Direct Upregulation of STAT3 by MicroRNA-551b-3p Deregulates Growth and Metastasis of Ovarian Cancer.
Direct Upregulation of STAT3 by MicroRNA-551b-3p Deregulates Growth and Metastasis of Ovarian Cancer.
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DOI：
10.1016/j.celrep.2016.04.034
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发表时间：
2016-05-17
期刊：
影响因子：
8.8
通讯作者：
Mills GB
中科院分区：
文献类型：
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作者：
Chaluvally-Raghavan P;Jeong KJ;Pradeep S;Silva AM;Yu S;Liu W;Moss T;Rodriguez-Aguayo C;Zhang D;Ram P;Liu J;Lu Y;Lopez-Berestein G;Calin GA;Sood AK;Mills GB
3q26.2扩增导致成熟microRNA miR551b-3p在高级别浆液性卵巢癌中表达增加，与临床预后不良有关。重要的是，miR551b-3p在体外和体内都有助于抵抗癌细胞的凋亡，增加癌细胞的存活和增殖。MiR551b-3p上调STAT3蛋白水平，而STAT3是miR551b-3p影响细胞增殖所必需的。我们证明，miR551b-3p没有像预期的那样降低靶mRNA的水平，而是与STAT3启动子上的互补序列结合，招募RNA聚合酶II和Twist1转录因子来激活STAT3的转录，从而直接上调STAT3的表达。此外，抗miR551b在体内外降低了STAT3在卵巢癌细胞中的表达，并抑制了卵巢癌细胞在体内的生长。综上所述，我们的数据证明了miR551b-3p在转录激活中的作用。因此，miR551b-3p有望成为卵巢癌的候选生物标志物和治疗靶点。
3q26.2 amplification in high-grade serous ovarian cancer leads to increased expression of mature microRNA miR551b-3p, which is associated with poor clinical outcome. Importantly, miR551b-3p contributes to resistance to apoptosis and increased survival and proliferation of cancer cells in vitro and in vivo. miR551b-3p up-regulates STAT3 protein levels with STAT3 being required for the effects of miR551b-3p on cell proliferation. Rather than decreasing levels of target mRNA as expected, we demonstrate that miR551b-3p binds a complementary sequence on the STAT3 promoter recruiting RNA Polymerase II and the TWIST1 transcription factor to activate STAT3 transcription and thus directly upregulates STAT3 expression. Furthermore, anti-miR551b reduced STAT3 expression in ovarian cancer cells in vitro and in vivo and reduced ovarian cancer growth in vivo. Together our data demonstrates a role for miR551b-3p in transcriptional activation. Thus miR551b-3p represents a promising candidate biomarker and therapeutic target in ovarian cancer.