Sensitization of hepatocellular carcinoma cells to HDACi is regulated through hsa-miR-342-5p/CFL1.

IF 5.3 2区 医学 Q1 ONCOLOGY
Parvathi Nakka, Chikondi Jassi, Ming-Cheng Chen, Yi-Sheng Liu, Jer-Yuh Liu, Chung-Min Yeh, Chi-Cheng Li, Yu-Chun Chang, Wei-Wen Kuo, Chih-Yang Huang
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Abstract

Background: Increased prevalence of hepatocellular carcinoma (HCC) remains a global health challenge. HCC chemoresistance is a clinical obstacle for its management. Aberrant miRNA expression is a hallmark for both cancer progression and drug resistance. However, it is unclear which miRNAs are involved in HCC chemoresistance.

Methods: MicroRNA microarray analysis revealed a differential expression profile of microRNAs between the hepatocellular carcinoma HA22T cell line and the HDACi-R cell line, which was validated by quantitative real-time PCR (qRT-PCR). To determine the biological function of miR-342-5p and the mechanism of the microRNA-342-5p/CFL1 axis in hepatocellular carcinoma HDACi resistance, loss- and gain-of-function studies were conducted in vitro.

Results: Here we demonstrated the molecular mechanism of histone deacetylase inhibitor (HDACi) resistance in HCC. Differential miRNA expression analysis showed significant down regulation of miR-342-5p in HDACi-R cells than in parental HA22T cells. Mimics of miR-342-5p enhanced apoptosis through upregulation of Bax, cyto-C, cleaved-caspase-3 expressions with concomitant decline in anti-apoptotic protein (Bcl-2) in HDACi-R cells. Although HDACi did not increase cell viability of HDACi-R, overexpression of miR-342-5p decreased cofilin-1 expression, upregulated reactive oxygen species (ROS) mediated apoptosis, and sensitized HDACi-R to HDACi in a dose-dependent manner.

Conclusion: Our findings demonstrated the critical role of miR-342-5p in HDACi resistance of HCC and that this mechanism might be attributed to miR-342-5p/cofilin-1 regulation.

肝癌细胞对 HDACi 的敏感性通过 hsa-miR-342-5p/CFL1 调节。
背景:肝细胞癌(HCC)发病率的增加仍是一项全球健康挑战。HCC 的化疗耐药性是临床治疗的一个障碍。miRNA 表达异常是癌症进展和耐药性的标志。然而,目前还不清楚哪些miRNA参与了HCC的化疗耐药性:方法:微RNA芯片分析显示,肝癌HA22T细胞系和HDACi-R细胞系的微RNA表达存在差异,并通过定量实时PCR(qRT-PCR)进行了验证。为了确定miR-342-5p的生物学功能以及microRNA-342-5p/CFL1轴在肝癌HDACi耐药中的作用机制,我们在体外进行了功能缺失和功能增益研究:结果:我们证明了组蛋白去乙酰化酶抑制剂(HDACi)在HCC中耐药的分子机制。差异miRNA表达分析表明,与亲本HA22T细胞相比,HDACi-R细胞中miR-342-5p的表达明显下降。在HDACi-R细胞中,miR-342-5p的模拟物通过上调Bax、cyto-C、裂解-caspase-3的表达增强了细胞凋亡,同时降低了抗凋亡蛋白(Bcl-2)的表达。虽然HDACi没有提高HDACi-R的细胞活力,但过表达miR-342-5p会降低cofilin-1的表达,上调活性氧(ROS)介导的细胞凋亡,并以剂量依赖的方式使HDACi-R对HDACi敏感:我们的研究结果表明,miR-342-5p在HCC的HDACi耐药中起着关键作用,而这一机制可能归因于miR-342-5p/cofilin-1的调控。
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
CiteScore
10.90
自引率
1.70%
发文量
360
审稿时长
1 months
期刊介绍: Cancer Cell International publishes articles on all aspects of cancer cell biology, originating largely from, but not limited to, work using cell culture techniques. The journal focuses on novel cancer studies reporting data from biological experiments performed on cells grown in vitro, in two- or three-dimensional systems, and/or in vivo (animal experiments). These types of experiments have provided crucial data in many fields, from cell proliferation and transformation, to epithelial-mesenchymal interaction, to apoptosis, and host immune response to tumors. Cancer Cell International also considers articles that focus on novel technologies or novel pathways in molecular analysis and on epidemiological studies that may affect patient care, as well as articles reporting translational cancer research studies where in vitro discoveries are bridged to the clinic. As such, the journal is interested in laboratory and animal studies reporting on novel biomarkers of tumor progression and response to therapy and on their applicability to human cancers.
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