Kim Yejin, Yeuni Yu, Heo Hye Jin, Kim Eun Sun, Myung Kyungjae, Baryawno Ninib, Kim Yun Hak, Oh Chang-Kyu
Department of Convergence Medical Sciences, School of Medicine, Pusan National University, Yangsan, Republic of Korea.
Biomedical research institute, School of Medicine, Pusan National University, Yangsan, Republic of Korea.
PLoS One. 2025 Apr 25;20(4):e0321020. doi: 10.1371/journal.pone.0321020. eCollection 2025.
GLUT2 (SLC2A2), a vital glucose transporter in liver, pancreas, and kidney tissues, regulates blood glucose levels and energy metabolism. Beyond its metabolic role, SLC2A2 contributes to cell differentiation and metabolic adaptation during embryogenesis and tissue regeneration. Despite its significance, the role of SLC2A2 in liver differentiation and hepatocellular carcinoma (HCC) remains underexplored. This study investigated SLC2A2's role in liver differentiation using in silico, in vitro, and in vivo approaches. Analysis of GEO datasets (GSE132606, GSE25417, GSE67848) and TCGA HCC data revealed that while SLC2A2 expression decreases with HCC progression, stemness-associated genes, including SOX2 and POU5F1, are upregulated. Zebrafish embryos injected with SLC2A2-targeting morpholino exhibited reduced expression of the liver differentiation marker fabp10a without significantly altering the hepatoblast marker hhex. In HepG2 cells, SLC2A2 knockdown increased stemness and IGF1R pathway markers, indicating a shift toward less differentiated states. These findings suggest that SLC2A2 supports liver differentiation by regulating glucose metabolism and suppressing pathways associated with stemness and malignancy. Targeting SLC2A2 may serve as a promising therapeutic strategy for liver-related diseases, particularly HCC, by addressing its dual role in differentiation and tumor progression. Further mechanistic studies are warranted to fully elucidate these processes.
葡萄糖转运蛋白2（GLUT2，溶质载体家族2成员2，SLC2A2）是肝脏、胰腺和肾脏组织中一种重要的葡萄糖转运体，可调节血糖水平和能量代谢。除了其代谢作用外，SLC2A2在胚胎发育和组织再生过程中有助于细胞分化和代谢适应。尽管其具有重要意义，但SLC2A2在肝脏分化和肝细胞癌（HCC）中的作用仍未得到充分探索。本研究采用计算机模拟、体外和体内方法研究了SLC2A2在肝脏分化中的作用。对基因表达综合数据库（GEO）数据集（GSE132606、GSE25417、GSE67848）和癌症基因组图谱（TCGA）的HCC数据进行分析后发现，虽然SLC2A2的表达随着HCC的进展而降低，但包括SOX2和POU5F1在内的干性相关基因却上调。注射了靶向SLC2A2的吗啉代寡核苷酸的斑马鱼胚胎表现出肝脏分化标志物脂肪酸结合蛋白10a（fabp10a）的表达降低，而肝母细胞标志物六转录因子（hhex）的表达没有明显改变。在肝癌细胞系HepG2细胞中，SLC2A2基因敲低增加了干性和胰岛素样生长因子1受体（IGF1R）信号通路标志物的表达，表明细胞向低分化状态转变。这些发现表明，SLC2A2通过调节葡萄糖代谢以及抑制与干性和恶性肿瘤相关的信号通路来支持肝脏分化。通过解决SLC2A2在分化和肿瘤进展中的双重作用，靶向SLC2A2可能成为治疗肝脏相关疾病，尤其是HCC的一种有前景的治疗策略。有必要进行进一步的机制研究以全面阐明这些过程。
