State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Oncogene. 2015 Jan 22;34(4):413-23. doi: 10.1038/onc.2013.574. Epub 2014 Jan 27.
The metastatic cascade is a complex and multistep process with many potential barriers. Recent evidence has shown that microRNAs (miRNAs) are involved in carcinogenesis and tumor progression in non-small-cell lung cancer (NSCLC). In this study, by comparing the miRNA expression profiles of SPC-A-1sci (high metastatic) and SPC-A-1 (weakly metastatic) cells, we demonstrated that the downregulation and function of miR-193a-3p and miR-193a-5p in NSCLC metastasis and the expression of these miRNAs was suppressed in NSCLC compared with corresponding non-tumorous tissues. Decreased miR-193a-3p/5p expression was significantly associated with tumor node metastasis (TNM) and lymph node metastasis. Furthermore, functional assays showed that the overexpression of miR-193a-3p/5p inhibited NSCLC cell migration, invasion and epithelial-mesenchymal transition (EMT) in vitro and lung metastasis formation in vivo. In addition, we discovered that ERBB4 and S6K2 were the direct targets of miR-193a-3p and that PIK3R3 and mTOR were the direct targets of miR-193a-5p in NSCLC. We also observed that miR-193a-3p/5p could inactivate the AKT/mTOR signaling pathway. Thus, miR-193a-3p/5p functions as a tumor suppressor and has an important role in NSCLC metastasis through ERBB signaling pathway.
转移级联是一个复杂的多步骤过程,有许多潜在的障碍。最近的证据表明,microRNAs(miRNAs)参与非小细胞肺癌(NSCLC)的癌变和肿瘤进展。在这项研究中,通过比较 SPC-A-1sci(高转移性)和 SPC-A-1(弱转移性)细胞的 miRNA 表达谱,我们证明了 miR-193a-3p 和 miR-193a-5p 在 NSCLC 转移中的下调和功能,以及这些 miRNA 在 NSCLC 中的表达与相应的非肿瘤组织相比受到抑制。miR-193a-3p/5p 表达的降低与肿瘤淋巴结转移(TNM)和淋巴结转移显著相关。此外,功能测定表明,miR-193a-3p/5p 的过表达抑制了 NSCLC 细胞在体外的迁移、侵袭和上皮间质转化(EMT),以及体内的肺转移形成。此外,我们发现 ERBB4 和 S6K2 是 miR-193a-3p 的直接靶标,而 PIK3R3 和 mTOR 是 miR-193a-5p 在 NSCLC 中的直接靶标。我们还观察到 miR-193a-3p/5p 可以使 AKT/mTOR 信号通路失活。因此,miR-193a-3p/5p 作为一种肿瘤抑制因子,通过 ERBB 信号通路在 NSCLC 转移中发挥重要作用。
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