Xiao Chaowen, Zhao Xinyang, Hu Zouxiao, Long Guanbao
Department of Hepatobiliary Surgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
Mol Carcinog. 2025 Mar;64(3):597-611. doi: 10.1002/mc.23875. Epub 2025 Jan 6.
Hepatocellular carcinoma (HCC) is a common primary malignancy of the liver and has a high mortality. Major facilitator superfamily domain containing 2 (MFSD2A) was previously demonstrated to inhibit tumor progression in several cancers. Here, we elucidated the association between MFSD2A expression and HCC progression and also investigated the underlying mechanism. The online tools were utilized to evaluate MFSD2A expression in HCC samples and predict the prognostic significance of MFSD2A in HCC patients. The biological role of MFSD2A in HCC cellular processes was examined by colony formation, wound healing, transwell, and western blotting. The in vivo role of MFSD2A in HCC was investigated in a xenograft tumor model. The miRNAs and RNA-binding proteins potentially targeting MFSD2A were identified using bioinformatics prediction tools. Luciferase reporter, RNA immunoprecipitation, actinomycin D, and immunofluorescence assays were performed to investigate the molecule mechanisms of MFSD2A. Transforming growth factor (TGF)-β1/Small mothers against decapentaplegic (Smad) signaling was detected using western blot analysis. We found that MFSD2A expression was significantly downregulated in HCC patients and cells and its downregulation predicted a poor prognosis. MFSD2A overexpression repressed HCC cell proliferation, migration, invasion, the epithelial-to-mesenchymal transition in vitro, as well as inhibited HCC tumor growth in vivo. MFSD2A was targeted by miR-3189-3p. High-density lipoprotein binding protein (HDLBP) inhibited MFSD2A expression by binding to and destabilizing MFSD2A mRNA. MFSD2A significantly suppressed activation of TGF-β/Smad signaling in HCC cells. Knockdown of MFSD2A abrogated the inhibitory effect of miR-3189-3p inhibitor on HCC cellular processes, and overexpression of MFSD2A reversed the tumor-promoting effect of HDLBP overexpression. Overall, MFSD2A exerts a tumor-inhibiting effect in HCC via suppression of TGF-β/Smad signaling, suggesting that MFSD2A may be a promising target for HCC therapy.
肝细胞癌（HCC）是一种常见的肝脏原发性恶性肿瘤，死亡率很高。先前已证明含主要易化子超家族结构域2（MFSD2A）可抑制多种癌症的肿瘤进展。在此，我们阐明了MFSD2A表达与HCC进展之间的关联，并研究了其潜在机制。利用在线工具评估HCC样本中MFSD2A的表达，并预测MFSD2A对HCC患者的预后意义。通过集落形成、伤口愈合、Transwell和蛋白质印迹法检测MFSD2A在HCC细胞过程中的生物学作用。在异种移植肿瘤模型中研究了MFSD2A在HCC中的体内作用。使用生物信息学预测工具鉴定了可能靶向MFSD2A的微小RNA（miRNA）和RNA结合蛋白。进行荧光素酶报告基因、RNA免疫沉淀、放线菌素D和免疫荧光测定以研究MFSD2A的分子机制。使用蛋白质印迹分析检测转化生长因子（TGF）-β1/抗五聚体蛋白母系小型蛋白（Smad）信号通路。我们发现，HCC患者和细胞中MFSD2A表达明显下调，其下调预示预后不良。MFSD2A过表达在体外抑制HCC细胞增殖、迁移、侵袭以及上皮-间质转化，在体内也抑制HCC肿瘤生长。MFSD2A是miR-3189-3p的靶标。高密度脂蛋白结合蛋白（HDLBP）通过与MFSD2A mRNA结合并使其不稳定来抑制MFSD2A表达。MFSD2A显著抑制HCC细胞中TGF-β/Smad信号通路的激活。敲低MFSD2A消除了miR-3189-3p抑制剂对HCC细胞过程的抑制作用，而MFSD2A过表达则逆转了HDLBP过表达的促肿瘤作用。总体而言，MFSD2A通过抑制TGF-β/Smad信号通路在HCC中发挥肿瘤抑制作用，表明MFSD2A可能是HCC治疗的一个有前景的靶点。
