MiR-106b induces cell radioresistance via the PTEN/PI3K/AKT pathways and p21 in colorectal cancer.
MiR-106b induces cell radioresistance via the PTEN/PI3K/AKT pathways and p21 in colorectal cancer.
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DOI：
10.1186/s12967-015-0592-z
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发表时间：
2015-08-04
影响因子：
7.4
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
Zheng L;Zhang Y;Liu Y;Zhou M;Lu Y;Yuan L;Zhang C;Hong M;Wang S;Li X
放射抗性是结肠直肠癌（CRC）患者治疗中的一个挑战。个体对术前放射治疗的反应不同，迫切需要靶向治疗。microRNA（miRNAs）参与了重要的生物学活性，包括化学抗性和辐射抗性。一些研究表明，miRNA在使细胞对电离辐射（IR）敏感方面发挥重要作用。miR-106 b是miR-106 b-25簇的成员，在许多人类癌症（包括CRC）中经常失调。然而，miR-106 b在放射抗性中的功能目前知之甚少。本研究通过一系列的体内外研究来探讨miR-106 b在结直肠癌细胞辐射抗性中的作用。我们发现miR-106 b过表达可诱导SW 620细胞在体内外对IR产生抵抗。相应地，在SW 480中敲低miR-106 b产生相反的效果。此外，miR-106 b过表达可增强IR条件下或无IR条件下的肿瘤起始细胞能力，如殖民地球形成能力和干细胞相关基因（CD 133，Sox 2）的上调。我们通过使用靶标预测算法和荧光素酶测定进一步鉴定了PTEN和p21作为miR-106 b的新的直接靶标。miR-106 b的过表达降低了PTEN和p21的表达，增加了PTEN下游的p-AKT的表达。在稳定过表达miR-106 b的细胞中恢复PTEN或p21的表达可以挽救miR-106 b对细胞辐射抗性的作用。总之，肿瘤起始细胞能力的获得赋予CRC细胞抵抗辐射的潜力。这些结果表明，miR-106 b可以通过直接靶向PTEN和p21来诱导细胞的辐射抗性，这一过程伴随着肿瘤起始细胞能力的增强，这被普遍证实与辐射抗性相关。我们的数据表明，miR-106 b至少部分诱导CRC中的细胞辐射抗性。本文的在线版本（doi：10.1186/s12967-015-0592-z）包含补充材料，可供授权用户使用。
Radioresistance is a challenge in the treatment of patients with colorectal cancer (CRC). Individuals display different therapeutic responses to preoperative radiotherapy, and the need of targeted therapies is urgent. MicroRNAs (miRNAs) are involved in essential biological activities, including chemoresistance and radioresistance. Several research studies have indicated that miRNA played an important role in sensitizing cells to ionizing radiation (IR). MiR-106b, a member of the miR-106b-25 cluster, is frequently dysregulated in many human cancers, including CRC. However, the function of miR-106b in radioresistance is currently poorly understood. A series of in vitro and in vivo studies were performed to investigate the roles of miR-106b on cell radioresistance in CRC. We found overexpression of miR-106b could induce resistance to IR in vitro and in vivo in SW620 cells. Correspondingly, knocking down miR-106b in SW480 yielded the opposite effect. In addition, overexpression of miR-106b could enhance the tumour-initiating cell capacity without or with IR condition, such as the colony sphere formation capacity and the upregulation of stemness-related genes (CD133, Sox2). We further identified PTEN and p21 as novel direct targets of miR-106b by using target prediction algorithms and a luciferase assay. Overexpression of miR-106b reduced the expression of PTEN and p21 and increased the expression of p-AKT, which is a downstream of PTEN. Restoring the expression of PTEN or p21 in stably miR-106b-overexpressed cells could rescue the effect of miR-106b on cell radioresistance. Together, the acquisition of tumour-initiating cell capacity endowed CRC cells with the potential of resistance to irradiation. These observations illustrated that miR-106b could induce cell radioresistance by directly targeting PTEN and p21, this process was accompanied by tumour-initiating cell capacity enhancement, which is universally confirmed to be associated with radioresistance. Our data suggested that miR-106b at least partly induces cell radioresistance in CRC. The online version of this article (doi:10.1186/s12967-015-0592-z) contains supplementary material, which is available to authorized users.