FUCA2 Is a Prognostic Biomarker and Correlated With an Immunosuppressive Microenvironment in Pan-Cancer

Abstract

BackgroundThe expression of Fucosidase, alpha-L-2 (FUCA2) varies across tumors. However, its role in various tumor types and relationship with the tumor immune microenvironment (TIME) is poorly defined.MethodsWe analyzed profiles of FUCA2 expression using datasets from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. Next, gene alteration, clinical characteristics and prognostic values of FUCA2 were elucidated based on TCGA pan-cancer data. This was followed by gene set enrichment analysis by R software. Relationships between FUCA2 expression and immune infiltration and immune-related genes were also evaluated. Moreover, the association of immune cell infiltration with FUCA2 expression was evaluated across three different sources of immune cell infiltration data, namely the TIMER online, ImmuCellAI databases, as well as a published study. In addition, MTT assays was also conducted to validate the oncogene role of FUCA2 in lung cancer cells.ResultsFUCA2 was upregulated in most tumors, and this was significantly associated with poor survival rates. Gene set enrichment analysis uncovered that FUCA2 correlated with immune pathways in different tumor types. FUCA2 expression was positively related to tumor associated macrophages (TAMs), especially M2-like TAMs. Moreover, FUCA2 level showed a positive relationship with most immunosuppression genes, including programmed death-ligand 1 (PD-L1), transforming growth factor beta 1 (TGFB1), and interleukin-10 (IL10) in most cancer types. FUCA2 knockdown inhibited the cell viability in lung cancer cells.ConclusionsOur study reveals that FUCA2 is a potential oncogene and is indicative biomarker of a worse prognosis in pan-cancer. High FUCA2 expression may contribute to increased infiltration of TAMs and associates with an immunosuppressive microenvironment, providing a potential target for tumor therapy.

Dual role of fucosidase in cancers and its clinical potential

“…Previous studies demonstrate the change of AFUs in serum and tumor samples of cancer patients 28 , 38 . AFUs could be employed as an indicator of tumor burden, metastasis and response to anti-cancer treatment 30 .…”

“…As for FUCA2, Zhong etc. has shown it is upregulated in most tumors such as thyroid carcinoma, lung squamous cell carcinoma, HCC, low grade glioma (LGG) and GBM and is significantly associated with poor survival 38 . Due to the diverse metabolic characteristics and related molecular mechanisms, AFUs may play even completely opposite roles in different types of cancer.…”

“…Moreover, recent study reveals that FUCA2 is also a diagnostic and prognostic biomarker a therapeutic target in pan-cancer 25 . The expression of FUCA2 is associated with immunosuppressive microenvironment such as TAMs, and studies have indicated that FUCA2 is overexpressed in 24 tumor types 38 . FUCA2 also can quantify AFU concentrations in human blood serum for early tumor detection such as HCC 70 .…”

“…However, N-glycans can inhibit the recognition of PD-L1 antibody on the surface of tumor cells 78 . Through database analysis, Zhong et al found that the expression of FUCA2 was positively correlated with the immunosuppressive gene such as PD-L1 38 . PD-L1 may be inhibited by targeting FUCA2.…”

COVID‐19 metabolism: Mechanisms and therapeutic targets

“…FUCA2 has been revealed as an oncogenic factor due to its immunosuppressive activity. 151 Whether ORF3a induces host immunosuppression through interacting with FUCA2 still needs further validation (Figure 4H ).…”