Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China.
Department of Neurology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China.
Mol Med Rep. 2018 Oct;18(4):3577-3588. doi: 10.3892/mmr.2018.9365. Epub 2018 Aug 9.
Ewing's sarcoma is the second most frequent bone and soft tissue sarcoma, which is commonly driven by the Ewing's sarcoma breakpoint region 1‑friend leukemia integration 1 transcription factor (EWS‑FLI1) fusion gene. Since microRNAs (miRs) can act as either oncogenes or tumor suppressor genes in human cancer, and miR‑34b has been reported to act as a tumor suppressor, the role of miR‑34b in Ewing's sarcoma was investigated in the present study. The results demonstrated that miR‑34b expression levels were higher in tumor samples compared within normal tissue samples. Notably, miR‑34b expression levels were significantly higher in EWS‑FLI1‑positive samples compared within EWS‑FLI1‑negative samples. The effects of miR‑34b expression on cell proliferation, migration and invasion were also examined. miR‑34b expression was inhibited using small interfering (si)RNA targeting the fusion gene. Transfection of a miR‑34b precursor sequence into siRNA‑treated tumor cells resulted in a significant increase in cell growth, migration and invasion compared within the control group. In addition, the adhesive ability was increased in the Ewing's sarcoma cell line RD‑ES, but not A673, following miR‑34b upregulation. Conversely, downregulation of miR‑34b expression led to a significant decrease in cell growth, migration and invasion. Notch has previously been reported to serve either oncogenic or tumor suppressive roles in human cancer. The results indicated that Notch1 and its target genes, Hes family BHLH transcription factor 1 and Hes‑related family BHLH transcription factor with YRPW motif 1, were suppressed by miR‑34b directly In conclusion, EWS‑FLI1 may modulate miR‑34b expression directly or indirectly, and miR‑34b potentially has an oncogenic role in Ewing's sarcoma by downregulating Notch1.
尤文肉瘤是第二常见的骨和软组织肉瘤，其通常由尤文肉瘤断点区域 1 友好白血病整合 1 转录因子（EWS-FLI1）融合基因驱动。由于 microRNAs（miRs）在人类癌症中既可以作为癌基因，也可以作为肿瘤抑制基因，并且已经报道 miR-34b 作为肿瘤抑制基因，因此本研究调查了 miR-34b 在尤文肉瘤中的作用。结果表明，与正常组织样本相比，肿瘤样本中的 miR-34b 表达水平更高。值得注意的是，与 EWS-FLI1 阴性样本相比，EWS-FLI1 阳性样本中的 miR-34b 表达水平显著更高。还检查了 miR-34b 表达对细胞增殖、迁移和侵袭的影响。使用靶向融合基因的小干扰（si）RNA 抑制 miR-34b 的表达。将 miR-34b 前体序列转染至 siRNA 处理的肿瘤细胞中，与对照组相比，细胞生长、迁移和侵袭显著增加。此外，在 miR-34b 上调后，RD-ES 尤文肉瘤细胞系的粘附能力增加，但 A673 细胞系没有增加。相反，下调 miR-34b 表达导致细胞生长、迁移和侵袭显著减少。Notch 先前已被报道在人类癌症中发挥致癌或肿瘤抑制作用。结果表明，Notch1 及其靶基因，包括 Hes 家族碱性螺旋-环-螺旋转录因子 1 和具有 YRPW 基序的 Hes 相关家族碱性螺旋-环-螺旋转录因子 1，被 miR-34b 直接抑制。总之，EWS-FLI1 可能直接或间接调节 miR-34b 的表达，miR-34b 通过下调 Notch1 在尤文肉瘤中具有致癌作用。
