Background

Uncovering molecular pathogenesis and mechanisms of small cell lung cancer (SCLC) will contribute to SCLC therapy. Multiple studies demonstrated that miR-451a acts as an anti-tumor miRNA in non-small cell lung cancer. However, the mechanism of miR-451a in SCLC was ambiguous.

Objective

We aimed to explore the function of miR-451a in SCLC and decipher the underlying mechanisms.

Methods

TargetScan and dual-luciferase reporter assays were used to analyze the target genes of miR-451a. Cell counting kit-8 and colony formation assays were performed to assess the roles of miR-451a on cell growth. Gene set enrichment analysis (GSEA) was utilized to enrich biological pathways. Western blot was used to measure protein expression.

Results

MiR-451a expression was reduced dramatically in SCLC tissues and cell lines (NCI-H1688 and NCI-H446). Helicase, Lymphoid Specific (HELLS) was proved to be a target gene of miR-451a. In addition, cell proliferation assays in SCLC cells transfected with miR-451a mimic and/or HELLS revealed that miR-451a inhibited cell proliferation via targeting HELLS. Moreover, the roles of miR-451a/HELLS in expression of key proteins in mTOR and apoptosis signaling pathways suggested that miR-451a inactivated mTOR and activated apoptosis signaling pathway via directly silencing HELLS.

Conclusions

Our study indicated that miR-451a hinders SCLC cell proliferation in vitro through regulating mTOR and apoptosis signaling pathways via silencing HELLS, suggesting that miR-451a could be a promising tumor suppressor in SCLC. And there is a potential for miR-451a to be a drug target and biomarker for SCLC.

中文翻译：

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miR-451a 抑制 HELLS 抑制 mTOR 通路以阻碍 SCLC 的侵袭性

背景

揭示小细胞肺癌 (SCLC) 的分子发病机制和机制将有助于 SCLC 治疗。多项研究表明，miR-451a在非小细胞肺癌中充当抗肿瘤 miRNA。然而，miR-451a在 SCLC 中的作用机制尚不明确。

客观的

我们旨在探索miR-451a在 SCLC 中的功能并破译其潜在机制。

方法

TargetScan 和双荧光素酶报告基因检测用于分析miR-451a的靶基因。进行细胞计数试剂盒 8 和集落形成试验以评估miR-451a对细胞生长的作用。基因集富集分析（GSEA）被用来丰富生物途径。蛋白质印迹用于测量蛋白质表达。

结果

在 SCLC 组织和细胞系（NCI-H1688 和 NCI-H446）中，MiR-451a 的表达显着降低。Helicase, Lymphoid Specific ( HELLS ) 被证明是miR-451a的靶基因。此外，用miR-451a模拟物和/或HELLS转染的 SCLC 细胞中的细胞增殖分析表明，miR-451a通过靶向HELLS抑制细胞增殖。此外，miR-451a / HELLS在mTOR和凋亡信号通路中关键蛋白的表达中的作用表明，miR-451a通过直接沉默HELLS来灭活mTOR并激活凋亡信号通路。

结论

我们的研究表明，miR-451a通过沉默HELLS调节 mTOR 和凋亡信号通路，从而在体外阻碍 SCLC 细胞增殖，表明miR-451a可能是 SCLC 中一种有前景的肿瘤抑制因子。并且miR-451a有可能成为 SCLC 的药物靶点和生物标志物。