Genes & Diseases ( IF 6.8 ) Pub Date : 2022-11-23 , DOI: 10.1016/j.gendis.2022.10.021 Xiangyu Zhai 1 , Zhijia Xia 2 , Gang Du 1, 3 , Xinlu Zhang 4 , Tong Xia 3 , Delin Ma 3 , Xiaosong Li 5 , Bin Jin 1, 3 , Hao Zhang 1, 3
Accumulating evidence supports the association of somatic mutations with tumor occurrence and development. We aimed to identify somatic mutations with important implications in hepatocellular carcinoma (HCC) and explore their possible mechanisms. The gene mutation profiles of HCC patients were assessed, and the tumor mutation burden was calculated. Gene mutations closely associated with tumor mutation burden and patient overall survival were identified. In vivo and in vitro experiments were performed to verify the effects of putative genes on proliferation, invasion, drug resistance, and other malignant biological behaviors of tumor cells. Fourteen genes with a high mutation frequency were identified. The mutation status of 12 of these genes was closely related to the mutation burden. Among these 12 genes, LRP1B mutation was closely associated with patient prognosis. Nine genes were associated with immune cell infiltration. The results of in vivo and in vitro experiments showed that the knockdown of LRP1B promotes tumor cell proliferation and migration and enhances the resistance of tumor cells to liposomal doxorubicin. LRP1B could directly bind to NCSTN and affect its protein expression level, thereby regulating the PI3K/AKT pathway. Our mutational analysis revealed complex and orchestrated liposomal alterations linked to doxorubicin resistance that may also render cancers less susceptible to immunotherapy and also provides new treatment alternatives.
中文翻译:
LRP1B 通过 NCSTN/PI3K/AKT 信号轴抑制 HCC 进展并影响阿霉素耐药性
越来越多的证据支持体细胞突变与肿瘤发生和发展的关联。我们的目的是鉴定对肝细胞癌(HCC)具有重要影响的体细胞突变并探索其可能的机制。评估HCC患者的基因突变谱,并计算肿瘤突变负荷。确定了与肿瘤突变负担和患者总体生存密切相关的基因突变。进行体内和体外实验来验证假定基因对肿瘤细胞增殖、侵袭、耐药和其他恶性生物学行为的影响。鉴定出十四个具有高突变频率的基因。其中12个基因的突变状态与突变负荷密切相关。在这12个基因中,LRP1B突变与患者预后密切相关。九个基因与免疫细胞浸润相关。体内外实验结果表明,敲低LRP1B可促进肿瘤细胞增殖和迁移,增强肿瘤细胞对脂质体阿霉素的耐药性。LRP1B可以直接与NCSTN结合并影响其蛋白表达水平,从而调节PI3K/AKT通路。我们的突变分析揭示了与阿霉素耐药性相关的复杂且精心策划的脂质体改变,这也可能使癌症不易受到免疫治疗的影响,并提供新的治疗替代方案。