过表达促进肝细胞癌的进展及对酪氨酸激酶抑制剂的耐药性。

Overexpression Facilitates the Progression and Tyrosine Kinase Inhibitor Resistance in Hepatocellular Carcinoma.

作者信息

Luo Jie, Qin Kai, He Rong Quan, Li Jian Di, Huang Zhi Guang, Yin Bin Tong, Wu Tong, Chen Yu Zhen, Qin Di Yuan, Luo Jia Yuan, Wu Mei, Chi Bang Teng, Chen Gang, Li Jian Jun, Huang Yu Bin

机构信息

Department of Oncology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530007, Guangxi, China.

These authors contributed equally to this work.

出版信息

World J Oncol. 2024 Dec;15(6):882-901. doi: 10.14740/wjon1944. Epub 2024 Dec 11.

DOI:10.14740/wjon1944

PMID:39697424

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11650614/

Abstract

BACKGROUND

In the present day, hepatocellular carcinoma (HCC) remains a formidable threat to human health. Actin-related protein 10 () is related to tyrosine kinase inhibitor (TKI) resistance. A comprehensive analysis of in HCC will further our understanding of the molecular mechanisms underlying this resistance phenomenon, shedding light on potential therapeutic strategies for combating TKI resistance in HCC.

METHODS

We conducted an integration of high-throughput datasets across various centers, analyzing expression using the Cancer Cell Line Encyclopedia (CCLE) and assessing its implications through clustered regularly interspaced short palindromic repeats (CRISPR) knockout screen. Pathogenic mechanisms were elucidated through enrichment analysis. Prognostic assessment utilized Kaplan-Meier survival and univariate Cox analyses. An integrated analysis of gene expression profiles related to TKI in HCC was conducted, and TKI resistance mechanisms were explored through enrichment analysis. Potential therapeutic drugs were identified using the Drug Gene Budger database and molecular docking techniques.

RESULTS

The standardized mean difference (SMD) of 0.34 (95% confidence interval (CI): 0.22 - 0.45, P < 0.05) and -dependent growth in HCC cells confirm its upregulation in HCC. The area under the summary receiver operating characteristic (sROC) curve was 0.69, indicating moderate discriminative ability of in HCC patients. exerts its pro-cancer effect by influencing RNA splicing, mRNA processing and nucleocytoplasmic transport. A hazard ratio of 2.19 (95% CI: 1.56 - 3.08, P < 0.05) identifies as an independent prognostic risk factor. Additionally, the SMD of 0.88 (95% CI: 0.01 - 0.76, P < 0.05) validates as a TKI-resistance gene, mediating resistance via enhanced exocytosis, autophagy, and apoptosis in HCC patients. Trichostatin A emerges as a prospective targeted agent for HCC.

CONCLUSION

The upregulation of accelerates HCC progression, promotes TKI resistance, and emerges as a prospective target for the treatment of HCC.

摘要

背景

如今，肝细胞癌（HCC）仍然是对人类健康的巨大威胁。肌动蛋白相关蛋白10（）与酪氨酸激酶抑制剂（TKI）耐药性有关。对HCC中进行全面分析将增进我们对这种耐药现象潜在分子机制的理解，为对抗HCC中TKI耐药性的潜在治疗策略提供线索。

方法

我们整合了各个中心的高通量数据集，使用癌细胞系百科全书（CCLE）分析表达情况，并通过成簇规律间隔短回文重复序列（CRISPR）敲除筛选评估其影响。通过富集分析阐明致病机制。预后评估采用Kaplan-Meier生存分析和单变量Cox分析。对HCC中与TKI相关的基因表达谱进行综合分析，并通过富集分析探索TKI耐药机制。使用药物基因预算数据库和分子对接技术鉴定潜在的治疗药物。

结果

标准化平均差（SMD）为0.34（95%置信区间（CI）：0.22 - 0.45，P < 0.05）以及HCC细胞中依赖生长证实了其在HCC中的上调。汇总接受者操作特征（sROC）曲线下面积为0.69，表明在HCC患者中的鉴别能力中等。通过影响RNA剪接、mRNA加工和核质运输发挥促癌作用。风险比为2.19（95% CI：1.56 - 3.08，P < 0.05）表明是一个独立的预后危险因素。此外，SMD为0.88（95% CI：0.01 - 0.76，P < 0.05）证实为TKI耐药基因，通过增强HCC患者的胞吐作用、自噬和凋亡介导耐药。曲古抑菌素A成为HCC的一种潜在靶向药物。