Identification of tRNA-derived small RNA (tsRNA) responsive to the tumor suppressor, RUNX1, in breast cancer
Identification of tRNA-derived small RNA (tsRNA) responsive to the tumor suppressor, RUNX1, in breast cancer
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DOI：
10.1002/jcp.29419
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发表时间：
2020-01-10
影响因子：
5.6
通讯作者：
Stein, Janet L.
中科院分区：
文献类型：
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作者：
Farina, Nicholas H.;Scalia, Stephanie;Stein, Janet L.
尽管最近在靶向治疗方面取得了进展，但人们对乳腺癌发生、发展和转移的分子机制了解很少。越来越多的证据表明，转移RNA(TRNA)衍生的小RNA(TsRNA)有助于与癌症发生和进展相关的生物控制和畸变。矮小相关转录因子1(RUNX1)转录因子是乳腺上皮中的一种肿瘤抑制因子，而RUNX1的下调与乳腺癌的发生和发展有关。我们鉴定了四个tsRNA(ts-19、ts-29、ts-46和ts-112)，它们对RUNX1肿瘤抑制因子的表达有选择性的反应。我们发现TS-112和RUNX1在正常乳腺上皮细胞和乳腺癌细胞株中呈反相关，与TS-112的肿瘤相关活性和RUNX1的肿瘤抑制活性是一致的。抑制TS-112对MCF10CA1a侵袭性乳腺癌细胞的增殖抑制作用显著。在类正常乳腺上皮MCF10A细胞中异位表达TS-112模拟基因可显著促进细胞增殖。这些发现支持TS-112的致癌潜力。此外，RUNX1可能抑制TS-112以防止乳腺上皮细胞过度增殖，从而增强其在维持乳腺上皮中的既定作用。
Despite recent advances in targeted therapies, the molecular mechanisms driving breast cancer initiation, progression, and metastasis are minimally understood. Growing evidence indicate that transfer RNA (tRNA)-derived small RNAs (tsRNA) contribute to biological control and aberrations associated with cancer development and progression. The runt-related transcription factor 1 (RUNX1) transcription factor is a tumor suppressor in the mammary epithelium whereas RUNX1 downregulation is functionally associated with breast cancer initiation and progression. We identified four tsRNA (ts-19, ts-29, ts-46, and ts-112) that are selectively responsive to expression of the RUNX1 tumor suppressor. Our finding that ts-112 and RUNX1 anticorrelate in normal-like mammary epithelial and breast cancer lines is consistent with tumor-related activity of ts-112 and tumor suppressor activity of RUNX1. Inhibition of ts-112 in MCF10CA1a aggressive breast cancer cells significantly reduced proliferation. Ectopic expression of a ts-112 mimic in normal-like mammary epithelial MCF10A cells significantly increased proliferation. These findings support an oncogenic potential for ts-112. Moreover, RUNX1 may repress ts-112 to prevent overactive proliferation in breast epithelial cells to augment its established roles in maintaining the mammary epithelium.