缺氧诱导的HIF1A通过nsun2介导的GDF15的稳定损害肝细胞癌中索拉非尼的敏感性

IF 3.7 2区 生物学 Q2 CELL BIOLOGY
Lude Wang , Bo Zhuang , Yiwen Jiang , Zewei Chen , Chenyang Ge , Min Yu , Shian Yu , Haiping Lin
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引用次数: 0

摘要

背景:肝细胞癌(HCC)是世界范围内癌症相关死亡的主要原因。尽管索拉非尼是晚期HCC的一线全身治疗,但对治疗的耐药性仍然是一个主要挑战。缺氧是肿瘤微环境的标志,已知可促进肿瘤生长和进展;然而,其在HCC中调节索拉非尼反应中的作用仍然知之甚少。方法在常氧或缺氧条件下培养shcc细胞株Hep3B和Huh7,并用索拉非尼处理。通过细胞活力、凋亡和集落形成试验来评估缺氧对索拉非尼敏感性的影响。荧光素酶报告基因和染色质免疫沉淀(ChIP)检测证实了hif1a介导的转录调节。通过RNA测序、m5C-RIP-Seq和生物信息学分析来鉴定nsun2介导的下游靶点。体外和体内评价GDF15中和联合索拉非尼的治疗效果。结果缺氧显著降低HCC细胞对索拉非尼的敏感性,IC50值升高,细胞凋亡减少。机制上,缺氧诱导的HIF1A上调RNA m5C甲基转移酶NSUN2,通过m5C修饰稳定GDF15 mRNA,导致GDF15分泌增强。在体外和体内模型中,中和GDF15抑制Akt/mTOR信号传导,增强对索拉非尼的敏感性。本研究揭示了缺氧诱导的HIF1A通过nsun2介导的GDF15的稳定和上调促进HCC索拉非尼耐药的新机制。靶向HIF1A/NSUN2/GDF15轴为HCC患者克服索拉非尼耐药提供了一种有希望的治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Hypoxia-induced HIF1A impairs sorafenib sensitivity in hepatocellular carcinoma through NSUN2-mediated stabilization of GDF15

Background

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Although sorafenib is a first-line systemic therapy for advanced HCC, resistance to treatment remains a major challenge. Hypoxia is a hallmark of the tumor microenvironment and is known to promote tumor growth and progression; however, its role in modulating sorafenib response in HCC remains poorly understood.

Methods

HCC cell lines (Hep3B and Huh7) were cultured under normoxic or hypoxic conditions and treated with sorafenib. Cell viability, apoptosis, and colony formation assays were conducted to evaluate the effect of hypoxia on sorafenib sensitivity. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays were used to confirm HIF1A-mediated transcriptional regulation. RNA sequencing, m5C-RIP-Seq, and bioinformatics analysis were performed to identify NSUN2-mediated downstream targets. The therapeutic efficacy of GDF15 neutralization in combination with sorafenib was assessed both in vitro and in vivo.

Results

Hypoxia significantly reduced HCC cell sensitivity to sorafenib, as evidenced by increased IC50 values and decreased apoptosis. Mechanistically, hypoxia-induced HIF1A upregulated the RNA m5C methyltransferase NSUN2, which stabilized GDF15 mRNA through m5C modification, leading to enhanced GDF15 secretion. Neutralization of GDF15 inhibited Akt/mTOR signaling and enhanced sensitivity to sorafenib in both in vitro and in vivo models.

Conclusion

This study uncovers a novel mechanism by which hypoxia-induced HIF1A promotes sorafenib resistance in HCC via the NSUN2-mediated stabilization and upregulation of GDF15. Targeting the HIF1A/NSUN2/GDF15 axis offers a promising therapeutic strategy to overcome sorafenib resistance in HCC patients.
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来源期刊
Cellular signalling
Cellular signalling 生物-细胞生物学
CiteScore
8.40
自引率
0.00%
发文量
250
审稿时长
27 days
期刊介绍: Cellular Signalling publishes original research describing fundamental and clinical findings on the mechanisms, actions and structural components of cellular signalling systems in vitro and in vivo. Cellular Signalling aims at full length research papers defining signalling systems ranging from microorganisms to cells, tissues and higher organisms.
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