MAPK10 Expression as a Prognostic Marker of the Immunosuppressive Tumor Microenvironment in Human Hepatocellular Carcinoma

Abstract

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.

Molecular characteristics and therapeutic implications of Toll-like receptor signaling pathway in melanoma

“…RAC1 protein is an Rho GTPase, which can regulate key processes such as melanoma occurrence and metastasis, and over activated RAC1 signaling pathway induces ERK phosphorylation and PI3K-AKT pathway regulation of melanocytes, promoting the occurrence, progression and metastatic spread of melanoma 53 . The specific mechanism of MAPK10 acting on melanoma has not been proven, and the carcinogenic effect of MAPK10 in hepatocellular carcinoma, renal cell carcinoma and gastric cancer has been extensively studied 54 – 56 .…”

Construction and validation of an oxidative-stress-related risk model for predicting the prognosis of osteosarcoma

“…Several studies have shown that MAPK1 is targeted by non-coding RNAs to modulate the invasion and proliferation of osteosarcoma cells [ 55 , 56 ]. MAPK10 is also associated with the prognosis of renal cell carcinoma [ 57 ] and hepatocellular carcinoma [ 58 ]. INS encodes insulin, a peptide hormone that plays a vital role in the regulation of carbohydrate and lipid metabolism, and is aberrantly expressed in various diseases.…”

Prognostic value and immunological roles of GPX3 in gastric cancer

“…In recent years, tumor immunotherapy has gained significant importance in the field. The prognosis of cancer patients can be influenced by the infiltration of immune cells within the tumor [46]. In this study, we categorized the samples based on CNA patterns of the GPX3 gene to examine the variations in infiltration levels of six distinct immune cell types among these groups.…”