Department of Immunology, Research Center of Basic Medical Sciences, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Medical University, Tianjin, China.
Department of Pathology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
Cancer Res. 2017 Jun 15;77(12):3194-3206. doi: 10.1158/0008-5472.CAN-16-3146. Epub 2017 Apr 26.
Several studies have shown that tRNAs can be enzymatically cleaved to generate distinct classes of tRNA-derived fragments (tRF). Here, we report that tRF/miR-1280, a 17-bp fragment derived from tRNA and pre-miRNA, influences Notch signaling pathways that support the function of cancer stem-like cells (CSC) in colorectal cancer progression. tRF/miR-1280 expression was decreased in human specimens of colorectal cancer. Ectopic expression of tRF/miR-1280 reduced cell proliferation and colony formation, whereas its suppression reversed these effects. Mechanistic investigations implicated the Notch ligand JAG2 as a direct target of tRF/miR-1280 binding through which it reduced tumor formation and metastasis. Notably, tRF/miR-1280-mediated inactivation of Notch signaling suppressed CSC phenotypes, including by direct transcriptional repression of the Gata1/3 and miR-200b genes. These results were consistent with findings of decreased levels of miR-200b and elevated levels of JAG2, Gata1, Gata3, Zeb1, and Suz12 in colorectal cancer tissue specimens. Taken together, our results established that tRF/miR-1280 suppresses colorectal cancer growth and metastasis by repressing Notch signaling pathways that support CSC phenotypes. Furthermore, they provide evidence that functionally active miRNA can be derived from tRNA, offering potential biomarker and therapeutic uses. .
几项研究表明，tRNA 可以被酶切生成不同类型的 tRNA 衍生片段（tRF）。在这里，我们报告说，tRF/miR-1280，一种源自 tRNA 和 pre-miRNA 的 17 个碱基片段，影响支持结直肠癌细胞（CSC）功能的 Notch 信号通路，促进了结直肠癌细胞的进展。tRF/miR-1280 在结直肠癌患者的标本中表达减少。tRF/miR-1280 的异位表达降低了细胞增殖和集落形成，而其抑制作用则逆转了这些效应。机制研究表明，Notch 配体 JAG2 是 tRF/miR-1280 结合的直接靶标，通过它减少了肿瘤的形成和转移。值得注意的是，tRF/miR-1280 介导的 Notch 信号失活抑制了 CSC 表型，包括通过直接转录抑制 Gata1/3 和 miR-200b 基因。这些结果与结直肠癌细胞组织标本中 miR-200b 水平降低和 JAG2、Gata1、Gata3、Zeb1 和 Suz12 水平升高的发现一致。综上所述，我们的研究结果表明，tRF/miR-1280 通过抑制支持 CSC 表型的 Notch 信号通路来抑制结直肠癌细胞的生长和转移。此外，它们提供了证据表明功能活性 miRNA 可以来自 tRNA，为其提供了潜在的生物标志物和治疗用途。
