Downregulation of FPN1 acts as a prognostic biomarker associated with immune infiltration in lung cancer

Abstract

Lung cancer morbidity and mortality remain the leading causes of tumor-associated death worldwide. The discovery of early diagnostic and prognostic markers of lung cancer could significantly improve the survival rate and decrease the mortality rate. FPN1 is the only known mammalian iron exporter. However, the molecular and biological functions of FPN1 in lung cancer remain unclear. Here, FPN1 mRNA expression in lung cancer was estimated using the TCGA, Oncomine, TIMER, and UALCAN databases. The prognostic role of FPN1 was evaluated using Kaplan-Meier plotter and PrognoScan. Associations between FPN1 and immune infiltration in lung cancer were evaluated by the TIMER and CIBERSORT algorithms. FPN1 mRNA and protein expressions were significantly downregulated in lung cancer. Low FPN1 expression was strongly related to worse prognosis in patients with lung cancer. GO and KEGG analyses and GSEA suggested that FPN1 was remarkably related to iron homeostasis and immunity. Importantly, FPN1 was remarkably associated with the infiltrating abundance of multiple immune cells. Moreover, FPN1 displayed a strong correlation with various immune marker sets. We investigated the clinical application value of FPN1 and provided a basis for the sensitive diagnosis, prognostication and targeted therapy of lung cancer.

Ceruloplasmin correlates with immune infiltration and serves as a prognostic biomarker in breast cancer

“…The complex interactions among multiple iron-binding proteins, transporters, ferrioxidases and receptors enable the safe handling of iron in vivo . Some iron chelators have been developed as antitumor agents, such as deferasirox (DFX), Dp44mt, deferoxamine (DFO) and triapine, which can induce apoptosis in many types of cancer [ 26 , 27 ]. Dp44mT exhibits anticancer activity in a number of cancers, such as leukemia, neuroblastoma, oral, lung, prostate and breast cancer, by promoting apoptosis, inducing cell cycle arrest and upregulating the expression of NDRG1 [ 27 ].…”

Integrated analysis identifies TfR1 as a prognostic biomarker which correlates with immune infiltration in breast cancer

“…BC is the most common cancer type and the first leading cause of cancer-associated deaths in females worldwide [ 1 – 3 ]. Increasing evidence has demonstrated that alterations in iron metabolism-associated proteins play vital roles in BC [ 17 – 19 ]. Among various iron-related proteins, TfR1 expression was reported to be dysregulated in some types of human cancer, including BC.…”

“…GeneMANIA ( http://www.genemania.org ) and STRING ( https://string-db.org/ ) were used to construct gene-gene and protein-protein interaction networks for TfR1 as previously described [ 4 , 18 , 19 ].…”

The Role of Iron in Cancer Progression

“…In view of the important role of TFR1 in iron uptake, TFR1 has been identified as a prognostic marker for many tumors, such as TFR1 expression in ER - tissue was significantly higher than that in ER + tissue ( 188 ); Compared with adjacent non-cancer tissues, the mRNA expression level of TFR1 in hepatocellular carcinoma tissues is remarkably increased, and the expression of TFR1 and TFR2 is negatively correlated with tumor differentiation ( 176 , 177 ); Furthermore, patients with a high TFR1 expression have a high risk of recurrence and death after hepatectomy ( 177 ); Similarly, TFR1 is significantly overexpressed in ovarian cancer and glioblastoma, and TFR1 expression may be related to tumor staging, progression or the short survival time ( 29 , 180 ). Additionally, the activation of EGFR induces cell redistribution of TFR1, and the highly expressed TFR1 is closely related to the progression of lung cancer ( 178 ). The assessment of 178 gastric cancer tissues revealed a negative correlation between TFR1 expression and patient prognosis, and the TFR1 positive sorting cells showed a strong proliferative capacity; however, the TFR1-negative cells showed a more aggressive tumor features ( 179 ).…”

“…In a gene expression profile of approximately 800 breast cancer patients, it was reported that decreased FPN1 expression was significantly associated with reduced metastasis-free and disease-free survival ( 45 ). And FPN1 mRNA and protein expression are significantly down-regulated, and patients with a low FPN1 expression have a poor prognosis in lung cancer and adrenocortical carcinoma (ACC) ( 178 , 183 ). Additionally, a similar effect was observed in multiple myeloma and ccRCC ( 43 , 184 ).…”