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长链非编码RNA DDX11-AS1通过Nrf2-Keap1途径抑制索拉非尼诱导的肝癌细胞铁死亡。

Long noncoding RNA DDX11-AS1 represses sorafenib-induced ferroptosis in hepatocellular carcinoma cells via Nrf2-Keap1 pathway.

作者信息

Wang Liang, Wang Liming

机构信息

The Second Affiliated Hospital of Dalian Medical University, Dalian, China, NO. 467, Zhongshan Road, Shahekou district, Liaoning, 116000.

出版信息

Discov Oncol. 2024 Oct 10;15(1):544. doi: 10.1007/s12672-024-01431-0.

DOI:10.1007/s12672-024-01431-0
PMID:39390130
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11467156/
Abstract

Sorafenib, a first-line therapeutic option for advanced hepatocellular carcinoma (HCC), faces a formidable challenge in the form of emerging resistance. Recently, the oncogene DDX11 antisense RNA 1 (DDX11-AS1) has been implicated in various cancers, including HCC. However, its role in sorafenib resistance remains unknown. Our findings reveal that DDX11-AS1 is upregulated in sorafenib-resistant HCC cells, contributing to their resistance by suppressing ferroptosis. Further investigation elucidated the mechanism by which DDX11-AS1 activates the antioxidant Nrf2-Keap1 pathway. By interacting with Nrf2 and hindering its association with Keap1, DDX11-AS1 enhances the stability and nuclear translocation of Nrf2. In summary, our study unveils the potent role of DDX11-AS1 as an enhancer of sorafenib resistance, inhibiting sorafenib-induced ferroptosis through the activation of the Nrf2-Keap1 pathway in HCC. These findings offer a promising therapeutic strategy to overcome resistance and effectively treat HCC.

摘要

索拉非尼作为晚期肝细胞癌（HCC）的一线治疗选择，面临着新出现的耐药性这一严峻挑战。最近，致癌基因DDX11反义RNA 1（DDX11-AS1）已被证明与包括HCC在内的多种癌症有关。然而，其在索拉非尼耐药中的作用尚不清楚。我们的研究结果表明，DDX11-AS1在索拉非尼耐药的HCC细胞中上调，通过抑制铁死亡促进其耐药性。进一步的研究阐明了DDX11-AS1激活抗氧化剂Nrf2-Keap1途径的机制。通过与Nrf2相互作用并阻碍其与Keap1的结合，DDX11-AS1增强了Nrf2的稳定性和核转位。总之，我们的研究揭示了DDX11-AS1作为索拉非尼耐药增强剂的重要作用，通过激活HCC中的Nrf2-Keap1途径抑制索拉非尼诱导的铁死亡。这些发现为克服耐药性并有效治疗HCC提供了一种有前景的治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fb91/11467156/daf126b0466a/12672_2024_1431_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fb91/11467156/1deaafba4c9b/12672_2024_1431_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fb91/11467156/bd6e1e99d2c6/12672_2024_1431_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fb91/11467156/3796bbec0660/12672_2024_1431_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fb91/11467156/d5450364ffce/12672_2024_1431_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fb91/11467156/daf126b0466a/12672_2024_1431_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fb91/11467156/1deaafba4c9b/12672_2024_1431_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fb91/11467156/bd6e1e99d2c6/12672_2024_1431_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fb91/11467156/3796bbec0660/12672_2024_1431_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fb91/11467156/d5450364ffce/12672_2024_1431_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fb91/11467156/daf126b0466a/12672_2024_1431_Fig5_HTML.jpg

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