Genome-wide screen identified let-7c/miR-99a/miR-125b regulating tumor progression and stem-like properties in cholangiocarcinoma.
Genome-wide screen identified let-7c/miR-99a/miR-125b regulating tumor progression and stem-like properties in cholangiocarcinoma.
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全基因组筛选发现let-7c/miR-99a/miR-125b调节胆管癌的肿瘤进展和干细胞样特性
DOI：
10.1038/onc.2015.396
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发表时间：
2016-06-30
期刊：
影响因子：
8
通讯作者：
Chen YQ
中科院分区：
文献类型：
--
作者：
Lin KY;Ye H;Han BW;Wang WT;Wei PP;He B;Li XJ;Chen YQ
胆管癌（CCA）是一种预后不良的恶性肿瘤，由胆管细胞的恶性转化引起，与胆管上皮的慢性炎症有关。到目前为止，炎症促进CCA的起源和肿瘤过程的分子机制仍然不清楚，需要充分阐明。在此，我们利用小RNA测序来确定microRNA（miRNA）在CCA中的表达谱，我们发现let-7 c、miR-99 a和miR-125 b这三种同一簇的miRNA在CCA中下调，并靶向白细胞介素6（IL-6）、IL-6 R和1型胰岛素样生长因子，其是IL-6/信号转导子和激活子3（STAT 3）途径的重要细胞因子和受体，并且在炎症和CCA起始中具有关键作用。我们还发现，let-7 c、miR-99 a或miR-125 b的强制表达可以降低STAT 3的活性，从而进一步抑制CCA体内致瘤性，并抑制CCA细胞的体外迁移和侵袭。令人惊讶的是，let-7 c/miR-99 a/miR-125 b簇还通过下调CD 133和CD 44显著降低CCA细胞产生癌症干细胞样乳腺球的能力，这表明let-7 c、miR-99 a和miR-125 b通过调节炎症和干细胞样性质在CCA中发挥关键作用。我们的研究结果显示了miRNA与炎症之间的潜在联系，并为通过IL-6/STAT 3靶向CCA开发基于miRNA的治疗提供了潜在的治疗策略。
Cholangiocarcinoma (CCA), which is a poor prognosis malignancy that arises from the malignant transformation of cholangiocytes, is associated with chronic inflammation of the biliary epithelium. Thus far, the molecular mechanisms of the origin and neoplastic processes of CCA that are promoted by inflammation are still unclear and need to be fully elucidated. Here using small RNA sequencing to determine the microRNA (miRNA) expression profiles in CCA, we found that let-7c, miR-99a and miR-125b, which are three miRNAs of the same cluster, were downregulated in CCA and targeted interleukin 6 (IL-6), IL-6R and type 1 insulin-like growth factor, which are important cytokines and receptors of the IL-6/signal transducer and activator 3 (STAT3) pathway and have key roles in inflammation and CCA initiation. We also found that enforced expression of let-7c, miR-99a or miR-125b could reduce the activity of STAT3 and further suppress CCA tumorigenicity in vivo and inhibit the migration and invasion of CCA cells in vitro. Surprisingly, let-7c/miR-99a/miR-125b cluster also significantly decreased the ability of CCA cells for cancer stem cell-like mammosphere generation by downregulating CD133 and CD44, which suggests the pivotal roles of let-7c, miR-99a and miR-125b in CCA by regulating both inflammation and stem-like properties. Our findings showed potential links between miRNAs and inflammation, and provide a potential treatment strategy for developing an miRNA-based therapy via IL-6/STAT3 targeting for CCA.