Burger Megan L, Xue Ling, Sun Yuefang, Kang Chulho, Winoto Astar
Department of Molecular and Cell Biology and Cancer Research Laboratory, University of California, Berkeley, CA.
Blood. 2014 Jun 26;123(26):4089-100. doi: 10.1182/blood-2013-11-539411. Epub 2014 Apr 15.
Cancer develops by a multistep process during which cells acquire characteristics that allow them to evade apoptosis and proliferate unchecked. Sequential acquisition of genetic alterations drives this process but also causes cellular stress, frequently prompting cells to enter a premalignant period during which they mount a defense against transformation. T cell-specific deletion of the tumor suppressor PTEN in mice induces premalignancy in the thymus and development of CD4(+) T-cell lymphomas in the periphery. Here we sought to identify factors mediating the cellular defense against transformation during the premalignant period. We identified several microRNAs upregulated specifically in premalignant thymocytes, including miR-146a, miR-146b, and the miR-183/96/182 cluster. CD4-driven T cell-specific transgenic overexpression of mir-146a and mir-146b significantly delayed PTEN-deficient lymphomagenesis and delayed c-myc oncogene induction, a key driver of transformation in PTEN-deficient T-cell malignancies. We found that miR-146a and miR-146b targeting of Traf6 attenuates TCR signaling in the thymus and inhibits downstream NF-κB-dependent induction of c-myc. Additionally, c-myc repression in mature CD4 T cells by miR-146b impaired TCR-mediated proliferation. Hence, we have identified 2 miRNAs that are upregulated as part of the cellular response against transformation that, when overrepresented, can effectively inhibit progression to malignancy in the context of PTEN deficiency.
癌症是通过一个多步骤过程发展而来的，在此过程中细胞获得了能够逃避凋亡并不受控制地增殖的特性。基因改变的顺序性获得驱动了这一过程，但也会导致细胞应激，常常促使细胞进入癌前阶段，在此期间它们会对转化发起防御。在小鼠中肿瘤抑制因子PTEN的T细胞特异性缺失会在胸腺中诱导癌前病变，并在外周引发CD4(+) T细胞淋巴瘤的发展。在这里，我们试图确定在癌前阶段介导细胞对转化防御的因素。我们鉴定出了几种在癌前胸腺细胞中特异性上调的微小RNA，包括miR-146a、miR-146b以及miR-183/96/182簇。由CD4驱动的mir-146a和mir-146b的T细胞特异性转基因过表达显著延迟了PTEN缺陷型淋巴瘤的发生，并延迟了c-myc癌基因的诱导，c-myc是PTEN缺陷型T细胞恶性肿瘤转化的关键驱动因素。我们发现miR-146a和miR-146b靶向Traf6会减弱胸腺中的TCR信号，并抑制下游NF-κB依赖性的c-myc诱导。此外，miR-146b对成熟CD4 T细胞中c-myc的抑制会损害TCR介导的增殖。因此，我们鉴定出了2种作为细胞对转化反应一部分而被上调的微小RNA，当它们过量表达时，在PTEN缺陷的情况下能够有效抑制向恶性肿瘤的进展。
