PDF(Pubmed)
Abstract：
Quercetin (Qc) inhibits cell proliferation and induces apoptosis in a variety of cancer cells. The molecular mechanism of action has not been fully elucidated; however, interplay with some miRNAs has been reported, specifically with miR-27a, an onco-miRNA overexpressed in several malignancies. Here, we show that Qc reduces cell viability and induces apoptosis in HCT116 and HT-29 colon cancer cells, by upregulating negative modulators of proliferation pathways such as Sprouty2, PTEN and SFRP1. These are targets of miR-27a whose high expression is reduced by Qc. Moreover, miR-23a, and miR-24-2, the two other components of the unique gene cluster, and the pri-miRNA transcript are reduced, evoking a transcriptional regulation of the entire cluster by Sp1. Mechanistically, we show that Qc is rapidly internalized and localizes in the nucleus, where it likely interacts with Sp1, inducing its proteasomal degradation. Sp1 is further repressed by ZBTB10, an Sp1 competitor for DNA binding that is an miR-27a target and whose levels increase following Qc. SP1 mRNA is also reduced, supporting the regulation of its own gene transcription. Finally, Sp1 knockdown elicits the impaired transcription of the entire cluster and the upregulation of the miR-27a targets, phenocopying the effects of Qc. Through this dual mode of action, Qc counteracts the protumoral Sp1-miR-27a axis, opening the way for novel therapies based on its association as neoadjuvant with known anticancer treatments.
摘要：
槲皮素（Qc）抑制细胞增殖并诱导多种癌细胞凋亡。作用的分子机制尚未完全阐明；然而，已经报道了与一些miRNA的相互作用，特别是miR-27a，在几种恶性肿瘤中过度表达的onco-miRNA。这里,我们显示Qc降低HCT116和HT-29结肠癌细胞的细胞活力并诱导细胞凋亡，通过上调增殖途径如Sprouty2、PTEN和SFRP1的负调节剂。这些是miR-27a的靶标,其高表达被Qc降低。此外，miR-23a,和miR-24-2，独特基因簇的另外两个组成部分，pri-miRNA转录物减少，通过Sp1引起整个簇的转录调节。机械上,我们表明Qc被迅速内化并定位在细胞核中，它可能与Sp1相互作用，诱导其蛋白酶体降解。Sp1进一步被ZBTB10抑制,ZBTB10是DNA结合的Sp1竞争物,其是miR-27a靶标,其水平在Qc后增加。SP1mRNA也减少，支持其自身基因转录的调控。最后,Sp1敲低引起整个簇的转录受损和miR-27a靶标的上调，对Qc的影响进行表型检验。通过这种双重行动模式，Qc抵消质子Sp1-miR-27a轴，基于其作为新辅助治疗与已知抗癌治疗的关联，为新疗法开辟了道路。
