MicroRNA‑875‑5p inhibits tumor growth and metastasis of hepatocellular carcinoma by targeting eukaryotic translation initiation factor 3 subunit a.
MicroRNA‑875‑5p inhibits tumor growth and metastasis of hepatocellular carcinoma by targeting eukaryotic translation initiation factor 3 subunit a.
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MicroRNA-875-5p通过靶向真核翻译起始因子3亚基a抑制肝细胞癌肿瘤生长和转移
DOI：
10.3892/or.2020.7743
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发表时间：
2020-11
期刊：
影响因子：
4.2
通讯作者：
Liu Q
中科院分区：
文献类型：
--
作者：
Chen T;Sun L;Yao B;Wang L;Wang Y;Niu Y;Liu R;Mo H;Liu Z;Tu K;Liu Q
越来越多的证据表明，微小RNA（microRNA，miRNA）的异常表达与肝细胞癌（HCC）的发生、发展密切相关。先前的研究结果表明，miRNA（miR）-875-5p参与各种类型癌症的发展。然而，miR-875- 5 p在HCC中的表达和功能仍不清楚。本研究中对临床样本的分析表明，与邻近非肿瘤组织相比，miR-875- 5 p在HCC组织中表达下调，这与肿瘤尺寸大、静脉浸润、晚期肿瘤淋巴结转移阶段和不利的总生存率相关。体外实验显示，miR-875- 5 p的异位表达抑制了HCC细胞的增殖、迁移、侵袭和上皮间质转化（EMT）进程，而抑制miR-875- 5 p则促进了HCC细胞的增殖、迁移、侵袭和EMT进程。miR-875- 5 p过表达抑制肝癌的生长和转移。在机制上，真核生物翻译起始因子3亚基a（eIF 3a）被鉴定为HCC中miR-875- 5 p的下游靶点。进一步的实验表明eIF 3a在HCC组织中的表达上调，并与miR-875- 5 p的表达呈负相关。此外，miR-875- 5 p对野生型eIF 3a mRNA的荧光素酶活性有负调控作用，但对突变型eIF 3a mRNA的3′非翻译区（3′UTR）无影响。miR-875- 5 p在mRNA和蛋白水平上抑制HCC细胞中eIF 3a的表达。此外，eIF 3a发挥致癌作用，敲低eIF 3a抑制HCC细胞的增殖、运动和EMT。此外，eIF 3a过表达可消除miR-875- 5 p对HCC细胞增殖、运动和EMT的抑制作用。结论：miR-875- 5 p在HCC中表达下调，可能通过靶向eIF 3a的3′UTR下调而抑制肿瘤的生长和转移，有望成为HCC的预后和治疗策略。
Accumulating evidence has demonstrated that aberrant microRNA (miRNA) expression is involved in hepatocellular carcinoma (HCC) progression. Previous findings suggested that miRNA (miR)-875-5p participates in the development of various types of cancer. However, the expression and function of miR-875-5p in HCC remains largely unclear. The analysis of clinical samples in the present study demonstrated that miR-875-5p expression was downregulated in HCC tissues compared to adjacent non-tumor tissues, which was associated with a large tumor size, venous infiltration, advanced tumor-node-metastasis stage and unfavorable overall survival. In vitro experiments revealed that ectopic expression of miR-875-5p suppressed, whereas inhibition of miR-875-5p promoted HCC cell proliferation, migration, invasion and epithelial-to-mesenchymal transition (EMT) progression. Overexpression of miR-875-5p restrained HCC tumor growth and metastasis in vivo. Mechanistically, eukaryotic translation initiation factor 3 subunit a (eIF3a) was identified as the downstream target of miR-875-5p in HCC. Further experiments demonstrated that the expression of eIF3a was upregulated and negatively correlated with that of miR-875-5p in HCC tissues. In addition, miR-875-5p negatively regulated the luciferase activity of wild-type, but not mutant 3′-untranslated region (3′UTR) of eIF3a mRNA. miR-875-5p suppressed eIF3a expression at the mRNA and protein level in HCC cells. Additionally, eIF3a exerted an oncogenic role, and knockdown of eIF3a inhibited the proliferation, motility and EMT of HCC cells. In addition, eIF3a overexpression abolished the inhibitory effects of miR-875-5p on the proliferation, motility and EMT in HCC cells. In conclusion, miR-875-5p, which was downregulated in HCC, may inhibit tumor growth and metastasis by eIF3a downregulation via targeting its 3′UTR and may be a promising prognostic and therapeutic strategy in HCC.
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