MicroRNA-320 suppresses the stem cell-like characteristics of prostate cancer cells by downregulating the Wnt/beta-catenin signaling pathway
MicroRNA-320 suppresses the stem cell-like characteristics of prostate cancer cells by downregulating the Wnt/beta-catenin signaling pathway
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DOI：
10.1093/carcin/bgs371
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发表时间：
2013-03-01
期刊：
影响因子：
4.7
通讯作者：
Chen, Yuh-Ling
中科院分区：
文献类型：
--
作者：
Hsieh, I-Shan;Chang, Kung-Chao;Chen, Yuh-Ling
前列腺癌（PCa）是全球男性死亡率和发病率的主要原因，新出现的证据表明，CD44（高）前列腺肿瘤启动细胞（TICs）与其预后不良有关。尽管microrna在人类癌症中经常失调，但microrna对PCa恶性肿瘤的影响以及靶向tic相关microrna是否抑制PCa进展仍不清楚。在本研究中，我们发现miR-320在PCa中显著下调。在体外和体内，在PCa细胞中过表达miR-320可降低PCa的肿瘤发生。mir -320过表达的PCa细胞的全局基因表达谱显示，Wnt/-catenin通路下游靶基因和肿瘤干细胞标志物显著降低。MicroRNA-320通过靶向-catenin mRNA的3-未翻译区抑制-catenin的表达。在前列腺癌细胞和临床PCa标本的CD44（高）亚群中也发现miR-320的降低与-catenin的增加相关。有趣的是，miR-320的敲低显著增加了癌症干细胞样特性，如肿瘤球形成、化疗耐药和致瘤能力，尽管丰富了PCa细胞中的干细胞样tic群体。此外，前列腺干细胞样tic中miR-320表达的增加显著抑制了PCa细胞的干细胞样特性。这些结果支持miR-320是前列腺前列腺癌的关键负调节因子，并提示开发miR-320作为一种新的治疗剂可能对前列腺癌的治疗有益。
Prostate cancer (PCa) is a leading cause of mortality and morbidity in men worldwide, and emerging evidence suggests that the CD44(high) prostate tumor-initiating cells (TICs) are associated with its poor prognosis. Although microRNAs are frequently dysregulated in human cancers, the influence of microRNAs on PCa malignancy and whether targeting TIC-associated microRNAs inhibit PCa progression remain unclear. In this study, we found that miR-320 is significantly downregulated in PCa. Overexpression of miR-320 in PCa cells decreases PCa tumorigenesis in vitro and in vivo. Global gene expression profiling of miR-320-overexpressing PCa cells reveals that downstream target genes of Wnt/-catenin pathway and cancer stem cell markers are significantly decreased. MicroRNA-320 inhibits -catenin expression by targeting the 3-untranslated region of -catenin mRNA. The reduction of miR-320 associated with increased -catenin was also found in CD44(high) subpopulation of prostate cancer cells and clinical PCa specimens. Interestingly, knockdown of miR-320 significantly increases the cancer stem-like properties, such as tumorsphere formation, chemoresistance and tumorigenic abilities, although enriching the population of stem-like TICs among PCa cells. Furthermore, increased miR-320 expression in prostate stem-like TICs significantly suppresses stem cell-like properties of PCa cells. These results support that miR-320 is a key negative regulator in prostate TICs, and suggest developing miR-320 as a novel therapeutic agent may offer benefits for PCa treatment.