The gene of IFI16 encodes a member of the HIN-20020 (hematopoietic interferon-inducible nuclear antigens with 200 amino acid repeats) family of cytokines. The encoded protein contains domains involved in DNA binding, transcriptional regulation, and protein-protein interactions. It modulates p53 function and inhibits cell growth in the Ras/Raf signaling pathway. IFI16 is an amplifier of DNA-damage response and involves in cellular senescence and aging-associated inflammatory diseases21. Studies have shown that IFI16 is poorly expressed in normal kidney tissue.
In bioinformatics analysis, we explored the mRNA expression of IFI16 are significantly higher in RCC tissues than the normal renal tissues, and the fold change is greater than 2, which strongly suggests that IFI16 is overexpressed in RCC. By comparing with the corresponding normal kidney tissues, the mRNA expression level of IFI16 expresses higher in KKIRC and KIRP tissues, while lower in KICH tissues. These findings are similar to some previous studies. For example, Overexpression IFI16 was observed in cervical squamous cell carcinoma12 and oral squamous cell carcinoma13. Therefore, we also investigated the relationship between the transcriptional level of IFI16 and the tumor stage in RCC. Due to the increasing TNM stage，the level of IFI16 expression are increases in KIRC and KIRP. To sum up, it’s reasonable to assume that IFI16 acts as an oncogene in the progression of kidney cancer. In this case, IFI16 can be used as a biomarker for early screening in RCC.
In this article, we also explored the relationship between IFI16 expression and survival in RCC. The results indicate the positive correlation between the IFI16 expression with DFS and OS in RCC13, 22. Furthermore, our study manifested the levels of expression IFI16 positively correlated with TIICs in KIRC and KIRP, while negatively correlated with the tumor purity in RCC. It is well known that higher the purity of the tumor, better the response to treatment and survival will be. Mast cell density has been reported to be highly correlated with the extent of both normal and pathologic angiogenesis, such as the angiogenesis observed in chronic inflammatory diseases and tumors, including gastric cancer and endometrial cancer23. An experimental study has demonstrated that interaction between lung cancer cells and macrophages promotes the invasiveness and matrix‐degrading activity of cancer cells24.To sum up the two results above, IFI16 can act as prognostic biomarker for RCC.
Moreover, due to the association between the TIICs and the tumour prognosis, we investigated the relationship between the transcriptional level of IFI16 and immune infiltration in RCC. The results revealed that the levels of IFI16 expression have a positively correlation with TIICs in RCC, while the negative correlation with macrophages in KICH. Existing studies indicated more TIICs reflects on less response to the treatment and survival. Recently, tumor-associated macrophage infiltration is correlated with angiogenesis and unfavorable prognosis in several kinds of cancer, including gastric cancer, endometrial cancer, and breast cancer25-27.Combined with the above research results and existing research data, we assume that IFI16 can be used as a biomarker for the diagnosis and prognosis of renal cancer, apart from that it can be used as a potential therapeutic target.
Tumor development and progression are associated with multiple genomic aberrations, which in turn may influence TIICs. In this study, we compared the abundance of TIICs under different mutation states of the IFI16 gene. The result of analysis in KIRC prompt the central TIICs in the arm-level deletion state of IFI16 were B cell, CD4+T cell, neutrophil, and dendritic cell, while the primary TIICs in the high amplification state of IFI16 was macrophages. The high expression of FI16 is positively correlated with the infiltration of macrophages, and the role of macrophages in KIRC require further studies.
Elucidating the underlying mechanism of RCC development is of great significance for the effective treatment of patients with RCC 28. The co-expression network of IFI16 is used to perform GO and KEGG function enrichment analysis. The results enriched in certain functions including neutrophil degranulation, phagocytosis, the regulation of vesicle-mediated transport, and enriched in certain signal pathways including tuberculosis, toxoplasmosis, phagosome, leishmaniasis and Fc gamma R-med8ted. These results also suggest that IFI16 involves in the immune response and mediates the development of the inflammatory diseases. Therefore, it is essential for us to better understand the interaction between the tumor microenvironment and the TIICs. The characterization of adaptive immune responses seems to become an indispensable prognostic tool in a wide range of cancers and might be more important than the current cancer staging systems29, 30. It requires further research and exploration.
This study provides evidence for the significance of IFI16 in renal cell carcinoma and the potential role of novel biomarkers. Our results indicate the association between the IFI16 expression with the clinicopathological features, prognosis, and immune cell infiltration in RCC. At the same time, we also identified the co-expressed genes of IFI16 in RCC. These genes play an important role in immune-related functions and signaling pathways through the functional enrichment analysis, which suggests the gene of IFI16 is not only a prognosis biomarker for RCC patients but also has the possibility to associate with the immune response to RCC. At the same time, our research has some limitations. On the one hand, our results have not been confirmed by the clinical samples. On the other hand, we did not delve into the mechanism of IFI16 in RCC progression. Our results indicate the association between the IFI16 expression with the clinicopathological features, prognosis, and immune cell infiltration in RCC.