转移。最近的研究表明，基质成纤维细胞衍生的分子特征可用于预测疾病进展和耐药性。为了确定基质非编码 RNA 在肿瘤微环境中肿瘤-基质相互作用中的表观遗传作用，我们对通过激光捕获解剖显微镜分离的患者癌症相关前列腺基质成纤维细胞和骨相关基质模型进行了 microRNA 分析。我们发现 miR-409-3p 和 miR-409-5p 的特异性上调位于人类 14 号染色体上胚胎和发育调节的 DLK1-DIO3（δ 样 1 同源物脱碘酶，碘甲状腺原氨酸 3）簇内。细胞系中的发现在人类前列腺癌组织中得到了进一步验证。引人注目的是，正常前列腺成纤维细胞中 miR-409 的异位表达赋予癌症相关基质样表型，并导致 miR-409 通过细胞外囊泡释放，从而在体外和体内促进肿瘤诱导和上皮间质转化。 miR-409通过抑制肿瘤抑制基因（例如Ras抑制子1和基质抗原2）促进肿瘤发生。因此，基质成纤维细胞衍生的miR-409诱导肿瘤发生、上皮间质转化和体内上皮癌细胞的干性。因此，miR-409似乎是一个有吸引力的治疗靶点，可以阻止困扰前列腺癌患者的肿瘤-基质相互作用的恶性循环。
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.