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miR-182-5p 通过抑制 FOXO3a 促进肝癌进展。

miR-182-5p promotes hepatocellular carcinoma progression by repressing FOXO3a.

机构信息

Department of Hepatobiliary Surgery, Liver Cancer Institute and Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.

Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China.

出版信息

J Hematol Oncol. 2018 Jan 24;11(1):12. doi: 10.1186/s13045-018-0555-y.

Abstract

BACKGROUND

High frequency of recurrence is the major cause of the poor outcomes for patients with hepatocellular carcinoma (HCC). microRNA (miR)-182-5p emerged as a high-priority miRNA in HCC and was found to be related to HCC metastasis. Whether the expression of miR-182-5p in tumor tissue correlated with early recurrence in HCC patients underwent curative surgery was unknown.

METHODS

Real-time PCR (RT-PCR) and in situ hybridization (ISH) were conducted to assess the expression of miR-182-5p in HCC cells and tissues. Cell Counting Kit-8 (CCK-8), transwell assays were performed to detected cells proliferation and migration ability. Flow cytometry assays were used to detect cell apoptosis rate, and xenograft model was employed to study miR-182-5p in HCC growth and lung metastasis. The target of miR-182-5p was validated with a dual-luciferase reporter assay and western blotting. Immunohistochemistry, immumoblotting, and immunoprecipitation were performed to test relative protein expression.

RESULTS

We showed that high expression of miR-182-5p in tumor tissues correlated with poor prognosis as well as early recurrence in HCC patients underwent curative surgery. miR-182-5p enhanced motility and invasive ability of HCC cells both in vitro and in vivo. miR-182-5p directly targets 3'-UTR of FOXO3a and repressed FOXO3a expression, activating AKT/FOXO3a pathway to promote HCC proliferation. Notably, miR-182-5p activated Wnt/β-catenin signaling by inhibiting the degradation of β-catenin and enhancing the interaction between β-catenin and TCF4 which was mediated by repressed FOXO3a.

CONCLUSIONS

Consistently, miR-182-5p can be a potential predictor of early recurrence for HCC patients underwent curative surgery, and FOXO3a plays a key mediator in miR-182-5p induced HCC progression.

摘要

背景

肝细胞癌(HCC)患者预后差的主要原因是复发频率高。微小 RNA(miR)-182-5p 作为 HCC 中的高优先级 miRNA 出现,并且被发现与 HCC 转移有关。肿瘤组织中 miR-182-5p 的表达是否与接受根治性手术的 HCC 患者的早期复发相关尚不清楚。

方法

采用实时 PCR(RT-PCR)和原位杂交(ISH)检测 HCC 细胞和组织中 miR-182-5p 的表达。采用细胞计数试剂盒-8(CCK-8)和 Transwell 检测细胞增殖和迁移能力。流式细胞术检测细胞凋亡率,建立异种移植模型研究 miR-182-5p 对 HCC 生长和肺转移的影响。采用双荧光素酶报告基因检测和 Western blot 验证 miR-182-5p 的靶标。采用免疫组化、免疫印迹和免疫沉淀检测相对蛋白表达。

结果

我们发现肿瘤组织中 miR-182-5p 的高表达与 HCC 患者根治性手术后的不良预后以及早期复发相关。miR-182-5p 可增强 HCC 细胞在体外和体内的迁移和侵袭能力。miR-182-5p 可直接靶向 FOXO3a 的 3'-UTR 并抑制 FOXO3a 的表达,激活 AKT/FOXO3a 通路促进 HCC 增殖。值得注意的是,miR-182-5p 通过抑制 β-catenin 的降解和增强 β-catenin 与 TCF4 的相互作用来激活 Wnt/β-catenin 信号,这种作用是由抑制 FOXO3a 介导的。

结论

综上所述,miR-182-5p 可能是 HCC 患者根治性手术后早期复发的潜在预测因子,FOXO3a 是 miR-182-5p 诱导 HCC 进展的关键介质。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f14/5782375/63b40ae4a1b5/13045_2018_555_Fig1_HTML.jpg

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