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抑制 miR-34a-5p 可以挽救 p53-DAPK 轴的破坏，从而抑制透明细胞肾细胞癌的进展。

Inhibition of miR-34a-5p can rescue disruption of the p53-DAPK axis to suppress progression of clear cell renal cell carcinoma.

机构信息

Department of Urology, First Hospital of China Medical University, Shenyang, Liaoning, China.

Institute of Urology, China Medical University, Shenyang, China.

出版信息

Mol Oncol. 2019 Oct;13(10):2079-2097. doi: 10.1002/1878-0261.12545. Epub 2019 Aug 24.

DOI:10.1002/1878-0261.12545
PMID:31294899
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6763763/
Abstract

DAPK, a transcriptional target of the p53 protein, has long been characterized as a tumor suppressor that acts as a negative regulator in multiple cellular processes. However, increasing studies have suggested that the role of DAPK may vary depending on cell type and cellular context. Thus far, the expression and function of DAPK in clear cell renal cell carcinoma (ccRCC) remain ambiguous. Since ccRCC behaves in an atypical way with respect to p53, whether the p53-DAPK axis functions normally in ccRCC is also an intriguing question. Here, tissue specimens from 61 ccRCC patients were examined for DAPK expression. Functional studies regarding apoptosis, growth, and migration were used to determine the role of DAPK in renal cancer cells. The validity of the p53-DAPK axis in ccRCC was also determined. Our study identified DAPK as a negative regulator of ccRCC, and its expression was reduced in certain subgroups. However, the p53-DAPK axis was disrupted due to upregulation of miR-34a-5p under stressed conditions. miR-34a-5p was identified as a novel repressor of DAPK acting downstream of p53. Inhibition of miR-34a-5p can correct the p53-DAPK axis disruption by upregulating DAPK protein and may have potential to be used as a therapeutic target to improve outcomes for ccRCC patients.

摘要

钙调蛋白依赖性蛋白激酶（DAPK）是 p53 蛋白的转录靶标，长期以来一直被认为是一种肿瘤抑制因子，在多种细胞过程中作为负调节剂发挥作用。然而，越来越多的研究表明，DAPK 的作用可能因细胞类型和细胞环境而异。迄今为止，DAPK 在透明细胞肾细胞癌（ccRCC）中的表达和功能仍不明确。由于 ccRCC 在 p53 方面表现出非典型行为，p53-DAPK 轴在 ccRCC 中是否正常发挥作用也是一个有趣的问题。在此，我们检查了 61 例 ccRCC 患者的组织标本，以检测 DAPK 的表达情况。我们还进行了凋亡、生长和迁移等功能研究，以确定 DAPK 在肾癌细胞中的作用。同时还确定了 p53-DAPK 轴在 ccRCC 中的有效性。我们的研究将 DAPK 鉴定为 ccRCC 的负调节剂，并且在某些亚组中其表达降低。但是，由于在应激条件下 miR-34a-5p 的上调，p53-DAPK 轴被破坏。miR-34a-5p 被鉴定为 p53 下游作用于 DAPK 的新型负调节剂。抑制 miR-34a-5p 可以通过上调 DAPK 蛋白来纠正 p53-DAPK 轴的破坏，并且可能具有作为改善 ccRCC 患者预后的治疗靶标的潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28ce/6763763/0e2d6359d533/MOL2-13-2079-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28ce/6763763/0ea6f3930486/MOL2-13-2079-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28ce/6763763/9308f851c0b5/MOL2-13-2079-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28ce/6763763/52c403efb04c/MOL2-13-2079-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28ce/6763763/647dd864a1f0/MOL2-13-2079-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28ce/6763763/7bc7306ba55e/MOL2-13-2079-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28ce/6763763/59ad8b5f9d03/MOL2-13-2079-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28ce/6763763/f6a2f404de80/MOL2-13-2079-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28ce/6763763/0e2d6359d533/MOL2-13-2079-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28ce/6763763/0ea6f3930486/MOL2-13-2079-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28ce/6763763/9308f851c0b5/MOL2-13-2079-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28ce/6763763/52c403efb04c/MOL2-13-2079-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28ce/6763763/647dd864a1f0/MOL2-13-2079-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28ce/6763763/7bc7306ba55e/MOL2-13-2079-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28ce/6763763/59ad8b5f9d03/MOL2-13-2079-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28ce/6763763/f6a2f404de80/MOL2-13-2079-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28ce/6763763/0e2d6359d533/MOL2-13-2079-g008.jpg

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