Oncogenic lncRNA BBOX1-AS1 promotes PHF8-mediated autophagy and elicits sorafenib resistance in hepatocellular carcinoma.

IF 5.3 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Molecular Therapy Oncolytics Pub Date : 2023-03-16 DOI:10.1016/j.omto.2022.12.005

Haisu Tao, Yuxin Zhang, Jiang Li, Junjie Liu, Tong Yuan, Wenqiang Wang, Huifang Liang, Erlei Zhang, Zhiyong Huang

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引用次数: 5

Abstract

Some long non-coding RNAs (lncRNAs) have been documented to be involved in cancer progression and anticancer drug resistance in hepatocellular carcinoma (HCC). Thus, approaches designed to target these genes may facilitate the development of promising strategies for treating HCC. Previously, we showed that lncRNA BBOX1-AS1 was highly expressed and played an oncogenic role in HCC. However, the potential functions and mechanisms through which BBOX1-AS1 regulates HCC progression and drug resistance remain unclear. This study revealed that BBOX1-AS1 could promote tumor progression, autophagy, and drug resistance by upregulating PHF8 in HCC cells. Mechanistically, BBOX1-AS1 enhanced the stability of PHF8 mRNA by targeting the PHF8 inhibitor miR-361-3p to regulate tumor progression and autophagy in HCC. The functional rescue experiments showed that PHF8 acted as a key factor in regulating the biological effects induced by BBOX1-AS1 and miR-361-3p in HCC, indicating that BBOX1-AS1 promotes tumor progression and sorafenib resistance by regulating miR-361-3p/PHF8. Finally, mouse tumor models and patient-derived organoid models were established to further confirm these findings. Taken together, the results demonstrate that BBOX1-AS1 promotes HCC progression and sorafenib resistance via the miR-361-3p/PHF8 axis.

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致癌lncRNA BBOX1-AS1在肝细胞癌中促进phf8介导的自噬并引发索拉非尼耐药。

一些长链非编码rna (lncRNAs)已被证实参与肝细胞癌(HCC)的癌症进展和抗癌耐药。因此，针对这些基因设计的方法可能促进HCC治疗策略的发展。之前，我们发现lncRNA BBOX1-AS1在HCC中高表达并发挥致瘤作用。然而，BBOX1-AS1调控HCC进展和耐药的潜在功能和机制尚不清楚。本研究发现BBOX1-AS1可通过上调肝癌细胞PHF8促进肿瘤进展、自噬和耐药。在机制上，BBOX1-AS1通过靶向PHF8抑制剂miR-361-3p来调节HCC中的肿瘤进展和自噬，从而增强PHF8 mRNA的稳定性。功能抢救实验显示，PHF8是调控BBOX1-AS1和miR-361-3p在HCC中诱导的生物学效应的关键因子，说明BBOX1-AS1通过调控miR-361-3p/PHF8促进肿瘤进展和索拉非尼耐药。最后，建立小鼠肿瘤模型和患者来源的类器官模型来进一步证实这些发现。综上所述，结果表明BBOX1-AS1通过miR-361-3p/PHF8轴促进HCC进展和索拉非尼耐药。

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

Molecular Therapy Oncolytics Medicine-Oncology

CiteScore

10.90

自引率

3.50%

发文量

152

审稿时长

6 weeks

期刊介绍： Molecular Therapy — Oncolytics is an international, online-only, open access journal focusing on the development and clinical testing of viral, cellular, and other biological therapies targeting cancer.