Musashi-2, a novel oncoprotein promoting cervical cancer cell growth and invasion, is negatively regulated by p53-induced miR-143 and miR-107 activation.
Musashi-2, a novel oncoprotein promoting cervical cancer cell growth and invasion, is negatively regulated by p53-induced miR-143 and miR-107 activation.
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DOI：
10.1186/s13046-017-0617-y
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发表时间：
2017-10-26
期刊：
影响因子：
--
通讯作者：
Watari H
中科院分区：
文献类型：
--
作者：
Dong P;Xiong Y;Hanley SJB;Yue J;Watari H
尽管先前的研究已经显示出在多种肿瘤中靶向Musashi RNA结合蛋白2（MSI-2）的前景，但MSI-2在宫颈癌（CC）进展中的作用和机制以及MSI-2表达的调控仍不清楚。通过基因表达和生物信息学分析，以及功能获得和丧失测定，我们将MSI-2鉴定为一种新的致癌驱动因子和CC的不良预后标记。我们通过RNA免疫沉淀和荧光素酶检测探讨了MSI-2对c-FOS的调控作用，并通过荧光素酶检测证实了miR-143/miR-107对MSI-2的直接抑制作用。我们评估了天然抗生素Mithramycin A对CC细胞中p53、miR-143/miR-107和MSI-2表达的影响。 MSI-2 mRNA在CC组织中高度表达，其过表达与较低的总生存率相关。MSI-2通过直接结合c-FOS mRNA和增加c-FOS蛋白表达促进CC细胞生长、侵袭和球体形成。此外，miR-143/miR-107是两种直接结合并抑制CC细胞中MSI-2表达的肿瘤抑制miRNA，并且miR-143/miR-107的下调与不良患者预后相关。重要的是，我们发现p53通过升高miR-143/miR-107水平来降低MSI-2的表达，并且用天然抗生素Mithramycin A处理增加了p53和miR-143/miR-107的表达并降低了MSI-2的表达，从而抑制了CC细胞的增殖、侵袭和球体形成。这些结果表明，MSI-2在促进CC细胞的侵袭性表型中起着至关重要的作用，并且通过Mithramycin A通过激活p53来恢复miR-143/miR-107可能代表CC的新的治疗方法。
Although previous studies have shown promise for targeting Musashi RNA-binding protein 2 (MSI-2) in diverse tumors, the role and mechanism of MSI-2 for cervical cancer (CC) progression and the regulation of MSI-2 expression remains unclear. Using gene expression and bioinformatic analysis, together with gain- and loss-of-function assays, we identified MSI-2 as a novel oncogenic driver and a poor prognostic marker in CC. We explored the regulation of c-FOS by MSI-2 via RNA-immunoprecipitation and luciferase assay, and confirmed a direct inhibition of MSI-2 by miR-143/miR-107 using luciferase assay. We assessed the effect of a natural antibiotic Mithramycin A on p53, miR-143/miR-107 and MSI-2 expression in CC cells. MSI-2 mRNA is highly expressed in CC tissues and its overexpression correlates with lower overall survival. MSI-2 promotes CC cell growth, invasiveness and sphere formation through directly binding to c-FOS mRNA and by increasing c-FOS protein expression. Furthermore, miR-143/miR-107 are two tumor suppressor miRNAs that directly bind and inhibit MSI-2 expression in CC cells, and downregulation of miR-143/miR-107 associates with poor patient prognosis. Importantly, we found that p53 decreases the expression of MSI-2 through elevating miR-143/miR-107 levels, and treatment with a natural antibiotic Mithramycin A increased p53 and miR-143/miR-107 expression and reduced MSI-2 expression, resulting in the inhibition of CC cell proliferation, invasion and sphere formation. These results suggest that MSI-2 plays a crucial role in promoting the aggressive phenotypes of CC cells, and restoration of miR-143/miR-107 by Mithramycin A via activation of p53 may represent a novel therapeutic approach for CC.
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影响因子：
--
作者：
Konno Y;Dong P;Xiong Y;Suzuki F;Lu J;Cai M;Watari H;Mitamura T;Hosaka M;Hanley SJ;Kudo M;Sakuragi N
通讯作者：
Sakuragi N
影响因子：
--
作者：
Ihira K;Dong P;Xiong Y;Watari H;Konno Y;Hanley SJ;Noguchi M;Hirata N;Suizu F;Yamada T;Kudo M;Sakuragi N
通讯作者：
Sakuragi N
影响因子：
3.8
作者：
Anaya, Jordan
通讯作者：
Anaya, Jordan
影响因子：
--
作者：
Dong P;Ihira K;Hamada J;Watari H;Yamada T;Hosaka M;Hanley SJ;Kudo M;Sakuragi N
通讯作者：
Sakuragi N
影响因子：
2.6
作者：
Kaeda, Jaspal;Ringel, Frauke;le Coutre, Philipp
通讯作者：
le Coutre, Philipp