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非肿瘤组织的全基因组转录组分析揭示了肾细胞癌中与衰老相关的预后标志物和药物靶点。

Genome-Wide Transcriptomic Analysis of Non-Tumorigenic Tissues Reveals Aging-Related Prognostic Markers and Drug Targets in Renal Cell Carcinoma.

作者信息

Oh Euiyoung, Kim Jun-Hyeong, Um JungIn, Jung Da-Woon, Williams Darren R, Lee Hyunju

机构信息

School of Electrical Engineering and Computer Science, Gwangju Institute of Science and Technology, 123 Cheomdangwagi-ro, Buk-Gu, Gwangju 61005, Korea.

New Drug Targets Laboratory, School of Life Sciences, Gwangju Institute of Science and Technology, 123 Cheomdangwagi-ro, Buk-Gu, Gwangju 61005, Korea.

出版信息

Cancers (Basel). 2021 Jun 18;13(12):3045. doi: 10.3390/cancers13123045.

DOI:10.3390/cancers13123045
PMID:34207247
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8234889/
Abstract

The relationship between expression of aging-related genes in normal tissues and cancer patient survival has not been assessed. We developed a genome-wide transcriptomic analysis approach for normal tissues adjacent to the tumor to identify aging-related transcripts associated with survival outcome, and applied it to 12 cancer types. As a result, five aging-related genes (DUSP22, MAPK14, MAPKAPK3, STAT1, and VCP) in normal tissues were found to be significantly associated with a worse survival outcome in patients with renal cell carcinoma (RCC). This computational approach was investigated using nontumorigenic immune cells purified from young and aged mice. Aged immune cells showed upregulated expression of all five aging-related genes and promoted RCC invasion compared to young immune cells. Further studies revealed DUSP22 as a regulator and druggable target of metastasis. DUSP22 gene knockdown reduced RCC invasion and the small molecule inhibitor BML-260 prevented RCC dissemination in a tumor/immune cell xenograft model. Overall, these results demonstrate that deciphering the relationship between aging-related gene expression in normal tissues and cancer patient survival can provide new prognostic markers, regulators of tumorigenesis and novel targets for drug development.

摘要

正常组织中衰老相关基因的表达与癌症患者生存率之间的关系尚未得到评估。我们开发了一种针对肿瘤旁正常组织的全基因组转录组分析方法，以鉴定与生存结果相关的衰老相关转录本，并将其应用于12种癌症类型。结果发现，正常组织中的五个衰老相关基因（DUSP22、MAPK14、MAPKAPK3、STAT1和VCP）与肾细胞癌（RCC）患者较差的生存结果显著相关。使用从小鼠和老年小鼠纯化的非致瘤免疫细胞对这种计算方法进行了研究。与年轻免疫细胞相比，老年免疫细胞显示出所有五个衰老相关基因的表达上调，并促进了RCC的侵袭。进一步的研究表明DUSP22是转移的调节因子和可成药靶点。DUSP22基因敲低减少了RCC的侵袭，小分子抑制剂BML-260在肿瘤/免疫细胞异种移植模型中阻止了RCC的扩散。总体而言，这些结果表明，解读正常组织中衰老相关基因表达与癌症患者生存率之间的关系可以提供新的预后标志物、肿瘤发生调节因子和药物开发的新靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83e5/8234889/8e02e1a0818f/cancers-13-03045-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83e5/8234889/fca06a7abeee/cancers-13-03045-g0A1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83e5/8234889/1d6329057591/cancers-13-03045-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83e5/8234889/ff4d58eae9e5/cancers-13-03045-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83e5/8234889/92bf2a2506a2/cancers-13-03045-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83e5/8234889/87d0d6c64ba0/cancers-13-03045-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83e5/8234889/8e02e1a0818f/cancers-13-03045-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83e5/8234889/fca06a7abeee/cancers-13-03045-g0A1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83e5/8234889/1d6329057591/cancers-13-03045-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83e5/8234889/ff4d58eae9e5/cancers-13-03045-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83e5/8234889/92bf2a2506a2/cancers-13-03045-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83e5/8234889/87d0d6c64ba0/cancers-13-03045-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/83e5/8234889/8e02e1a0818f/cancers-13-03045-g005.jpg

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