Huang Yujun, He Jinyong, Chen Nan, Du Xiuting, Peng Junhui
Department of Oncology III, Shunde Hospital Guangzhou University of Chinese Medicine, Foshan City, Guangdong 528000, China.
Department of Clinical laboratory, Shunde Hospital Guangzhou University of Chinese Medicine, Foshan City, Guangdong 528000, China.
Pathol Res Pract. 2025 Jul;271:156033. doi: 10.1016/j.prp.2025.156033. Epub 2025 May 21.
Colorectal cancer (CRC) is one of the most common malignancies worldwide with a poor prognosis. Previous studies have indicated that solute carrier family 38 member 5 (SLC38A5), an amino acid transporter, plays an important role in some solid tumors. However, the role and mechanism of SLC38A5 in the progression of CRC are poorly defined.
In this research, TIMER, UALCAN, and GEPIA databases were applied to analyze the expression of SLC38A5 in CRC. SLC38A5 and E26 transformation-specific variant 4 (ETV4) mRNA levels were determined using real-time quantitative polymerase chain reaction (RT-qPCR) assay. SLC38A5, ETV4, HK-2, and LDHA protein levels were measured using western blot. Cell proliferation, migration, invasion, and Oxaliplatin (L-OHP) resistance were examined using Cell Counting Kit-8 (CCK-8) assay and Transwell assay. Glucose consumption, lactate production, and ATP levels were assessed using relevant kits. Binding between ETV4 and SLC38A5 promoter was predicted by JASPAR and validated using Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays. The biological role of ETV4 on CRC tumor growth was examined by the xenograft tumor model in vivo.
ETV4 and SLC38A5 were highly expressed in CRC tissues and cells. Moreover, SLC38A5 deficiency could hinder CRC cell proliferation, migration, invasion, glycolysis, and improved L-OHP sensitivity in vitro. Mechanistically, ETV4 was a transcription factor of SLC38A5 and activated the transcriptional activity of SLC38A5 via binding to its promoter region. ETV4 silencing knockdown repressed tumor growth in vivo.
SLC38A5 transcriptionally mediated by ETV4 expedites CRC cell growth, metastasis, glycolysis, L-OHP resistance, which provides a promising therapeutic target for CRC treatment.
结直肠癌（CRC）是全球最常见的恶性肿瘤之一，预后较差。先前的研究表明，溶质载体家族38成员5（SLC38A5）作为一种氨基酸转运蛋白，在某些实体瘤中发挥重要作用。然而，SLC38A5在CRC进展中的作用和机制尚不清楚。
在本研究中，应用TIMER、UALCAN和GEPIA数据库分析SLC38A5在CRC中的表达。使用实时定量聚合酶链反应（RT-qPCR）检测SLC38A5和E26转化特异性变体4（ETV4）的mRNA水平。使用蛋白质免疫印迹法检测SLC38A5、ETV4、HK-2和LDHA的蛋白水平。使用细胞计数试剂盒-8（CCK-8）检测法和Transwell检测法检测细胞增殖、迁移、侵袭及对奥沙利铂（L-OHP）的耐药性。使用相关试剂盒评估葡萄糖消耗、乳酸生成和ATP水平。通过JASPAR预测ETV4与SLC38A5启动子之间的结合，并使用染色质免疫沉淀（ChIP）和双荧光素酶报告基因检测进行验证。通过体内异种移植瘤模型研究ETV4对CRC肿瘤生长的生物学作用。
ETV4和SLC38A5在CRC组织和细胞中高表达。此外，SLC38A5缺陷可阻碍CRC细胞的增殖、迁移、侵袭、糖酵解，并提高其对L-OHP的体外敏感性。机制上，ETV4是SLC38A5的转录因子，通过与其启动子区域结合激活SLC38A5的转录活性。ETV4沉默抑制体内肿瘤生长。
ETV4转录介导的SLC38A5促进CRC细胞生长、转移、糖酵解及对L-OHP的耐药性，为CRC治疗提供了一个有前景的治疗靶点。
