Synthetic miR-143 Inhibits Growth of HER2-Positive Gastric Cancer Cells by Suppressing KRAS Networks Including DDX6 RNA Helicase
Synthetic miR-143 Inhibits Growth of HER2-Positive Gastric Cancer Cells by Suppressing KRAS Networks Including DDX6 RNA Helicase
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DOI：
10.3390/ijms20071697
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发表时间：
2019-04-05
影响因子：
5.6
通讯作者：
Yoshida, Kazuhiro
中科院分区：
文献类型：
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作者：
Tokumaru, Yoshihisa;Tajirika, Toshihiro;Yoshida, Kazuhiro
胃癌（GC）是全世界最常见的癌症之一。在临床环境中，GC 中 HER2 过度表达的鉴定是一个重要发现，因为抗 HER2 药物曲妥珠单抗为 HER2 阳性 GC 患者提供了生存优势。在 HER2 阳性 GC 中，PI3K/AKT 和 MAPK/ERK 信号通路失调已被报道，抑制这些通路是一种重要的治疗策略。已知 MiR-143 在多种癌症中发挥肿瘤抑制作用，例如膀胱癌、乳腺癌、结直肠癌和胃癌。在当前的研究中，我们开发了一种新型化学修饰的miR-143，并探索了这种合成的miR-143（syn-miR-143）在HER2阳性胃癌中的功能。 miR-143的表达水平在GC细胞系中下调，包括HER2阳性GC细胞系、MKN7和KATO-III。这些细胞系中 miR-143 的异位表达通过系统性沉默 KRAS 及其效应信号分子 AKT 和 ERK 来抑制细胞生长。此外，syn-miR-143通过沉默DEAD/H-box RNA解旋酶6（DDX6）（RNA解旋酶）间接下调KRAS上游分子HER2的表达，从而增强HER2阳性GC细胞翻译步骤中HER2蛋白的表达。这些发现表明，syn-miR-143 通过损害包括 DDX6 在内的 KRAS 网络发挥肿瘤抑制因子的作用。
Gastric cancer (GC) is one of the most common cancers worldwide. In the clinical setting, the identification of HER2 overexpression in GC was a significant finding, as trastuzumab, an anti-HER2 drug, provides a survival advantage to HER2-positive GC patients. In HER2-postive GC, the dysregulation of PI3K/AKT and MAPK/ERK signaling pathways has been reported, and inhibition of these pathways is an important therapeutic strategy. MiR-143 is known to act as a tumor suppressor in several cancers, such as bladder cancer, breast cancer, colorectal cancer, and gastric cancer. In the current study, we developed a novel chemically-modified miR-143 and explored the functions of this synthetic miR-143 (syn-miR-143) in HER2-positive gastric cancer. The expression level of miR-143 was down-regulated in GC cell lines, including HER2-positive GC cell lines, MKN7, and KATO-III. The ectopic expression of miR-143 in those cell lines suppressed cell growth through systemic silencing of KRAS and its effector signaling molecules, AKT and ERK. Furthermore, syn-miR-143 indirectly down-regulated the expression of HER2, an upstream molecule of KRAS, through silencing DEAD/H-box RNA helicase 6 (DDX6), RNA helicase, which enhanced HER2 protein expression at the translational step in HER2-positive GC cells. These findings suggested that syn-miR-143 acted as a tumor suppressor through the impairment of KRAS networks including the DDX6.