Chun-Yan Feng, Cheng-Song Cai, Xiao-Qian Shi, Zhi-Juan Zhang, Dan Su, Yun-Qing Qiu
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引用次数: 0
摘要
目的:白藜芦醇(Res)是一种治疗肝细胞癌(HCC)的抗癌药物,但其抗HCC作用是否与有丝分裂有关仍不清楚。方法:采用 HepG2 细胞和肿瘤移植裸鼠,分别研究低、中、高剂量的 Res 在体外和体内对 HCC 进展和有丝分裂的影响。研究采用了一系列方法来评估肿瘤细胞的功能,包括细胞计数试剂盒-8、流式细胞术、伤口愈合和透孔试验。透射电子显微镜、免疫荧光和 Western 印迹技术用于评估有丝分裂。线粒体耗氧率、活性氧和膜电位用于反映线粒体功能。在破坏转移相关肺腺癌转录本1(MALAT1)、miR-143-3p和核糖核苷还原酶M2(RRM2)的表达后,体外研究了MALAT1/miR-143-3p/RRM2轴在Res处理下对细胞功能和有丝分裂的影响。此外,还使用双荧光素酶报告和染色质免疫沉淀来确认靶基因之间的相互作用:结果:Res在体外能明显抑制HCC细胞的增殖并促进其凋亡,在体内能以剂量依赖性方式明显抑制肿瘤生长并诱导有丝分裂和线粒体功能障碍。有趣的是,MALAT1在HCC细胞中高表达,其敲除可上调HCC细胞中miR-143-3p的表达,进而抑制RRM2的表达。此外,在移植了 HCC 肿瘤并接受 Res 治疗的裸鼠体内,MALAT1、miR-143-3p 和 RRM2 的表达也发生了显著变化。体外数据进一步证实了 MALAT1 和 miR-143-3p 以及 miR-143-3p 和 RRM2 之间的靶向结合关系。因此,我们开展了一系列基于细胞的实验,研究MALAT1/miR-143-3p/RRM2轴参与有丝分裂和HCC的机制;这些实验显示,MALAT1敲除、miR-143-3p模拟和RRM沉默增强了Res的抗肿瘤作用及其激活有丝分裂的作用:结论:Res通过靶向MALAT1/miR-143-3p/RRM2轴促进HCC中的有丝分裂并发挥抗癌作用。本文引用如前Feng CY, Cai CS, Shi XQ, Zhang ZJ, Su D, Qiu YQ.白藜芦醇通过MALAT1/miR-143-3p/RRM2轴促进有丝分裂并抑制肝细胞癌的癌症进展J Integr Med.2024; Epub ahead of print.
Resveratrol promotes mitophagy via the MALAT1/miR-143-3p/RRM2 axis and suppresses cancer progression in hepatocellular carcinoma.
Objective: Resveratrol (Res) is a promising anticancer drug against hepatocellular carcinoma (HCC), but whether its anti-HCC effects implicate mitophagy remains unclear. Therefore, we aimed to explore the specific role of Res in mitophagy and the related mechanisms during the treatment of HCC.
Methods: HepG2 cells and tumor-grafted nude mice were used to investigate the effects of low-, middle- and high-dose of Res on HCC progression and mitophagy in vitro and in vivo, respectively. A series of approaches including cell counting kit-8, flow cytometry, wound healing and transwell assays were used to evaluate tumor cell functions. Transmission electron microscopy, immunofluorescence and Western blotting were used to assess mitophagy. Mitochondrial oxygen consumption rate, reactive oxygen species and membrane potential were used to reflect mitochondrial function. After disrupting the expression of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), miR-143-3p, and ribonucleoside reductase M2 (RRM2), the effects of the MALAT1/miR-143-3p/RRM2 axis on cell function and mitophagy under Res treatment were explored in vitro. Additionally, dual-luciferase reporter and chromatin immunoprecipitation were used to confirm interactions between target genes.
Results: Res significantly inhibited the proliferation and promoted apoptosis of HCC cells in vitro, while significantly suppressing tumor growth in a dose-dependent manner and inducing mitophagy and mitochondrial dysfunction in vivo. Interestingly, MALAT1 was highly expressed in HCC cells and its knockdown upregulated miR-143-3p expression in HCC cells, which subsequently inhibited RRM2 expression. Furthermore, in nude mice grafted with HCC tumors and treated with Res, the expression of MALAT1, miR-143-3p and RRM2 were altered significantly. In vitro data further supported the targeted binding relationships between MALAT1 and miR-143-3p and between miR-143-3p and RRM2. Therefore, a series of cell-based experiments were carried out to study the mechanism of the MALAT1/miR-143-3p/RRM2 axis involved in mitophagy and HCC; these experiments revealed that MALAT1 knockdown, miR-143-3p mimic and RRM silencing potentiated the antitumor effects of Res and its activation of mitophagy.
Conclusion: Res facilitated mitophagy in HCC and exerted anti-cancer effects by targeting the MALAT1/miR-143-3p/RRM2 axis. Please cite this article as: Feng CY, Cai CS, Shi XQ, Zhang ZJ, Su D, Qiu YQ. Resveratrol promotes mitophagy via the MALAT1/miR-143-3p/RRM2 axis and suppresses cancer progression in hepatocellular carcinoma. J Integr Med. 2024; Epub ahead of print.
期刊介绍:
The predecessor of JIM is the Journal of Chinese Integrative Medicine (Zhong Xi Yi Jie He Xue Bao). With this new, English-language publication, we are committed to make JIM an international platform for publishing high-quality papers on complementary and alternative medicine (CAM) and an open forum in which the different professions and international scholarly communities can exchange views, share research and their clinical experience, discuss CAM education, and confer about issues and problems in our various disciplines and in CAM as a whole in order to promote integrative medicine.
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