Zhang Guan-Lan, Li Jian-Di, He Ji-Feng, Wu Kun-Jun, Mo Ying-Yu, Zhong Song-Yang, Wang Xuan-Fei, Wu Fei-Fei, Qin Yi-Si, Zhao Hong, Huang Zhi-Guang, Chen Gang, He Rong-Quan
Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
Adv Clin Exp Med. 2025 May;34(5):787-801. doi: 10.17219/acem/188425.
Novel treatments such as monotherapy and combined immunotherapy significantly extend overall survival (OS) for hepatocellular carcinoma (HCC) patients, but HCC is susceptible to treatment resistance during long-term therapy. The resistance mechanism to targeted drugs in HCC remains ambiguous, making research on HCC drug resistance targets crucial for the development of precision medicine.
To investigate the transcriptional features, biological functions and potential clinical value of the tyrosine kinase inhibitor (TKI)-resistant gene ZNF687 in HCC.
The TKI-resistant genes of HCC were identified using clustered regularly interspaced short palindromic repeats (CRISPR) in vitro screening. Then, the dependence of HCC cell lines on ZNF687 was investigated in silico. We collected global mRNA datasets of HCC tissue, integrated the mRNA expression characteristics of ZNF687 in HCC and explored the impact of ZNF687 on HCC patient prognoses using the Kaplan-Meier method (in silico). The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analyses were then conducted, and a connectivity map and molecular docking technology were applied to find the underlying agent opposing ZNF687.
In vitro, the guide RNA corresponding to ZNF687 was weakly detected in HCC cells, and ZNF687 deficiency was found to inhibit growth in HCC cell lines. ZNF687 mRNA was overexpressed and had a high discriminatory ability for HCC in 2,975 HCC samples, contrasting with 2,340 non-HCC samples. Moreover, an excessive ZNF687 transcript level was related to a worse overall survival (OS) prognosis. Histone modification, spliceosome, transcription coregulator activity, and nucleocytoplasmic transport were the most significant pathways for ZNF687 differential-related gene enrichment. Chaetocin was found to be a candidate compound and presented a strong affinity to ZNF687.
ZNF687 represents a TKI-resistant and growth-dependent gene for HCC, the overexpression of which indicates poor OS for HCC patients. Additionally, ZNF687 is expected to be a druggable target for overcoming TKI resistance, and chaetocin may be a candidate therapeutic compound for ZNF687.
单药治疗和联合免疫治疗等新型疗法显著延长了肝细胞癌（HCC）患者的总生存期（OS），但HCC在长期治疗过程中易产生耐药性。HCC中靶向药物的耐药机制仍不明确，因此研究HCC耐药靶点对精准医学的发展至关重要。
研究酪氨酸激酶抑制剂（TKI）耐药基因ZNF687在HCC中的转录特征、生物学功能及潜在临床价值。
采用成簇规律间隔短回文重复序列（CRISPR）体外筛选鉴定HCC的TKI耐药基因。然后，通过计算机模拟研究HCC细胞系对ZNF687的依赖性。我们收集了HCC组织的全基因组mRNA数据集，整合了ZNF687在HCC中的mRNA表达特征，并使用Kaplan-Meier方法（计算机模拟）探讨ZNF687对HCC患者预后的影响。随后进行基因本体论（GO）和京都基因与基因组百科全书（KEGG）通路分析，并应用连通性图谱和分子对接技术寻找对抗ZNF687的潜在药物。
在体外，HCC细胞中与ZNF687对应的引导RNA检测较弱，且发现ZNF687缺陷可抑制HCC细胞系的生长。在2975例HCC样本中，ZNF687 mRNA过表达，对HCC具有较高的鉴别能力，而在2340例非HCC样本中则不然。此外，ZNF687转录水平过高与总生存期（OS）预后较差有关。组蛋白修饰、剪接体、转录共调节因子活性和核质运输是ZNF687差异相关基因富集最显著的通路。发现茶托菌素是一种候选化合物，对ZNF687具有较强亲和力。
ZNF687是HCC的一种TKI耐药且生长依赖的基因，其过表达表明HCC患者的OS较差。此外，ZNF687有望成为克服TKI耐药性的可成药靶点，茶托菌素可能是ZNF687的候选治疗化合物。
