Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China.
Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China.
Int J Oncol. 2018 Nov;53(5):2241-2257. doi: 10.3892/ijo.2018.4543. Epub 2018 Aug 28.
The miR-17-92 cluster plays either an oncogenic or anti-oncogenic role in cancer progression in diverse human cancers. However, the underlying mechanisms of the miR-17-92 cluster in gastric cancer have not yet been fully elucidated. In this study, the function of the miR-17-92 cluster in diverse aspects of MGC-803 gastric cancer cells was systematically elucidated. The enforced introduction of the miR-17-92 cluster into the MGC-803 cells significantly promoted cell growth due to the increased cellular proliferation and decreased cellular apoptosis, which were detected by CCK-8, cell viability and TUNEL assays. Moreover, the results of western blot analyses revealed that the activated protein kinase B (AKT), extracellular-signal-regulated kinase (ERK) and nuclear factor (NF-κB) signaling pathways were activated in these processes. Moreover, the overexpression of the miR-17-92 cluster markedly enhanced the migratory and invasive abilities of the MGC-803 cells, which was associated with the occurrence of epithelial-mesenchymal transition (EMT). Tumor necrosis factor receptor associated factor 3 (TRAF3), which negatively regulates the NF-κB signaling pathway, was identified as a direct target of miR-17-92. Furthermore, TRAF3 silencing enhanced the oncogenic functions of the miR-17-92 cluster in the MGC-803 cells, including the increased cellular proliferation, migration and invasion. Moreover, immunohistochemical staining and survival analyses of a gastric cancer tissue microarray revealed that TRAF3 functioned as a tumor suppressor in gastric cancer. Taken together, the findings of this study provide new insight into the specific biological functions of the miR-17-92 cluster in gastric cancer progression by directly targeting TRAF3.
miR-17-92 簇在多种人类癌症的癌症进展中发挥致癌或抑癌作用。然而，miR-17-92 簇在胃癌中的潜在机制尚未完全阐明。在这项研究中，系统地阐明了 miR-17-92 簇在不同方面对 MGC-803 胃癌细胞的功能。强制将 miR-17-92 簇引入 MGC-803 细胞中，由于细胞增殖增加和细胞凋亡减少，显著促进了细胞生长，这通过 CCK-8、细胞活力和 TUNEL 测定检测到。此外，Western blot 分析的结果表明，在这些过程中激活了蛋白激酶 B (AKT)、细胞外信号调节激酶 (ERK) 和核因子 (NF-κB) 信号通路。此外，miR-17-92 簇的过表达显著增强了 MGC-803 细胞的迁移和侵袭能力，这与上皮-间充质转化 (EMT) 的发生有关。肿瘤坏死因子受体相关因子 3 (TRAF3) 被鉴定为 miR-17-92 的直接靶标，它负调节 NF-κB 信号通路。此外，TRAF3 沉默增强了 miR-17-92 簇在 MGC-803 细胞中的致癌功能，包括细胞增殖、迁移和侵袭的增加。此外，胃癌组织微阵列的免疫组织化学染色和生存分析表明，TRAF3 在胃癌中起肿瘤抑制因子的作用。总之，这项研究的结果通过直接靶向 TRAF3，为 miR-17-92 簇在胃癌进展中的特定生物学功能提供了新的见解。
