NRF1 is expressed in many tissues and cells. NRF1 plays an important or even indispensable role in regulating different target gene subsets, which are related to antioxidation, disintoxication, oxidoreanabolism, protesomal degradation, adaptive cytoprotection and other physiological and pathological responses to different cellular stress [21–23]. Some literatures have proved the functional relationship between NRF1 and clinical diseases, particularly cancers. Whether NRF1 participates in the pathogenesis of diverse cancers remains to be proved. We have not found any literature on pan-cancer analysis of NRF1 from the overall tumor point of view. Therefore, data support is provided in TCGA, CPTAC and GEO databases, as well as the molecular characteristics of gene expression, gene change and DNA methylation, we detected the NRF1 gene in 33 diverse cancers.
NRF1 is high-expressed in vast majority of cancers. However, NRF1 gene survival and prognosis analysis data suggest different conclusions for different tumors. In the prognosis and survival analysis of TCGA-ACC disease, the survival status of the high-expression group (n=38) was significantly lower than that of the low-expression group (P<0.01, n=37). In the disease-free prognosis, the survival status of the same low-expression group was better (P< 0.0016). In the analysis of disease stages, the expression of NRF1 was increased to different degrees in the different disease stages. Surprisingly, the expression of NRF1 in patients was lower than that in normal control group, but the difference was not statistically significant (P>0.05), which may be due to the lack of data. In the genetic analysis of ACC, "amplification" (2.2%, n=91) was the main mutation type, and the effect of this mutation on ACC and downstream proteins remains to be further studied. Studies have shown that activate Wnt/β-catenin and delete p53 synergically induce adrenal cortical carcinoma in mice , and studies have shown that NRF1 has inhibitory effect on Wnt/β-catenin signal transduction in mouse liver . However, the role of NRF1 in regulating of Wnt/β-catenin activation and p53 in adrenal cortical carcinoma remains to be further studied.
In the prognostic survival analysis of TCGA-PAAD disease, the survival status of the high-expression group (n=89) was significantly lower than that of the low-expression group (P<0.0006, n=89). In the disease-free prognosis, the survival status of the same low-expression group was better (P< 0.042). In the TCGA + GTEx data, the expression of NRF1 in PAAD was higher than in normal team (P<0.05). Based on Kaplan-Meier plotter datasets uniting GEO datasets, we found that high expression of NRF1 was bound up with overall prognostic survival (P=0.0024, n=177) and disease-free survival (P=0.037, n=177) (Figure S3) results. This suggests that the expression of NRF1 in PAAD disease may involve in the occurrence and progression of the disease. The expression of NRF1 in patients was different from that in normal team (P<0.05, n=178). In the Cibersort-ABS algorithm, CD8+ immunoinfiltration of T cells showed a positive relationship between NRF1 expression and infiltration (Figure S2). At the same time, the expression of NRF1 was positively related with the immune infiltration of T cells CD4+, B cells, Tregs cells, NK cells and DCs (Figure S4), which may be because the over expression of NRF1 enhances the expression of TCF7 (Transcriptionfactor7) (Figure S5a). TCF7 is a transcriptional activator necessary for the survival of immature CD4(+), CD8(+) thymocytes . This suggests that the expression of NRF1 is corelated to cellular immunity. The expression of LEF1 (Lymphoid enhancer-binding factor1) interacting with NRF1 also increases (Figure S5b), and LEF1 has a variety of functions in adjusting T cell merisis and differentiation, which is crucial in maintaining the inhibition function of Treg and preventing loss of self-tolerance [27. Meanwhile, LEF1 is a key mediator of Wnt signal transduction , indicating that NRF1 enhances Wnt signal transduction by increasing the expression of LEF1. Studies have found that inhibition of Wnt signal can block the proliferation of adenocarcinoma cells in vitro and induce cell apoptosis . These results suggest that the over expression of NRF1 protein to promote cellular immunity, and has a certain therapeutic effect on PAAD. Conversely, the over expression of NRF1 may also enhance Wnt signal transduction and promote the proliferation of PAAD. In general, the high expression of NRF1 can increase the differentiation of immune cells and promote the survival of PAAD patients. On the contrary, it can promote the spread of PAAD through the WNT signaling pathway.
In the prognostic analysis of KIRC, the survival status of the high-expression group (n=258) was significantly higher than that of the low-expression group (P<0.04, n=257). In the disease-free prognosis, the survival status of the same low-expression group was better (P< 0.03,n=258). This suggests that KIRC may be involved in the expression of NRF1. However, the expression of NRF1 was increased in the patients with KIRC which used the normal group as control team, but no marked difference was found (P>0.05). Nrf1 can activate Wnt signal pathway . The function of Wnt signaling pathway in KIRC remains to be further studied.
In conclusion, our first pan-cancer analysis of NRF1 shows that NRF1 expression is statistically associated with clinical prognosis, DNA methylation, immune cell infiltration, and tumor mutation in some tumors. This conduce to comprehend the role of NRF1 in tumorigenesis from the point of view of clinical tumor specimens.