MiroRNA-188 Acts as Tumor Suppressor in Non-Small-Cell Lung Cancer by Targeting MAP3K3,Molecular Pharmaceutics

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MiroRNA-188 Acts as Tumor Suppressor in Non-Small-Cell Lung Cancer by Targeting MAP3K3
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-03-12 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b00071
Lili Zhao ₁ , Xin Ni ₁ , Linlin Zhao ₁ , Yao Zhang ₁ , Dan Jin ₂ , Wei Yin ₃ , Dandan Wang ₁ , Wei Zhang ₁

Affiliation

Non-small cell lung cancer (NSCLC) is the most prevalent form of lung cancer. MicroRNAs have been increasingly implicated in NSCLC and may serve as novel therapeutic targets to combat cancer. Here we investigated the functional implication of miR-188 in NSCLC. We first analyzed miR-188 expression in both NSCLC clinical samples and cancer cell lines. Next we investigated its role in A549 and H2126 cells with cell proliferation, migration, and apoptosis assays. To extend the in vitro study, we employed both xenograft model and LSL-K-ras G12D lung cancer model to examine the role of miR-188 in tumorigenesis. Last we tested MAP3K3 as miR-188 target in NSCLC model. MiR-188 expression was significantly downregulated at the NSCLC tumor sites and lung cancer cells. In vitro transfection of miR-188 reduced cell proliferation and migration potential and promoted cell apoptosis. In xenograft model, miR-188 inhibited tumor growth derived from cancer cells. Intranasal miR-188 administration reduced tumor formation in NSCLC animal model. MAP3K3 was validated as direct target of miR-188. Knocking down MAP3K3 in mice also inhibited tumorigenesis in LSL-K-ras G12D model. Our results demonstrate that miR-188 and its downstream target MAP3K3 could be a potential therapeutic target for NSCLC.

中文翻译：

MiroRNA-188通过靶向MAP3K3充当非小细胞肺癌的肿瘤抑制因子

非小细胞肺癌（NSCLC）是最普遍的肺癌形式。MicroRNA已越来越多地牵涉到NSCLC中，并可作为对抗癌症的新型治疗靶标。在这里，我们研究了miR-188在NSCLC中的功能含义。我们首先分析了NSCLC临床样品和癌细胞系中的miR-188表达。接下来，我们通过细胞增殖，迁移和凋亡分析研究了其在A549和H2126细胞中的作用。为了扩展体外研究，我们采用异种移植模型和LSL -K-ras G12D肺癌模型来研究miR-188在肿瘤发生中的作用。最后，我们在非小细胞肺癌模型中测试了MAP3K3作为miR-188靶标。在NSCLC肿瘤部位和肺癌细胞中，MiR-188表达显着下调。体外转染miR-188可降低细胞增殖和迁移潜能，并促进细胞凋亡。在异种移植模型中，miR-188抑制了源自癌细胞的肿瘤生长。鼻内施用miR-188可减少NSCLC动物模型中的肿瘤形成。MAP3K3被确认为miR-188的直接靶标。敲除小鼠中的MAP3K3在LSL -K-ras G12D模型中也抑制了肿瘤发生。我们的结果表明，miR-188及其下游靶标MAP3K3可能是NSCLC的潜在治疗靶标。

更新日期：2018-03-12

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