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首页> 外文期刊>Cell cycle >miR-221/222 control luminal breast cancer tumor progression by regulating different targets
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miR-221/222 control luminal breast cancer tumor progression by regulating different targets

机译：MiR-221/222通过调节不同的目标来控制腔乳腺癌肿瘤进展

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摘要

α6β4 integrin is an adhesion molecule for laminin receptors involved in tumor progression. We present a link between β4 integrin expression and miR-221/222 in the most prevalent human mammary tumor: luminal invasive carcinomas (Lum-ICs). Using human primary tumors that display different β4 integrin expression and grade, we show that miR-221/222 expression inversely correlates with tumor proliferating index, Ki67. Interestingly, most high-grade tumors express β4 integrin and low miR-221/222 levels. We ectopically transfected miR-221/222 into a human-derived mammary tumor cell line that recapitulates the luminal subtype to investigate whether miR-221/222 regulates β4 expression. We demonstrate that miR-221/222 overexpression results in β4 expression downregulation, breast cancer cell proliferation, and invasion inhibition. The role of miR-221/222 in driving β4 integrin expression is also confirmed via mutating the miR-221/222 seed sequence for β4 integrin 3′UTR. Furthermore, we show that these 2 miRNAs are also key breast cancer cell proliferation and invasion regulators, via the post-transcriptional regulation of signal transducer and activator of transcription 5A (STAT5A) and of a disintegrin and metalloprotease-17 (ADAM-17). We further confirm these data by silencing ADAM-17, using a dominant-negative or an activated STAT5A form. miR-221/222-driven β4 integrin, STAT5A, and ADAM-17 did not occur in MCF-10A cells, denoted "normal" breast epithelial cells, indicating that the mechanism is cancer cell-specific. These results provide the first evidence of a post-transcriptional mechanism that regulates β4 integrin, STAT5A, and ADAM-17 expression, thus controlling breast cancer cell proliferation and invasion. Pre-miR-221/222 use in the aggressive luminal subtype may be a powerful therapeutic anti-cancer strategy.
机译：α6β4整联蛋白是参与肿瘤进展的层粘连蛋白受体的粘附分子。我们在最普遍的人类乳腺肿瘤中呈β4整联蛋白表达和miR-221/222之间的联系：腔侵入癌（LUM-IC）。使用展示不同β4整联蛋白表达和等级的人的原发性肿瘤，我们表明miR-221/222表达与肿瘤增殖指数，Ki67相反。有趣的是，大多数高级肿瘤表达β4整联蛋白和低miR-221/222水平。我们将MiR-221/222强制转染到人源乳腺肿瘤细胞系中，该细胞系重新承载腔亚型以研究MIR-221/222是否调节β4表达。我们证明MIR-221/222过表达导致β4表达下调，乳腺癌细胞增殖和侵袭抑制。 MiR-221/222在驱动β4整合蛋白表达中的作用也通过突变β4整合蛋白3'UTR的miR-221/222种子序列来证实。此外，我们表明，通过转录的信号传感器和转录5a（stat5a）和Metallopotease-17（ADAM-17）的信号传感器和激活剂的后转录调节，这些2 miRNA也是关键的乳腺癌细胞增殖和侵袭调节剂。我们通过使用主导负面或激活的Stat5a表单来进一步通过沉默ADAM-17确认这些数据。 MIR-221/222驱动β4整合蛋白，STAT5a和ADAM-17在MCF-10A细胞中没有发生，表示“正常”乳房上皮细胞，表明该机制是癌细胞特异性。这些结果提供了调节β4整合蛋白，Stat5a和Adam-17表达的转录后机制的第一种证据，从而控制乳腺癌细胞增殖和侵袭。在侵袭性腔亚型中使用前MiR-221/222可能是一种强大的治疗性抗癌策略。

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  • 来源
    《Cell cycle》 |2014年第11期|共16页
  • 作者

    DentelliP.; TraversaM.; RossoA.; TogliattoG.; OlgasiC.; MarchiòC.; ProveroP.; LemboA.; BonG.; AnnaratoneL.; SapinoA.; FalcioniR.; BrizziM.F.;

  • 作者单位

    Department of Medical Sciences University of Torino Torino Italy;

    Department of Medical Sciences University of Torino Torino Italy;

    Department of Medical Sciences University of Torino Torino Italy;

    Department of Medical Sciences University of Torino Torino Italy;

    Department of Medical Sciences University of Torino Torino Italy;

    Department of Medical Sciences University of Torino Torino Italy;

    Department of Molecular Biotechnology and Health Sciences University of Torino Torino Italy;

    Department of Molecular Biotechnology and Health Sciences University of Torino Torino Italy;

    Department of Experimental Oncology Regina Elena National Cancer Institute Rome Italy;

    Department of Medical Sciences University of Torino Torino Italy;

    Department of Medical Sciences University of Torino Torino Italy;

    Department of Experimental Oncology Regina Elena National Cancer Institute Rome Italy;

    Department of Medical Sciences University of Torino Torino Italy;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 细胞生物学;
  • 关键词

    ADAM-17; Breast cancers; miR-221/222; STAT5A; β4 integrin;

    机译：adam-17;乳腺癌;mir-221/222;stat5a;β4整合蛋白;

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