HCC has become a major health problem worldwide with the characteristics of invasion, metastasis and frequent recurrence(17, 18). The treatment of HCC has made great progress, but the prognosis of HCC still remains unsatisfactory(19). Thus, it is necessary to explore new immunotherapy targets for HCC. IKBIP is located on chromosome 12, which was described as the target of p53 with pro-apoptotic activity(20). A recent paper reported that IKBIP was upregulated in glioma and correlated with an unsatisfactory prognosis (21). However, the clinical values of IKBIP have not been utterly revealed in HCC.
In this study, our results found that IKBIP was elevated in various cancers by pan-cancer analysis. Moreover, we also confirmed that IKBIP expression in HCC was significantly upregulated in multiple databases. The IKBIP expression was associated with tumor sizes, high pathologic stage and histologic grade. ROC curve analysis found that IKBIP serves as a promising diagnostic biomarker in HCC patients. Based on K-M plotter and univariate analysis, we found that high IKBIP expression was related to short OS, PFS and DFS. Univariate Cox analysis further confirmed that the level of IKBIP was risk factors for the prognosis in HCC. These results indicated that IKBIP might serve as a novel prognostic factor and a potential new target for the treatment of HCC patients.
Recent studies have demonstrated that IKBIP could promote the occurrence and development of tumor by Epithelial-to-mesenchymal transition (EMT) induction(8). EMT plays a crucial role not only in promoting tumor invasion and migration, but also in tumor recurrence and treatment resistance(22, 23). Besides, IKBIP has also been shown to be related to immune and inflammatory responses (24). Based on these, we conclude that IKBIP may play an immunosuppressive role in tumor. However, the biological function of IKBIP has not been investigated in HCC. Thus, we further elucidated the function of IKBIP in HCC. We found that Hub genes of IKBIP in PPI network were apoptotic protease-activating factor 1 (APAF1), GTPase-activating protein 3 (ARFGAP3), clathrin light chain B (CLTB), NFU1, protein kinase C and casein kinase substrate in neurons 2 (PACSIN2), patched domain containing 3 (PTCHD3), RAB11 family interacting protein 1 (RAB11FIP1), RPUSD4, serine/arginine-rich splicing factor 7 (SRSF7) and TTLL1. GO and KEGG analysis indicated that KIBIP and its co-expressed genes were enriched in endocytosis, Golgi-associated vesicle membrane, coated membrane, membrane coat and vesicle coat. Among co-expressed genes, ARFGAP3, a GTPase-activating protein, which was correlated with the Golgi-apparatus and involve in the vesicular trafficking pathway, and it has been confirmed that ARFGAP3 could promote the proliferation and migration of prostate cancer cell(25). RAB11FIP1, also known as Rab-coupling protein (RCP), which was involved in tumor invasion and metastasis in breast cancer(26). SRSF7 was frequently upregulated in colon and lung cancer, which supported that SRSF7 might serve as a proto-oncogene(27). These findings indicated IKBIP might be involved in the occurrence and development of tumors by synergizing other tumor-related genes.
In recent years, the role of the immune system in cancer has been received increasing attention with the wide application of tumor immunotherapy (28, 29). Accumulating studies demonstrated that immune cells in the tumor microenvironment (TME) contribute to tumor occurrence and progression (30). Therefore, we explored the interrelation between IKBIP expression and TILs. In this study, we found that IKBIP expression was closely correlated with to six tumor infiltrating immune cells (B cell, CD8+ T cell, CD4+ T cell, macrophage, neutrophil, dendritic cell) in HCC. Besides, we also found IKBIP expression was positively correlated with Act-CD4+ T cells, Tem-CD4+ T cells, NKT cells and Th2 cells. Our results suggested that there was a potential interrelation between IKBIP and immune infiltration cells in HCC. Nevertheless, relevant research should be explored to verify the above findings in future studies.
There are some limitations to address in this study. First, IKBIP expression and its prognostic value were analyzed by online public databases, which should be required to be validated in large-scale clinical samples. Second, the vivo/vitro experiments are needed to further explore the influence of IKBIP on the immune infiltrations in HCC.
In conclusion, we first found that IKBIP expression was upregulated and correlated with tumor sizes, pathologic stage and histologic grade in HCC. Moreover, IKBIP expression was also closely associated with the poor prognosis and immune infiltrations. Therefore, our findings suggested that IKBIP could serve as a potential biomarker for poor prognosis and might play a crucial role in immune infiltrations in HCC.