Yang Ting, Zou Minhong, Xie Yujie, Zhang Yong, Wang Kun, Jiang Shihai, Zou Qiong
Department of Nuclear Medicine, Third Affiliated Hospital of Sun Yat-sen University, Guang Zhou, 510630, Guangdong, China.
Department of Ultrasonic Diagnosis, Third Affiliated Hospital of Sun Yat-sen University, Guang Zhou, 510630, Guangdong, China.
Cell Div. 2024 Dec 24;19(1):35. doi: 10.1186/s13008-024-00140-y.
Abnormal expression of six-transmembrane epithelial antigen of prostate 4 (STEAP4) has been implicated in the carcinogenesis of hepatocellular carcinoma (HCC). However, the biological role and regulatory mechanisms of STEAP4 in HCC remain unclear.
Here, we analyzed STEAP4 expression levels and differentially expressed genes (DEGs) between STEAP4 high- and low-expression groups using multiple databases. Proliferation assays, 5-ethynyl-2'-deoxyuridine (EdU) assays, propidium iodide (PI) flow cytometry, and colony formation assays were conducted to assess the effects of STEAP4 on HCC cell proliferation, cell cycle progression, and clonogenic capacity. STEAP4 was downregulated in HCC tumor tissues, with lower expression associated with poorer overall survival (OS) and disease-free survival (DFS) in patients. Functional network analysis suggested that STEAP4 regulates cell cycle signaling, with tumor sections showing a negative correlation between STEAP4 and cell cycle proteins. Overexpression of STEAP4, combined with non-cytotoxic copper exposure in the HepG2 cell line, reduced proliferation and clonogenicity, induced cell cycle arrest, and downregulated the mRNA and protein levels of cell cycle-regulating genes. A predictive model based on STEAP4 and cell cycle gene demonstrated prognostic value in HCC patients.
Our results lay a foundation for further study of the cell cycle regulatory role of STEAP4 with Cu reductase activity in HCC, indicating that STEAP4 may be a promising therapeutic target for HCC.
前列腺六跨膜上皮抗原4（STEAP4）的异常表达与肝细胞癌（HCC）的致癌作用有关。然而，STEAP4在HCC中的生物学作用和调控机制仍不清楚。
在此，我们使用多个数据库分析了STEAP4高表达组和低表达组之间的STEAP4表达水平和差异表达基因（DEG）。进行增殖试验、5-乙炔基-2'-脱氧尿苷（EdU）试验、碘化丙啶（PI）流式细胞术和集落形成试验，以评估STEAP4对HCC细胞增殖、细胞周期进程和克隆形成能力的影响。STEAP4在HCC肿瘤组织中表达下调，其低表达与患者较差的总生存期（OS）和无病生存期（DFS）相关。功能网络分析表明，STEAP4调节细胞周期信号，肿瘤切片显示STEAP4与细胞周期蛋白之间呈负相关。STEAP4的过表达，结合HepG2细胞系中的无细胞毒性铜暴露，降低了增殖和克隆形成能力，诱导细胞周期停滞，并下调了细胞周期调节基因的mRNA和蛋白质水平。基于STEAP4和细胞周期基因的预测模型在HCC患者中显示出预后价值。
我们的结果为进一步研究具有铜还原酶活性的STEAP4在HCC中的细胞周期调节作用奠定了基础，表明STEAP4可能是HCC的一个有前景的治疗靶点。
