miR-4461 inhibits liver cancer stem cells expansion and chemoresistance via regulating SIRT1.

IF 3.3 3区医学 Q2 ONCOLOGY Carcinogenesis Pub Date : 2024-07-08 DOI:10.1093/carcin/bgac093

Daji Yang, Ping Zhang, Ziting Yang, Guojun Hou, Ziyu Yang

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Abstract

MicroRNAs (miRNAs) were involved in tumorigenesis, progression, recurrence and drug resistance of hepatocellular carcinoma (HCC). However, few miRNAs have been identified and entered clinical practice. We show here that miR-4461 expression is reduced in liver cancer stem cells (CSCs) and predicts the poor prognosis of HCC patients. Knockdown of miR-4461 enhances the self-renewal and tumorigenicity of liver CSCs. Conversely, forced miR-4461 expression inhibits liver CSCs self-renewal and tumorigenesis. Mechanically, miR-4461 directly targets sirtuin 1 (SIRT1) via binding to its 3' untranslated region in liver CSCs. The correlation of miR-4461 and SIRT1 was confirmed in human HCC patients' tissues. Additionally, we found that miR-4461 overexpression hepatoma cells are more sensitive to cisplatin treatment. Patient-derived xenografts also showed that miR-4461 high HCC xenografts are sensitive to cisplatin treatment. Clinical cohort analysis further confirmed that HCC patients with high miR-4461 benefited more from transcatheter arterial chemoembolization treatment. In conclusion, our findings revealed the crucial role of miR-4461 in liver CSCs expansion and cisplatin response, rendering miR-4461 as an optimal target for the prevention and intervention of HCC.

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miR-4461 通过调节 SIRT1 抑制肝癌干细胞扩增和化疗抗性

微RNA（miRNA）参与了肝细胞癌（HCC）的肿瘤发生、发展、复发和耐药性。然而，目前已发现并进入临床实践的 miRNA 甚少。我们在此发现，肝癌干细胞（CSCs）中 miR-4461 的表达减少，并可预测 HCC 患者的不良预后。敲除 miR-4461 会增强肝癌干细胞的自我更新能力和致瘤性。相反，强制表达 miR-4461 会抑制肝脏 CSCs 的自我更新和肿瘤发生。在机制上，miR-4461 通过与肝脏 CSCs 中的 sirtuin 1（SIRT1）的 3'-UTR 结合直接靶向 SIRT1。在人类 HCC 患者组织中证实了 miR-4461 与 SIRT1 的相关性。此外，我们发现过表达 miR-4461 的肝癌细胞对顺铂治疗更敏感。PDXs也显示，miR-4461高表达的HCC异种移植物对顺铂治疗更敏感。临床队列分析进一步证实，miR-4461 高的 HCC 患者从经导管动脉化疗栓塞（TACE）治疗中获益更多。总之，我们的研究结果揭示了miR-4461在肝脏造血干细胞扩增和顺铂反应中的关键作用，使miR-4461成为预防和干预HCC的最佳靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Carcinogenesis 医学-肿瘤学

CiteScore

9.20

自引率

2.10%

发文量

审稿时长

1 months

期刊介绍： Carcinogenesis: Integrative Cancer Research is a multi-disciplinary journal that brings together all the varied aspects of research that will ultimately lead to the prevention of cancer in man. The journal publishes papers that warrant prompt publication in the areas of Biology, Genetics and Epigenetics (including the processes of promotion, progression, signal transduction, apoptosis, genomic instability, growth factors, cell and molecular biology, mutation, DNA repair, genetics, etc.), Cancer Biomarkers and Molecular Epidemiology (including genetic predisposition to cancer, and epidemiology), Inflammation, Microenvironment and Prevention (including molecular dosimetry, chemoprevention, nutrition and cancer, etc.), and Carcinogenesis (including oncogenes and tumor suppressor genes in carcinogenesis, therapy resistance of solid tumors, cancer mouse models, apoptosis and senescence, novel therapeutic targets and cancer drugs).