Li Dahuan, Bao Xin, Lei Shan, Cao Wenpeng, Zeng Zhirui, Chen Tengxiang
Engineering Research Center of Chronic Disease Diagnosis and Treatment, Guizhou Medical University, Guiyang 550025, China.
Department of Physiology, School of Basic Medicine, Guizhou Medical University, Guiyang 550025, China.
Biology (Basel). 2024 Aug 19;13(8):633. doi: 10.3390/biology13080633.
Hepatocellular carcinoma (HCC) is a prevalent malignant digestive tumor. Numerous genetic mutations have been documented in HCC, yet the clinical significance of these mutations remains largely unexplored. The objective of this study is to ascertain the clinical value and biological effects of xin actin binding repeat containing 2 () mutation in HCC. The gene mutation landscape of HCC was examined using data from the Cancer Genome Atlas and the International Cancer Genome Consortium databases. The prognostic significance of the mutation was assessed through KM plot analysis. The association between drug sensitivity and the mutation was investigated using the TIDE algorithm and CCK-8 experiments. The biological effects of the mutation were evaluated through qRT-PCR, protein stability experiments, and relevant biological experiments. The mutation is one of the high-frequency mutations in HCC, and is associated with poor prognosis. A total of 72 differentially expressed genes (DEGs) were observed in HCC tissues with the mutation as compared to those with the wildtype, and these DEGs were closely related to ion metabolic processes. The mutation was linked to alterations in the sensitivity of fludarabine, oxaliplatin, WEHI-539, and LCL-161. CCK-8 assays demonstrated that HCC cells carrying the mutation exhibited increased resistance to fludarabine and oxaliplatin, but enhanced sensitivity to WEHI-539 and LCL-161 as compared with those HCC cells with the wildtype. The mutation was found to have no impact on the mRNA levels of XIRP2 in tissues and cells, but it did enhance the stability of the XIRP2 protein. Mechanically, the inhibition of resulted in a significant increase in sensitivity to oxaliplatin through an elevation in zinc ions and a calcium ion overload. In conclusion, the mutation holds potential as a biomarker for predicting the prognosis and drug sensitivity of HCC and serves as a therapeutic target to enhance the efficacy of oxaliplatin.
肝细胞癌（HCC）是一种常见的恶性消化肿瘤。HCC中已记录了众多基因突变，但其临床意义在很大程度上仍未得到充分探索。本研究的目的是确定含xin肌动蛋白结合重复序列2（XIRP2）突变在HCC中的临床价值和生物学效应。利用癌症基因组图谱（The Cancer Genome Atlas）和国际癌症基因组联盟（International Cancer Genome Consortium）数据库的数据，研究了HCC的基因突变图谱。通过KM曲线分析评估XIRP2突变的预后意义。利用TIDE算法和CCK-8实验研究药物敏感性与XIRP2突变之间的关联。通过qRT-PCR、蛋白质稳定性实验及相关生物学实验评估XIRP2突变的生物学效应。XIRP2突变是HCC中的高频突变之一，与预后不良相关。与野生型XIRP2的HCC组织相比，携带XIRP2突变的HCC组织中共观察到72个差异表达基因（DEG），这些DEG与离子代谢过程密切相关。XIRP2突变与氟达拉滨、奥沙利铂、WEHI-539和LCL-161的敏感性改变有关。CCK-8实验表明，与野生型XIRP2的HCC细胞相比，携带XIRP2突变的HCC细胞对氟达拉滨和奥沙利铂的耐药性增加，但对WEHI-539和LCL-161的敏感性增强。发现XIRP2突变对组织和细胞中XIRP2的mRNA水平没有影响，但确实增强了XIRP2蛋白的稳定性。从机制上讲，抑制XIRP2会通过锌离子升高和钙离子过载导致对奥沙利铂的敏感性显著增加。总之，XIRP2突变具有作为预测HCC预后和药物敏感性的生物标志物的潜力，并可作为增强奥沙利铂疗效的治疗靶点。
