Li Huahui, Li Yuting, Zhang Ying, Tan Binbin, Huang Tuxiong, Xiong Jixian, Tan Xiangyu, Ermolaeva Maria A, Fu Li
Guangdong Province Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and Shenzhen University International Cancer Center, Shenzhen University Health Science Center, Shenzhen, China.
Group of Homeostasis and Stress Tolerance, Leibniz Institute on Aging-Fritz Lipmann Institute, Jena, Germany.
Front Oncol. 2021 Aug 2;11:687371. doi: 10.3389/fonc.2021.687371. eCollection 2021.
Hepatocellular carcinoma (HCC) remains a devastating malignancy worldwide due to lack of effective therapy. The immune-rich contexture of HCC tumor microenvironment (TME) makes this tumor an appealing target for immune-based therapies; however, the immunosuppressive TME is still a major challenge for more efficient immunotherapy in HCC. Using bioinformatics analysis based on the TCGA database, here we found that MAPK10 is frequently down-regulated in HCC tumors and significantly correlates with poor survival of HCC patients. HCC patients with low MAPK10 expression have lower expression scores of tumor infiltration lymphocytes (TILs) and stromal cells in the TME and increased scores of tumor cells than those with high MAPK10 expression. Further transcriptomic analyses revealed that the immune activity in the TME of HCC was markedly reduced in the low-MAPK10 group of HCC patients compared to the high-MAPK10 group. Additionally, we identified 495 differentially expressed immune-associated genes (DIGs), with 482 genes down-regulated and 13 genes up-regulated in parallel with the decrease of MAPK10 expression. GO enrichment and KEGG pathway analyses indicated that the biological functions of these DIGs included cell chemotaxis, leukocyte migration and positive regulation of the response to cytokine-cytokine receptor interaction, T cell receptor activation and MAPK signaling pathway. Protein-protein interaction (PPI) analyses of the 495 DIGs revealed five potential downstream hub genes of MAPK10, including SYK, CBL, VAV1, LCK, and CD3G. Several hub genes such as SYK, LCK, and VAV1 could respond to the immunological costimulatory signaling mediated by the transmembrane protein ICAM1, which was identified as a down-regulated DIG associated with low-MAPK10 expression. Moreover, ectopic overexpression or knock-down of MAPK10 could up-regulate or down-regulate ICAM1 expression via phosphorylation of c-jun at Ser63 in HCC cell lines, respectively. Collectively, our results demonstrated that MAPK10 down-regulation likely contributes to the immunosuppressive TME of HCC, and this gene might serve as a potential immunotherapeutic target and a prognostic factor for HCC patients.
由于缺乏有效的治疗方法，肝细胞癌（HCC）在全球范围内仍然是一种极具毁灭性的恶性肿瘤。HCC肿瘤微环境（TME）富含免疫细胞的结构使这种肿瘤成为基于免疫疗法的一个有吸引力的靶点；然而，免疫抑制性TME仍然是HCC中更有效免疫治疗的一个主要挑战。基于TCGA数据库进行生物信息学分析，我们发现MAPK10在HCC肿瘤中经常下调，并且与HCC患者的不良生存显著相关。与高MAPK10表达的患者相比，低MAPK10表达的HCC患者肿瘤浸润淋巴细胞（TILs）和TME中基质细胞的表达分数较低，肿瘤细胞分数较高。进一步的转录组分析显示，与高MAPK10组相比，低MAPK10组HCC患者TME中的免疫活性明显降低。此外，我们鉴定了495个差异表达的免疫相关基因（DIGs），随着MAPK10表达的降低，有482个基因下调，13个基因上调。GO富集和KEGG通路分析表明，这些DIGs的生物学功能包括细胞趋化性、白细胞迁移以及对细胞因子-细胞因子受体相互作用、T细胞受体激活和MAPK信号通路反应的正调控。对495个DIGs进行蛋白质-蛋白质相互作用（PPI）分析，揭示了MAPK10的五个潜在下游枢纽基因，包括SYK、CBL、VAV1、LCK和CD3G。一些枢纽基因如SYK、LCK和VAV1可以对由跨膜蛋白ICAM1介导的免疫共刺激信号作出反应，ICAM1被鉴定为与低MAPK10表达相关的下调DIG。此外，在HCC细胞系中，异位过表达或敲低MAPK10可分别通过c-jun的Ser63磷酸化上调或下调ICAM1表达。总的来说,我们的结果表明,MAPK10下调可能导致HCC的免疫抑制性TME,并且该基因可能作为HCC患者潜在的免疫治疗靶点和预后因素。
