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microRNA-296 通过调控 HMGA1 表达影响前列腺癌的生长和侵袭。

Regulation of HMGA1 expression by microRNA-296 affects prostate cancer growth and invasion.

机构信息

Department of Pathology, Northwestern University, Feinberg Medical School, Chicago, Illinois, USA.

出版信息

Clin Cancer Res. 2011 Mar 15;17(6):1297-305. doi: 10.1158/1078-0432.CCR-10-0993. Epub 2010 Dec 7.

DOI:10.1158/1078-0432.CCR-10-0993
PMID:21138859
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3196617/
Abstract

PURPOSE

High-motility group AT-hook gene 1 (HMGA1) is a non-histone nuclear binding protein that is developmentally regulated. HMGA1 is significantly overexpressed in and associated with high grade and advance stage of prostate cancer (PC). The oncogenic role of HMGA1 is at least mediated through chromosomal instability and structural aberrations. However, regulation of HMGA1 expression is not well understood. Identification of microRNA-mediated HMGA1 regulation will provide a promising therapeutic target in treating PC.

EXPERIMENTAL DESIGN

In this study, we examined the functional relation between miR-296 and HMGA1 expression in several PC cell lines and a large PC cohort. We further examined the oncogenic property of HMGA1 regulated by miR-296.

RESULTS

Here we report that miR-296, a microRNA predicted to target HMGA1, specifically represses HMGA1 expression by promoting degradation and inhibiting HMGA1translation. Repression of HMGA1 by miR-296 is direct and sequence specific. Importantly, ectopic miR-296 expression significantly reduced PC cell proliferation and invasion, in part through the downregulation of HMGA1. Examining PC patient samples, we found an inverse correlation between HMGA1 and miR-296 expression: high levels of HMGA1 were associated with low miR-296 expression and strongly linked to more advanced tumor grade and stage.

CONCLUSIONS

Our results indicate that miR-296 regulates HMGA1 expression and is associated with PC growth and invasion.

摘要

目的

高迁移率族 AT 钩状结构域 1（HMGA1）是一种发育调控的非组蛋白核结合蛋白。HMGA1 在高级别和晚期前列腺癌（PC）中显著过表达，并与之相关。HMGA1 的致癌作用至少是通过染色体不稳定性和结构异常介导的。然而，HMGA1 表达的调控机制尚不清楚。鉴定 microRNA 介导的 HMGA1 调控将为治疗 PC 提供一个有前途的治疗靶点。

实验设计

在这项研究中，我们在几种 PC 细胞系和一个大型 PC 队列中研究了 miR-296 与 HMGA1 表达之间的功能关系。我们进一步研究了由 miR-296 调节的 HMGA1 的致癌特性。

结果

我们报告说，miR-296 是一种预测靶向 HMGA1 的 microRNA，通过促进降解和抑制 HMGA1 的翻译，特异性地抑制 HMGA1 的表达。miR-296 对 HMGA1 的抑制是直接的和序列特异性的。重要的是，外源性 miR-296 表达显著降低了 PC 细胞的增殖和侵袭，部分是通过下调 HMGA1。在检查 PC 患者样本时，我们发现 HMGA1 和 miR-296 表达之间存在负相关：HMGA1 水平高与 miR-296 表达水平低相关，并与更高级别的肿瘤分级和分期密切相关。

结论

我们的结果表明，miR-296 调节 HMGA1 的表达，并与 PC 的生长和侵袭有关。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b1d/3196617/6391ba254283/nihms-310888-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b1d/3196617/e0a6ccd2d9dc/nihms-310888-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b1d/3196617/8892f9c775b6/nihms-310888-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b1d/3196617/8f87b1e0458d/nihms-310888-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b1d/3196617/4b9cc3c963e0/nihms-310888-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b1d/3196617/d2ff49a26253/nihms-310888-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b1d/3196617/6391ba254283/nihms-310888-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b1d/3196617/e0a6ccd2d9dc/nihms-310888-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b1d/3196617/8892f9c775b6/nihms-310888-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b1d/3196617/8f87b1e0458d/nihms-310888-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b1d/3196617/4b9cc3c963e0/nihms-310888-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b1d/3196617/d2ff49a26253/nihms-310888-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b1d/3196617/6391ba254283/nihms-310888-f0006.jpg

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