Nakka Parvathi, Jassi Chikondi, Chen Ming-Cheng, Liu Yi-Sheng, Liu Jer-Yuh, Yeh Chung-Min, Li Chi-Cheng, Chang Yu-Chun, Kuo Wei-Wen, Huang Chih-Yang
Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 404, Taiwan.
Department of Biological Science and Technology, China Medical University, Taichung, 406, Taiwan.
Cancer Cell Int. 2024 Aug 16;24(1):291. doi: 10.1186/s12935-024-03450-x.
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.
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.
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.
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.
肝细胞癌（HCC）患病率的上升仍然是一项全球性的健康挑战。HCC化疗耐药是其治疗过程中的一个临床障碍。异常的miRNA表达是癌症进展和耐药的一个标志。然而，尚不清楚哪些miRNA参与了HCC化疗耐药。
MicroRNA微阵列分析揭示了肝细胞癌HA22T细胞系和HDACi-R细胞系之间miRNA的差异表达谱，该结果通过定量实时PCR（qRT-PCR）得到验证。为了确定miR-342-5p的生物学功能以及microRNA-342-5p/CFL1轴在肝细胞癌HDACi耐药中的机制，在体外进行了功能缺失和功能获得研究。
在此我们展示了HCC中组蛋白去乙酰化酶抑制剂（HDACi）耐药的分子机制。差异miRNA表达分析显示，与亲代HA22T细胞相比，HDACi-R细胞中miR-342-5p显著下调。miR-342-5p模拟物通过上调Bax、细胞色素C、裂解的半胱天冬酶-3的表达增强了HDACi-R细胞的凋亡，同时抗凋亡蛋白（Bcl-2）下降。虽然HDACi没有增加HDACi-R细胞的活力，但miR-342-5p的过表达降低了丝切蛋白-1的表达，上调了活性氧（ROS）介导的凋亡，并使HDACi-R对HDACi呈剂量依赖性敏感。
我们的研究结果证明了miR-342-5p在HCC的HDACi耐药中起关键作用，并且这种机制可能归因于miR-342-5p/丝切蛋白-1调控。
