Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Division of Gastrointestinal Cancer Translational Research Laboratory, Peking University Cancer Hospital, Fu-Cheng Road, Beijing, 100142, China.
Department of Orthopedics, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, 518000, China.
Int J Biol Sci. 2021 May 10;17(8):1940-1952. doi: 10.7150/ijbs.58062. eCollection 2021.
There is a continued need for investigating the roles of microRNAs (miRNAs) and their targets on the progression of gastric cancer (GC), especially metastasis. Here, we performed an integrated study to identify dysregulated miRNAs critical for GC development and progression. miR-135b was determined as a promising biomarker for GC. The expression level of miR-135b was increased among GC cell lines, patient tumor tissues, serum samples, and correlation with aggravation of the GC patients. The functional assays demonstrated overexpression of miR-135b promoted cell proliferation, migration and invasion in GC, while miR-135b inhibition led to the opposite results. CAMK2D was found to be the direct target of miR-135b, serving as a tumor suppressor in GC cells. Based on our and public datasets, we confirmed the attenuation of CAMK2D expression in GC tissues. And, the expression levels of miR-135b and CAMK2D were closely associated with prognosis of GC patients. Ectopic expression of miR-135b resulted in the down-regulation of CAMK2D. Additionally, CAMK2D was a prerequisite for miR-135b to promote GC cells proliferation and migration by regulating the EMT process, which was confirmed by the experiments. Importantly, injection of miR-135b antagomir significantly repressed the tumor growth and metastasis of xenograft models, which suggested that the miR-135b antagomir were promising for clinical applications. Taken together, these results indicate that miR-135b/CAMK2D axis drives GC progression by EMT process remodeling, suggesting that miR-135b may be utilized as a new therapeutic target and prognostic marker for GC patients.
仍然需要研究 microRNAs（miRNAs）及其靶基因在胃癌（GC）进展中的作用，特别是转移。在这里，我们进行了一项综合研究，以确定对 GC 发生和发展至关重要的失调 miRNA。miR-135b 被确定为 GC 的有前途的生物标志物。miR-135b 在 GC 细胞系、患者肿瘤组织、血清样本中的表达水平升高，且与 GC 患者病情加重相关。功能测定表明，miR-135b 的过表达促进了 GC 中的细胞增殖、迁移和侵袭，而 miR-135b 的抑制则导致相反的结果。CAMK2D 被发现是 miR-135b 的直接靶基因，在 GC 细胞中作为肿瘤抑制因子。基于我们和公共数据集，我们证实了 GC 组织中 CAMK2D 表达的衰减。并且，miR-135b 和 CAMK2D 的表达水平与 GC 患者的预后密切相关。miR-135b 的异位表达导致 CAMK2D 的下调。此外，CAMK2D 是 miR-135b 通过调节 EMT 过程促进 GC 细胞增殖和迁移的前提条件，这通过实验得到了证实。重要的是，miR-135b 拮抗剂的注射显著抑制了异种移植模型的肿瘤生长和转移，这表明 miR-135b 拮抗剂具有临床应用的潜力。总之，这些结果表明，miR-135b/CAMK2D 轴通过 EMT 过程重塑驱动 GC 进展，表明 miR-135b 可能被用作 GC 患者的新治疗靶点和预后标志物。
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