Department of Interventional Oncology, the First Affiliated Hospital, Sun Yat-Sen University, No. 58 Zhongshan 2 Road, Guangzhou, Guangdong Province, 510080, P. R. China.
Department of Endoscopy, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, Guangdong Province, 510060, P. R. China.
J Transl Med. 2024 Jun 6;22(1):543. doi: 10.1186/s12967-024-05298-1.
Hepatocellular carcinoma (HCC) is a common malignant tumor, and glutamine is vital for tumor cells. The role of glutamine transporter SLC1A5 in tumor progression and transarterial chemoembolization (TACE) efficacy is under study. This research seeks to determine the impact of SLC1A5 expression on the prognosis and TACE efficacy of HCC and elucidate its mechanisms.
SLC1A5 expression in HCC, correlation with patient outcomes, and response to TACE were studied in an open access liver cancer dataset and confirmed in our cohort. Additionally, the correlation between SLC1A5 expression and hypoxia, angiogenesis and immune infiltration was analyzed and verified by immunohistochemistry, immunofluorescence and transcriptome sequencing. Liver cancer cell lines with SLC1A5 expression knockdown or overexpression were constructed, and cell proliferation, colony formation, apoptosis, migration and drug sensitivity as well as in vivo xenograft tumor were measured. A gene set enrichment analysis was conducted to determine the signaling pathway influenced by SLC1A5, and a western blot analysis was performed to detect protein expression alterations.
SLC1A5 expression was higher in HCC tissue and associated with poor survival and TACE resistance. Hypoxia could stimulate the upregulation of glutamine transport, angiogenesis and SLC1A5 expression. The SLC1A5 expression was positively correlated with hypoxia and angiogenesis-related genes, immune checkpoint pathways, macrophage, Tregs, and other immunosuppressive cells infiltration. Knockdown of SLC1A5 decreased proliferation, colony formation, and migration, but increased apoptosis and increased sensitivity to chemotherapy drugs. Downregulation of SLC1A5 resulted in a decrease in Vimentin and N-cadherin expression, yet an increase in E-cadherin expression. Upregulation of SLC1A5 increased Vimentin and N-cadherin expression, while decreasing E-cadherin. Overexpression of β-catenin in SLC1A5-knockdown HCC cell lines could augment Vimentin and N-cadherin expression, suppress E-cadherin expression, and increase the migration and drug resistance.
Elevated SLC1A5 was linked to TACE resistance and survival shortening in HCC patients. SLC1A5 was positively correlated with hypoxia, angiogenesis, and immunosuppression. SLC1A5 may mediate HCC cell migration and drug resistance via Epithelial-mesenchymal transition (EMT) pathway.
肝细胞癌（HCC）是一种常见的恶性肿瘤，谷氨酰胺对肿瘤细胞至关重要。谷氨酰胺转运体 SLC1A5 在肿瘤进展和经动脉化疗栓塞（TACE）疗效中的作用正在研究中。本研究旨在确定 SLC1A5 表达对 HCC 患者预后和 TACE 疗效的影响，并阐明其机制。
在一个开放获取的肝癌数据集和我们的队列中研究了 SLC1A5 在 HCC 中的表达、与患者结局的相关性以及对 TACE 的反应。此外，通过免疫组织化学、免疫荧光和转录组测序分析并验证了 SLC1A5 表达与缺氧、血管生成和免疫浸润的相关性。构建了 SLC1A5 表达下调或过表达的肝癌细胞系，并测量了细胞增殖、集落形成、凋亡、迁移和药物敏感性以及体内异种移植肿瘤。进行了基因集富集分析以确定受 SLC1A5 影响的信号通路，并进行了 Western blot 分析以检测蛋白表达变化。
SLC1A5 在 HCC 组织中的表达较高，与生存不良和 TACE 耐药有关。缺氧可刺激谷氨酰胺转运、血管生成和 SLC1A5 表达上调。SLC1A5 表达与缺氧和血管生成相关基因、免疫检查点途径、巨噬细胞、Tregs 和其他免疫抑制细胞浸润呈正相关。SLC1A5 下调可降低增殖、集落形成和迁移，但增加凋亡并增加对化疗药物的敏感性。SLC1A5 下调导致波形蛋白和 N-钙粘蛋白表达降低，而 E-钙粘蛋白表达增加。SLC1A5 过表达可增加 HCC 细胞系中β-catenin 的 Vimentin 和 N-cadherin 表达，降低 E-cadherin 表达，并增加迁移和耐药性。
SLC1A5 升高与 HCC 患者 TACE 耐药和生存时间缩短有关。SLC1A5 与缺氧、血管生成和免疫抑制呈正相关。SLC1A5 可能通过上皮-间充质转化（EMT）途径介导 HCC 细胞迁移和耐药性。
