摘要
U-104是一类高效的碳酸酐酶(CA)抑制剂,有望作为潜在的抗肿瘤药物应用于少数几类肿瘤的治疗.然而,U-104的下游机制及其在舌鳞状细胞癌中的功能尚不明确;其抗肿瘤效果是否依赖于CA9和CA12也未被证明.在本工作中,我们通过RNA测序发现了受U-104调节的差异表达基因和U-104可能影响的细胞内生物过程.在差异基因的富集分析中,排名位于前列的生物学过程包括与细胞死亡相关、细胞增殖、迁移和药物反应等生物学过程;这与我们利用U-104处理TSCC15舌癌细胞后观察到的生物学效应一致.进一步地,干扰CA9或CA12的表达完全消除了U-104对细胞迁移、死亡及关键差异基因表达的影响.总体而言,我们的研究在转录组水平提示了U-104的下游调节机制,并证明了在舌鳞状细胞癌中U-104的抗肿瘤功能依赖于CA9和CA12.此工作拓展了现阶段人们对于U-104抗肿瘤功能的认知,并提供了一类针对舌鳞状细胞癌的潜在治疗方法.
U-104,an effective inhibitor of carbonic anhydrases(CAs),has been shown as a potential anti-tumor drug in several human cancer types.However,the downstream mechanisms of U-104 and its functions in tongue squamous cell carcinoma(TSCC)remain unclear.It is neither confirmed that whether the anti-tumor effects of U-104 are dependent on CA9 and CA12.In this work,we found differentially expressed genes(DEGs)and potential cellular processes regulated by U-104 through RNA sequencing.The cell death-related,cell proliferation,migration and response to drug cellular processes were among the top GO(gene ontology)processes,which were consistent with the observed biological effects upon U-104 treatment in TSCC15 cells.Furthermore,knockdown(KD)of CA9 or CA12 completely eliminated the U-104 effects on the cell migration,cell death,and the expression of critical DEGs.All together,our study suggests the regulatory mechanisms of U-104 at the transcriptome level and demonstrates the anti-tumor functions of U-104 dependent on CA9 and CA12 in TSCC.Our findings expand the current knowledge on the anti-tumor functions of U-104 and provide a potential therapeutic option for TSCC.
作者
杨紫暄
张雪寒
申涛
施荣华
汪香婷
Yang Zixuan;Zhang Xuehan;Shen Tao;Shi Ronghua;Wang Xiangting(Division of Life Sciences and Medicine,University of Science and Technology of China,Hefei 230026,China;Core Facility Center for Life Sciences,School of Life Sciences,University of Science and Technology of China,Hefei 230026,China)
基金
supported by the National Natural Science Foundation of China(31970598)
the Fundamental Research Funds for the Central Universities(YD2070002010).