Expression and clinical significance of ERBB4 in gastric cancer

Introduction

Gastric cancer (GC) is a common malignant tumor of the digestive tract, and is the fifth most common cancer and the fourth leading cause of cancer-related death worldwide (1,2). There were more than 1 million new cases of GC in 2020 (2). Despite significant advancements in its early diagnosis and treatment (1), most GC patients are already at an advanced stage at the time of diagnosis, and often have poor treatment outcomes. Studies have reported that the overall survival (OS) of patients with advanced-stage disease ranges from 10 to 12 months (3), and the 5-year survival rate of patients with non-metastatic disease is only 28% to 36% (4). Thus, a new prognostic biomarker urgently needs to be identified to prolong the survival time of GC patients.

The human epidermal growth factor receptor (EGFR/HER) family is involved in the regulation of various cellular processes, including cell proliferation, organ development and organ repair. Research (5) has shown that abnormal EGFR signaling is related to the development of various solid tumors. EGFR belongs to the ErbB family of receptor tyrosine kinases, including HER1, HER2, HER3, and HER4, also known as ErbB1, ErbB2, ErbB3, and ErbB4, respectively (6). Extensive, wide-ranging, and in-depth investigations have been conducted to examine the role of HER2 in GC and its pertinent biological characteristics. Cheng et al. found that HER2-positive GC patients have a poor prognosis (7). Trastuzumab, a targeted therapeutic agent, can improve patient prognosis by inhibiting the expression of the HER2 gene (8).

Research has shown that HER4 exhibits a stronger promoting effect on the growth and development of GC cells than other members of the EGFR family (9). Song et al. reported that miR-551b regulates the epithelial-mesenchymal transition and metastasis of GC by inhibiting ERBB4 expression (10). Liu et al. noted that miR-936 overexpression inhibits the proliferation and invasion of GC cells by targeting ERBB4 and promotes apoptosis via AKT signaling pathways (11). However, a study has found no clinical relationship between GC and ERBB4-positive expression (12). Given the inconsistencies in the results of relevant studies on the association between ERBB4 and GC, further research needs to be conducted to investigate the clinicopathological expression and features of ERBB4 in GC. Using relevant data from the Cancer Genome Atlas (TCGA) database, we analyzed and further evaluated the expression of ERBB4 in GC. We also explored the connections between the ERBB4 gene and the clinicopathological features and prognosis of GC patients. We present this article in accordance with the REMARK reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-673/rc).

Methods

Data collection

The gene expression data and clinically relevant data of 375 GC tissue samples and 32 adjacent non-cancerous tissue samples were downloaded from TCGA database (https://www.cancer.gov/tcga) for the gene expression difference analysis. Among these, matched adjacent non-cancerous tissues were available for a subset of cases (n=32), which served as the normal control group. Furthermore, the expression profile of the ERBB4 gene in GC was acquired from the Human Protein Atlas (HPA) database (http://www.proteinatlas.org/). To evaluate the prognostic value of ERBB4, we utilized the Kaplan-Meier plotter to assess its relationship with clinical outcomes in GC. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Analysis of clinicopathologic features

The relationship between ERBB4 gene methylation and stomach adenocarcinoma (STAD) was visualized using MEXPRESS (http://mexpress.be) based on TCGA data (13). A Spearman correlation analysis was conducted to examine the correlation between ERBB4 messenger RNA (mRNA) expression and copy number variations (CNVs). Analyses were also conducted to examine the association between the methylation level of the ERBB4 gene promoter region and ERBB4 mRNA expression, and the association between the CNVs and ERBB4 mRNA expression in the ERBB4-STAD cohort.

Survival analysis of ERBB4 expression

To analyze the GC survival rate in TCGA dataset the median ERBB4 expression value was used to group the included subjects into high- and low-expression groups. The relationship between the clinicopathological features and ERBB4 expression was then examined. Next, publicly accessible gene expression data of ERBB4 were acquired from the Kaplan-Meier plotter database. Using this platform, survival curves for OS and progression-free survival (PFS) based on ERBB4 expression levels were plotted in a GC cohort. A Cox regression model was then used to conduct univariate and multivariate analyses of the risk factors affecting patient prognosis.

Statistical analysis

TCGA data were preprocessed and analyzed by R package (version 4.1.1). The t-test results of ERBB4 expression values were checked using two independent samples, and a paired analysis was then performed. Fisher’s exact test was used to compare categorical clinicopathological features, and the Chi-squared test (with Yates’ continuity correction where applicable) was used for variables with sufficient sample sizes. The log-rank test was used to compare the Kaplan-Meier survival curves. All the statistical analyses were performed using SPSS 26.0 (SPSS, Chicago, USA).

Univariate and multivariate Cox regression analyses of the clinical features and ERBB4 expression were conducted to assess whether the clinical features or ERBB4 expression were independent prognostic factors in GC. R package (version 4.1.1) was used for the analysis. A P value <0.05 was considered statistically significant.

Results

ERBB4 expression is significantly down-regulated in GC tissues

The expression of ERBB4 in the tumor tissues of 375 GC patients and the adjacent non-cancerous (normal) tissues of 32 patients in TCGA dataset was analyzed. ERBB4 expression was significantly lower in the GC tissues (0.070±0.192) than the adjacent non-cancerous tissues (0.086±0.095) (Figure 1A). The paired analysis results also showed that ERBB4 expression was significantly lower in the GC tissues than the adjacent non-cancerous tissues (Figure 1B). The immunohistochemical staining of the ERBB4 protein in the HPA dataset showed that ERBB4 expression was lower in the GC tissues than the normal tissues (Figure 1C).

Figure 1 ERBB4 expression is significantly down-regulated in GC tissues. (A) Scatter plot of the expression level of ERBB4 in GC tissues and adjacent non-cancerous tissues from TCGA database. (B) Paired testing of the expression level of ERBB4 in adjacent non-cancerous tissues and GC tissues. **, P<0.01; ***, P<0.001. (C) Immunohistochemical examination of ERBB4 expression in GC tissues and normal tissues from HPA database (normal: https://www.proteinatlas.org/ENSG00000178568-ERBB4/tissue/stomach#img; tumor: https://www.proteinatlas.org/ENSG00000178568-ERBB4/cancer/stomach+cancer#img). The magnification for HPA tissue images is 40×. FPKM, fragments per kilobase of transcript per million mapped reads; GC, gastric cancer; HPA, Human Protein Atlas; TCGA, The Cancer Genome Atlas.

Factors influencing ERBB4 expression in GC tissues

We analyzed the relationship between ERBB4 expression and the clinical factors of STAD by MEXPRESS visualization in TCGA dataset. The results revealed that ERBB4 expression was related to age at the initial pathological diagnosis, the risk of recurrence, and the tumor type of STAD (Figure 2A).

Figure 2 Factors influencing ERBB4 expression in GC tissues. (A) MEXPRESS tool was used to analyze the correlation between ERBB4 expression and clinical features of patients. (B) Pie chart of ERBB4 homologous amplification/deletion and heterologous amplification/deletion. (C) A Spearman analysis showed the correlation between ERBB4 CNVs and mRNA expression in STAD. (D) A Spearman analysis displayed the correlation between ERBB4 DNA methylation and mRNA expression in STAD. (E) MEXPRESS analysis of ERBB4 methylation sites. *, P<0.05; **, P<0.01; ***, P<0.001. Amp., amplification; CNV, copy number variation; Cor., correlation; CpG, cytosine-phosphate-guanine; dele., deletion; FDR, false discovery rate; hete., heterologous; homo., homologous; mRNA, messenger RNA; RSEM, RNA-seq by expectation-maximization; STAD, stomach adenocarcinoma.

Subsequently, we examined the DNA expression of the ERBB4 gene in the GC tissues, as well as the CNVs and methylation. Analysis of 375 GC patients in the TCGA-STAD cohort demonstrated the frequency distribution of ERBB4 copy number alterations: homozygous amplification occurred in 0.68% of cases (n=3), heterozygous amplification in 16.33% (n=61), homozygous deletion in 1.36% (n=5), heterozygous deletion in 11.56% (n=43), and diploid status (no alteration) in 70.07% (n=263), with total percentages equaling 100% after rounding (Figure 2B). The results of the Spearman correlation analysis revealed no correlation between ERBB4 CNVs and ERBB4 mRNA expression in STAD [correlation (Cor) =−0.01, false discovery rate (FDR) =0.84] (Figure 2C). These results suggest that copy number amplification was not a regulator of ERBB4 mRNA expression. We also investigated whether DNA methylation was a cause of high ERBB4 expression in GC tissues, and found a negative correlation between DNA methylation and ERBB4 mRNA expression (Cor =−0.27, FDR =8.5×10⁻⁸) (Figure 2D).

DNA methylation generally occurs at the cytosine-phosphate-guanine (CpG) dinucleotide sites. Given the correlation between DNA methylation and ERBB4 mRNA expression in STAD, we examined the CpG site status of the GC patients by MEXPRESS visualization in TCGA dataset. In total, 28 CpG sites were found to be correlated with ERBB4 expression, of which, 8 were positively correlated and 16 were negatively correlated (Figure 2E). Thus, ERBB4 promoter methylation may be relevant to ERBB4 expression in GC.

Correlation between ERBB4 expression and the prognosis of GC patients

Based on the median value of ERBB4 expression, the included subjects were divided into low- and high-expression groups. The Kaplan-Meier survival analysis showed that OS and PFS were worse in the high-expression group than the low-expression group (Figure 3A,3B).

Figure 3 Correlation between ERBB4 and the prognosis of patients with GC. (A,B) The correlation between high/low ERBB4 expression and OS (A) and PFS (B) in the GC patients. (C,D) The correlation between the high/low methylation of ERBB4 and OS (C) and PFS (D) in the GC patients. (E,F) The relationship between various CNVs of ERBB4 in STAD and the OS and PFS of the patients. (G,H) Kaplan-Meier plotter analysis of the correlation between the high/low expression of ERBB4 and the OS and PFS of GC patients. Amp., amplification; CI, confidence interval; CNV, copy number variation; dele., deletion; GC, gastric cancer; HR, hazard ratio; meth., methylation; OS, overall survival; PFS, progression-free survival; STAD, stomach adenocarcinoma; WT, wild type.

Given the negative correlation between DNA methylation and ERBB4 expression, we examined the relationship between ERBB4 methylation and patient prognosis. The results showed that the GC patients in the ERBB4 hypermethylation group had higher OS and PFS than those in the hypomethylation group, indicating that the patients in ERBB4 hypermethylation group had a better prognosis (Figure 3C,3D). The relationship between ERBB4 CNVs and patient prognosis was also analyzed; however, no significant differences in OS and PFS among the ERBB4 deletion, ERBB4 amplification, and adjacent non-cancerous groups of GC patients were found (Figure 3E,3F).

To further confirm these findings, we analyzed ERBB4 expression and survival data from 875 GC patients in the Kaplan-Meier plotter cohort for OS and 164 patients for PFS. The results revealed that the high-expression group (n=371) had significantly lower OS than the low-expression group (n=504) (Figure 3G). Additionally, an analysis of 164 GC patients was also conducted, and the high-expression group (n=88) had significantly lower PFS than the low-expression group (n=76) (Figure 3H). Overall, high ERBB4 expression was associated with a poor prognosis in GC.

Relationship between ERBB4 expression and patient survival

Univariate and multivariate Cox regression analyses were conducted to examine the relationship between ERBB4 expression and patient survival. The results showed that high ERBB4 expression was significantly correlated with worse PFS and OS (Tables 1,2). Moreover, the univariate Cox regression analysis showed that PFS was correlated with gender (P=0.02), clinical stage (P=0.009), tumor (T) stage (P=0.02), lymph node metastasis (P<0.001), and distant metastasis (P=0.01) in the GC patients (Table 1). While OS was correlated with age (>65 years) (P=0.005), clinical stage (P=0.008), T stage (P=0.03), lymph node metastasis (P<0.001), distant metastasis (P=0.004), residual tumor R1 and R2 (P<0.001), and the primary treatment effects [partial response (PR) and complete response (CR); P<0.001] (Table 2). In addition, the multivariate Cox regression analysis showed that high ERBB4 expression was an independent risk factor for OS in GC patients (P<0.001), but not for PFS. OS was significantly affected by age (>65 years) (P=0.006) and the initial treatment effects (P<0.001), while PFS was significantly affected by gender (female) (P=0.045) and the initial treatment effects (PR and CR) (P<0.001) (Tables 1,2).

Discussion

Due to continuous advancements in molecular biological detection technology, the era of “precise medical treatment” for GC is rapidly approaching. However, targeted therapy for GC is still not satisfactory. Thus, effective biomarkers for the individualized treatment and prognostic evaluation of GC urgently need to be established.

ERBB4, a member of the EGFR family, is crucial for normal tissue development, especially in the heart, nervous system, and breast system (14). However, its role in cancer is debatable. Most studies have reported that ERBB4 is abnormally expressed in various malignant tumors, including lung cancer (15), breast cancer (16), malignant melanoma (17), and ovarian cancer (18). Due to its dual effects on tumor development and progression, ERBB4 can function as both an oncogene and tumor suppressor (19). According to a study, ERBB4 is lowly expressed in invasive tumors, and slows tumor growth in breast and liver cancer, but plays a promoting role in GC and melanoma (14). In this study, we analyzed RNA-sequencing data from TCGA database, and compared ERBB4 expression in GC and adjacent non-cancerous tissues. The results showed that the ERBB4 expression level was down-regulated in the GC tissues compared with the adjacent non-cancerous tissues. These results were also verified by the immunohistochemical staining data obtained from the HPA database. Chen et al. previously sequenced 294 GC samples, and discovered ERBB4 gene mutations in GC patients (20). ERBB4 participates in cell proliferation, Ras protein signaling transduction, mitogen-activated protein kinase signaling, transmembrane receptor protein tyrosine kinase signaling, endothelial growth factor receptor signaling, and insulin receptor signaling pathways (14).

In this study, we discovered that the CNVs were not a factor affecting ERBB4-mRNA expression, and the normal DNA amplification of ERBB4 accounted for 70.07% of DNA expression changes. CNVs are an important factor influencing gene expression in cancer. The microarray analysis results displayed the CNVs in the GC tissues, and 163 genes were found to be related to the CNVs in GC (21). Unfortunately, we did not find any correlation between ERBB4 expression and the CNVs. This could be because numerous variables affect gene expression, and copy number changes do not necessarily induce actual alterations in gene expression.

The DNA methylation of CpG sites has been reported to be correlated with the occurrence of GC (22). Global hypomethylation of the cancer genome may induce cancer through methylated cytosine deamination (23). Moreover, downstream gene expression is frequently inhibited by hypermethylated DNA gene levels but typically increased by hypomethylated gene levels. This study found a negative correlation between ERBB4 mRNA expression and ERBB4 methylation. The low methylation level could result in an increase in the ERBB4 expression level. Since DNA methylation negatively correlates with ERBB4 expression, we further investigated its impact on patient survival. The survival analysis revealed that the patients with hypomethylated ERBB4 levels had lower PFS and OS than those with hypermethylated ERBB4 levels.

In this study, we also attempted to examine the relationship between ERBB4 expression and the clinical characteristic of GC, and assess whether ERBB4 was a prognostic factor in GC. The Kaplan-Meier survival analysis showed that the high ERBB4 expression group had a worse prognosis than the low ERBB4 expression group. Thus, ERBB4 may act as an oncogene in the progression of GC. Subsequently, further research was conducted to examine the connection between ERBB4 expression and the clinicopathological parameters. We found that high ERBB4 expression resulted in worse PFS and OS in the GC patients, and ERBB4 was an independent risk factor for OS in the GC patients. Many studies have shown that high ERBB4 expression enhances tumor metastasis and GC progression (9,11). A report has also pointed out that ERBB4 could act as a target of miR-551b, and high ERBB4 expression indicates a poor prognosis (10), which reflects our findings. It should be noted that the results between the differential expression analysis and the survival analysis of ERBB4 in GC were contradictory. TCGA and HPA results showed that ERBB4 was lowly expressed in the GC tissues. The survival analysis results revealed a link between the high expression of ERBB4 and the poor prognosis of GC patients. Our study reveals a complex relationship between ERBB4 expression and GC outcomes. While overall downregulated in tumors, high ERBB4 mRNA levels are a robust indicator of poor prognosis, highlighting its context-dependent role. This paradox positions ERBB4 not as a straightforward oncogene or tumor suppressor, but as a compelling biomarker whose biological complexity warrants deeper mechanistic investigation. This paradox may be explained by factors the study did not investigate, such as the expression of different ERBB4 isoforms or the subcellular localization of the protein (e.g., membrane-bound vs. nuclear), which are known to have opposing effects on cancer progression. In addition, the physiological function of ERBB4 is regulated by a variety of different molecular mechanisms (19), which may be the basis for the dual action of ERBB4 in GC.

The Cox univariate regression analysis showed that poor OS was associated with high ERBB4 expression, age, clinical stage, T stage, lymph node metastasis, distant metastasis, residual tumor R1 and R2, and the primary treatment effects of PR and CR in GC patients. The multivariate Cox regression analysis showed that high ERBB4 expression was an independent risk factor for OS in the GC patients, indicating that ERBB4 was an independent prognostic factor and may serve as a new target for the molecular therapy of GC. It should be noted that during the multivariate COX regression analysis, quasi-complete separation occurred with the T stage variable, which was caused by the extremely low number of events (deaths) in the T1 reference group. However, we contend that the model adjusted for overall pathologic stage and other factors effectively accounts for the advanced disease burden it represents. Furthermore, the dichotomization of ERBB4 expression at the median, while methodologically common, is a simplification of the underlying continuous relationship that may not fully capture its true association with survival. Future studies with larger sample sizes could benefit from analyzing ERBB4 as a continuous variable or by determining data-driven optimal cut-off values to better define prognostic groups.

However, this study has several limitations. First, the reliance on retrospective data from public databases means that our findings are correlative and do not establish causality. Second, the lack of experimental validation in cellular or animal models limits our ability to confirm the functional role of ERBB4 in GC pathogenesis and its potential as a therapeutic target. Future studies involving in vitro and in vivo functional assays are warranted to elucidate the mechanistic underpinnings of ERBB4 in GC progression and to evaluate its suitability for targeted therapy. Third, we did not analyze the relationship between ERBB4 expression and established molecular subtypes of GC, such as HER2 amplification status, microsatellite instability (MSI), or PD-L1 expression. This omission limits our ability to place ERBB4 within the modern molecular context of GC and to determine whether its prognostic effect is universal or specific to certain subtypes. For example, the role of ERBB4 may be fundamentally different in HER2-positive tumors where ERBB family signaling is already aberrant. Consequently, the therapeutic implications of our findings remain speculative. Our data cannot answer the fundamental question of whether a potential therapy should aim to inhibit or activate ERBB4, as this would be entirely dependent on the aforementioned molecular context and the specific oncogenic or tumor-suppressive isoforms present. Therefore, our work should be seen as a hypothesis-generating study that identifies a complex biomarker and underscores the critical need for future research to integrate ERBB4 expression with comprehensive molecular subtyping.

Gene expression and clinical data, comprising 375 GC samples and 32 adjacent non-tumor control tissues, were obtained from TCGA. ERBB4 expression data at the protein level were independently sourced from the HPA database. It is important to note that the TCGA “normal” controls were derived from adjacent tissues, which may not represent truly healthy gastric mucosa due to potential field cancerization effects. Furthermore, the analysis was limited by a significant sample size imbalance between the tumor (n=375) and control (n=32) groups. To mitigate the potential confounding effect of inter-individual variation, a paired analysis of the 32 available patient-matched tissue pairs was performed; this analysis confirmed ERBB4 downregulation in tumors. While this paired approach strengthens the findings, future studies utilizing true normal controls from healthy individuals are warranted.

Conclusions

Patients with high ERBB4 expression have a poor prognosis and a short survival time. Furthermore, our data suggest an inverse relationship between ERBB4 expression and its promoter methylation level in GC tissues. Our findings may guide the development of a molecular targeted therapy and individualized treatment plans for GC patients.

Acknowledgments

We gratefully acknowledge the support and assistance provided by the Oncology Key Discipline Cluster at Taizhou Cancer Hospital.

Footnote

Reporting Checklist: The authors have completed the REMARK reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-673/rc

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-673/prf

Funding: This research was supported by the National Natural Science Foundation of China (No. 82074245), the Taizhou Science and Technology Program (No. 22ywb127), and the Wenling Science and Technology Program (Nos. 2021S00002, 2023S00002, 2024S00093, 2024S00113, and 2024S00035).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-673/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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