酒精在肝细胞癌中诱导索拉费尼布耐药性:一个翻译性研究
Anoïsia Courtois1, Constance Marié2, Gregory Fouquet1
1Groupe de Recherche Sur L'Alcool Et Les Pharmacodépendances (GRAP), UMR 1247, INSERM, Centre Universitaire de Recherche en Santé (CURS) CHU Sud, Université de Picardie Jules Verne, Avenue de Conty, 80000, Salouel, Amiens, France.
Journal of molecular medicine (Berlin, Germany)
|January 24, 2026
概括
长期暴露于酒精显著降低了索拉芬尼在肝细胞癌 (HCC) 的有效性. 这导致药物耐药性增加,患者存活率降低,并表明需要替代性治疗与酒精有关的HCC.
科学领域:
- 在瘤学瘤学.
- 肝病学 肝病学是一种肝病学.
- 药理学 药理学是指药理学的学科.
背景情况:
- 酒精消费是肝细胞癌 (HCC) 的主要原因,占全球病例的30%.
- 索拉菲尼布是一种氨酸激酶抑制剂 (TKI),是高级HCC的标准一线治疗方法,但通常会遇到抗药性.
研究的目的:
- 调查慢性酒精暴露 (CAE) 对HCC索拉芬尼布反应的影响.
- 确定与酒精相关的HCC中索拉芬尼抗性背后的分子机制.
主要方法:
- 在体外:Huh-7 HCC细胞长期暴露在酒精中,随后评估索拉芬尼的敏感性 (IC50) 和信号通路分析 (免疫阻塞).
- 使用RNA测序来识别差异表达的基因.
- 临床:一项对86名HCC患者的回顾性研究评估了基于酒精病因的索拉费尼布反应 (RECIST 1.1),总生存率 (OS) 和无进展生存率 (PFS).
主要成果:
- 在体外,CAE显著增加了索拉芬尼抗性 (p=0.006),与ERK通路激活和80个差异表达基因相关.
- 与酒精相关的HCC患者的索拉费尼布反应率较低 (35%对65%,p=0.014).
- 与非酒精相关的HCC患者相比,与酒精相关的HCC患者相比,与酒精相关的HCC患者相比,与酒精相关的HCC患者相比,与酒精相关的HCC患者相比,与酒精相关的HCC患者相比,与酒精相关的HCC患者相比,与酒精相关的HCC患者相比,与酒精相关的HCC患者相比,与酒精相关的HCC患者相比,与酒精相关的HCC患者相比,与酒精相关的HCC患者相比,与酒精相关的HCC患者相比,与酒精相关的HCC患者相比,与酒精相关的HCC患者相比,与酒精相关的HCC患者相比,与酒精相关的HCC患者相比,与酒精相关的HCC患者相比,与酒精相关的HCC患者相比,与酒精相关的HCC患者相比,与酒精相关的HCC患者相比,与酒精相关的HCC.
结论:
- 慢性饮酒使HCC患者对索拉费尼布产生耐药性,这在实验模型和临床数据中得到了验证.
- 这些发现突出了ERK途径和酒精诱导的索拉芬尼布耐药性的特定基因表达变化.
- 与酒精相关的HCC可能需要个性化治疗策略,超出目前的TKI治疗.
相关概念视频
01:31Translation
156.0K
Lesson: Translation
Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
Translation Produces the Building Blocks of...
Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
Translation Produces the Building Blocks of...
156.0K
01:31Translation
17.7K
Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
Translation Produces the Building Blocks of Life
Proteins are...
Translation Produces the Building Blocks of Life
Proteins are...
17.7K
02:07Improving Translational Accuracy
14.1K
Base complementarity between the three base pairs of mRNA codon and the tRNA anticodon is not a failsafe mechanism. Inaccuracies can range from a single mismatch to no correct base pairing at all. The free energy difference between the correct and nearly correct base pairs can be as small as 3 kcal/ mol. With complementarity being the only proofreading step, the estimated error frequency would be one wrong amino acid in every 100 amino acids incorporated. However, error frequencies observed in...
14.1K
02:33Initiation of Translation
38.5K
Initiating translation is complex because it involves multiple molecules. Initiator tRNA, ribosomal subunits, and eukaryotic initiation factors (eIFs) are all required to assemble on the initiation codon of mRNA. This process consists of several steps that are mediated by different eIFs.
First, the initiator tRNA must be selected from the pool of elongator tRNAs by eukaryotic initiation factor 2 (eIF2). The initiator tRNA (Met-tRNAi) has conserved sequence elements including modified bases at...
First, the initiator tRNA must be selected from the pool of elongator tRNAs by eukaryotic initiation factor 2 (eIF2). The initiator tRNA (Met-tRNAi) has conserved sequence elements including modified bases at...
38.5K
01:44Termination of Translation
27.5K
The large ribosomal subunit has several important structures essential to translation. These include the peptidyl transferase center (PTC) - which is the site where the peptide bond is formed - and a large, internal, water-filled tube through which the nascent polypeptide moves. This latter structure is called the Peptide Exit Tunnel, and it begins at the PTC and spans the body of the large ribosomal subunit. During translation, as the nascent polypeptide chain is synthesized, it passes through...
27.5K
02:37Oxidation of Alcohols
15.8K
In this lesson, the oxidation of alcohols is discussed in depth. The various reagents used for oxidation of primary and secondary alcohols are detailed, and their mechanism of action is provided.
The process of oxidation in a chemical reaction is observed in any of the three forms:
The process of oxidation in a chemical reaction is observed in any of the three forms:
15.8K