Dysregulation of a family of short noncoding RNAs, tsRNAs, in human cancer
Dysregulation of a family of short noncoding RNAs, tsRNAs, in human cancer
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DOI：
10.1073/pnas.1604266113
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发表时间：
2016-05-03
影响因子：
11.1
通讯作者：
Croce, Carlo M.
中科院分区：
文献类型：
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作者：
Pekarsky, Yuri;Balatti, Veronica;Croce, Carlo M.
慢性淋巴细胞白血病（CLL）是最常见的人类白血病，转基因小鼠研究表明T细胞白血病/淋巴瘤1（TCL 1）癌基因的激活是这种疾病侵袭性形式的发病机制中的一个促成事件。在研究TCL 1表达的调控时，我们鉴定了microRNA簇miR-4521/3676，并发现这两种microRNA与tRNA序列相关，并且该区域可以产生两种小RNA，这是最近发现的一类小非编码RNA的成员，即tRNA衍生的小RNA（tsRNA）。通过北方印迹分析进一步证明了miR-3676和miR-4521是tsRNA。我们发现，与ts-3676一样，ts-4521在CLL中下调并发生突变。肺癌样本的分析显示，ts-3676和ts-4521在患者肿瘤样本中均下调和突变。由于tsRNA在性质上与piRNA [P元件诱导的懦弱睾丸（Piwi）相互作用的小RNA]相似，我们研究了ts-3676和ts-4521是否可以与Piwi蛋白相互作用，并在含有Piwi样蛋白2（PIWIL 2）的复合物中发现了这两种tsRNA。为了确定其他的tsRNA是否与癌症有关，我们制作了一个定制的微阵列芯片，其中包含120个大小为16 bp或更大的tsRNA。微阵列杂交实验揭示了CLL和肺癌中的tsRNA特征，表明与microRNA一样，tsRNA在造血系统恶性肿瘤和实体瘤中可能具有致癌和/或肿瘤抑制功能。因此，我们的研究结果表明，在人类癌症中，tsRNAs是失调的。
Chronic lymphocytic leukemia (CLL) is the most common human leukemia, and transgenic mouse studies indicate that activation of the T-cell leukemia/lymphoma 1 (TCL1) oncogene is a contributing event in the pathogenesis of the aggressive form of this disease. While studying the regulation of TCL1 expression, we identified the microRNA cluster miR-4521/3676 and discovered that these two microRNAs are associated with tRNA sequences and that this region can produce two small RNAs, members of a recently identified class of small noncoding RNAs, tRNA-derived small RNAs (tsRNAs). We further proved that miR-3676 and miR-4521 are tsRNAs using Northern blot analysis. We found that, like ts-3676, ts-4521 is down-regulated and mutated in CLL. Analysis of lung cancer samples revealed that both ts-3676 and ts-4521 are down-regulated and mutated in patient tumor samples. Because tsRNAs are similar in nature to piRNAs [P-element-induced wimpy testis (Piwi)-interacting small RNAs], we investigated whether ts-3676 and ts-4521 can interact with Piwi proteins and found these two tsRNAs in complexes containing Piwi-like protein 2 (PIWIL2). To determine whether other tsRNAs are involved in cancer, we generated a custom microarray chip containing 120 tsRNAs 16 bp or more in size. Microarray hybridization experiments revealed tsRNA signatures in CLL and lung cancer, indicating that, like microRNAs, tsRNAs may have an oncogenic and/or tumor-suppressor function in hematopoietic malignancies and solid tumors. Thus, our results show that tsRNAs are dysregulated in human cancer.