Liver cancer is a common malignant tumor with a dismal prognosis. The discovery of novel biomarkers for liver cancer could improve its early detection rate and prognosis (Shen et al. 2020). A growing number of studies have utilized various methodologies to search for prognostic genes in HCC and used them as biomarkers to predict prognosis. CBX6 was reported to play a role as an oncogenic gene in HCC. It was associated with an increased risk of HCC metastasis via the EMT pathway controlled by the transcription factor Snail/Zeb1 and was proposed as a new therapeutic target for HCC (Wang et al. 2020). In this present study, we used the TCGA and GEO database to explore the hub genes associated with HCC diagnosis and treatment. FCGR2A was identified as the target gene via mining DEGs in the TME and the PPI network and univariate COX analysis. Further, FCGR2A was significantly up-regulated in HCC tumor tissues and was linked to tumor volume and poor prognosis. Differential studies of infiltrating immune cells showed that the eosinophil content in tissues with low expression of FCGR2A was higher. Single-cell sequencing analysis showed that FCGR2A was mostly expressed on macrophages and monocytes and involved in various immune-related processes.
FCGR2A is a low-affinity immunoglobulin γFc receptor II-A that can bind to the Fc region of immunoglobulin γ. Due to the relationship between innate and humoral immunity, as well as its importance in inflammation and infectious illnesses, FcγR has been the subject of a lot of research. Within the human FcγR family, FcγRII (active FcγRIIa and FcγRIIc, as well as inhibitory FcγRIIb) are unique in their ability to signal independently of the common γ chain (Patel and Bussel 2020; Mohr et al. 2022). An Fc receptor, by definition, is a receptor for the Fc component of an immunoglobulin (Ig). These cell-surface receptors have traditionally been thought of as Ig, and their interactions are reflected in a range of immune system reactions or physiological processes triggered by antibodies during immunization (Anania et al. 2019).
The human FcγRII family, also known as CD32 in the differentiated name cluster, consists of important cell membrane receptor proteins. Splicing mRNA variations of three closely related genes, FCGR2A, FCGR2B and FCGR2C, were shown to encode them (Qiu et al. 1990). FcγR receptors (low-affinity receptors for the Fc portion of IgG) are a crucial connection between the innate and adaptive immunity. Immune complexes (IC) are naturally occurring ligands for the low-affinity FcγR receptor, and significant amounts of IC are frequently found in chronic viral infections and autoimmune disorders.
Oncological studies proposed FCGR2A as a prognostic marker for head and neck squamous cell carcinoma, which could trigger cellular responses targeting pathogens and soluble antigens by binding to IgG (Dai et al. 2021). However, more investigation on the efficiency of FCGR2A inhibitors in interfering with immune cells was needed. FCGR2A expression was shown to increase in myeloid cells from normal pancreas to pancreatic adenosquamous cancer (Zhao et al. 2021). The expression of FCGR2A was significantly different between the tumor tissue of renal clear cell carcinoma (ccRCC) and normal renal tissue (Li et al. 2021). High levels of FcgR DNA methylation are associated with low amounts of mRNA and protein as well as a poor prognosis in patients with ccRCC, which may offer new insights into the selection of therapeutic targets and prognostic indicators (Nie et al. 2022). FCGR2A may serve as a new potential prognostic biomarker for esophageal squamous cell carcinoma (Lu et al. 2021). Studies have revealed that FCGR2A-rich genomes control the immune response of Fc receptor signaling pathways as well as cell surface receptor signaling pathways, and they may be involved in the process of shielding patients with osteosarcoma from metastasis (Li et al. 2020). In the future, FCGR2A may serve as both a target for osteosarcoma assays and a biomarker to help detect osteosarcoma metastasis. Sinus endothelial cells (SECs) surrounding HCC tumor cells showed phenotypic traits related to SEC function in normal liver, such as CD4, CD14 and CD32 (FCGR2A) (Nakamura et al. 1997). It also showed capillary EC characteristics, such as endothelial mucin deposition, FVIIIRAg, PAL-E Ag. As a result, CD32, Fcg receptor II, was only found in SECs of healthy livers but not in healthy vascular endothelial cells (ECs).
The tumor immune microenvironment influences tumor occurrence and development, as well as immunotherapy and targeted therapy response rates. Various immune cells such as T cells, macrophages, NK cells, and monocytes interact with each other in complicated TME. Various immune cells also communicated with one another by secreting cytokines, and macrophages and monocytes are unquestionably at the core of the tumor immune microenvironment’ s regulation (Kloc et al. 2019; Wu et al. 2020). Macrophages derive from embryonic stem cells can survive into adulthood and become self-sustaining through local proliferation. Comparatively, monocytes in the local environment of macrophage populations contribute to the maintenance of tissue-specific macrophage function in some tissues (Gentek et al. 2014). Macrophages are cells of the innate immune system regulating tissue homeostasis, host defense during pathogen infection, and tissue repair in the aftermath of tissue injury (Yan and Horng 2020). It showed obvious morphological and functional changes in diverse environments and physiological situations. Activated macrophages could clear necrotic and apoptotic cells, allowing the tissue to maintain stability and operate normally.
We discovered an intriguing correlation during the course of the research, according to the two conclusions: 1. Eosinophil concentration was greater in HCC patients with decreased FCGR2A expression; 2. It was mostly expressed in macrophages and monocytes and involved in phagocytosis and immunological complex clearance. It was previously reported that FCGRII was implicated in the apoptotic pathways of mouse granulocyte precursors and mature eosinophils. The attachment of the IgG-Ag complex to CD32 after eosinophils were threshed induced the apoptotic pathway via the Fas-Fas ligand, resulting in the elimination of these cells. The presence of macrophages at the location of inflammation can also trigger the following mechanism (de Andrés et al. 1997). These findings revealed that there must be a link between FCGR2A and eosinophils, which was confirmed in our study. Furthermore, we speculated that the FCGR2A-encoded protein was engaged in the associated functions of macrophages and eosinophils in the HCC TME, which was worth further investigation.
There was also some indication of a link between macrophages and eosinophils. For instance, it was demonstrated that midbrain astrocyte-derived neurotrophic factor reduced the severity of acute lung injury by preventing macrophages of the M1 functional type from polarizing, or activating. Eosinophils might influence macrophage polarization and transition from M1 to M2 type, increasing the expression of anti-inflammatory transmitters (Shen et al. 2022). Tumor-derived exosome non-coding RNA (ncRNA) caused the polarization of M2 macrophages via signaling pathway activation, signal transduction, transcription, and post-transcriptional regulation (Xu et al. 2022). According to available data, the TME contained a considerable number of macrophages, and their M2 polarization promotes the growth of malignant tumors, while ncRNA can influence the occurrence of this process (Entezari et al. 2022).
Furthermore, miRNA was reported to affect tumor growth and therapeutic response by modulating numerous molecular pathways and inducing/inhibiting M2 polarization of macrophages. MiR-934, a tumor-derived exosome, was found to increase colorectal cancer liver metastases (CRLM) by modulating cross-talk between colorectal cancer cells (CRC) and tumor-associated macrophages (TAM) (Zhao et al. 2020). Several macrophage regulatory pathways had been uncovered in secondary liver cancer. These findings would provide a strong platform for our future research.
Research on FCGR2A in the pathogenesis of liver cancer was limited despite primary liver cancer being the fourth most common cause of cancer-related death worldwide (Yang et al. 2019). HCC, the most common histological type of liver cancer, may be the cause of most liver cancer diagnoses and deaths (McGlynn et al. 2021). In contrast to other common malignancies e.g., breast, lung, and prostate, HCC mortality continued to rise by about 2–3% per year, owing to the fact that HCC was frequently diagnosed in advanced stages where there was no curative treatment (Wang and Wei 2020). Despite identifying several risk factors and developing reasonably comprehensive treatment regimens, the 5-year survival rate of HCC in some underdeveloped nations was still very low, ~ 18% (Lee and Lee 2020; Sung et al. 2021). This study reported that FCGR2A might be employed as a predictive biomarker for HCC. Immunohistochemistry investigation revealed that FCGR2A had distinct mRNA transcription and no significant variation in protein expression between normal and liver cancer tissues. The mechanism influencing the post-transcriptional expression of FCGR2A in liver cancer tissues should be further analyzed to confirm the molecular mechanism of its involvement in tumor genesis and development and its impact on immune-related functions.