Research ArticleClinical Studies

Clinical Significance of EREG Gene Expression in Gastric Cancer Tissue After Curative Surgery

HIDEAKI SUEMATSU, ITARU HASHIMOTO, YUKIHIKO HIROSHIMA, HAYATO WATANABE, KAZUKI KANO, KOSUKE TAKAHASHI, TORU AOYAMA, TAKANOBU YAMADA, HIROSHI TAMAGAWA, TAKASHI OGATA, NORIO YUKAWA, YASUSHI RINO, MUNETAKA MASUDA, YOHEI MIYAGI and TAKASHI OSHIMA
Anticancer Research August 2022, 42 (8) 3873-3878; DOI: https://doi.org/10.21873/anticanres.15880

Abstract

Background/Aim: Epiregulin (EREG) is a ligand of the epidermal growth factor receptor (EGFR) and promotes tumour progression mainly by stimulating the EGF pathway. We investigated the clinical significance of EREG mRNA expression in cancer tissues from patients with gastric cancer (GC) in pathological (p) Stage II/III who have undergone curative surgery. Patients and Methods: Expression of EREG mRNA was measured in cancer tissues obtained from 253 patients with pStage II/III GC who underwent curative surgery. Patients were divided into groups based on high or low expression of EREG mRNA. We examined the relationship between EREG mRNA expression levels and clinicopathological features and survival. Results: Clinicopathological features did not vary between the high and low EREG mRNA expression groups. Overall survival was significantly lower in the high-expression group compared to that in the low-expression group (5-year survival probability: 55.0% vs. 73.0%; p=0.005). Multivariate analysis showed EREG mRNA expression to be an independent predictor of poor survival (hazard ratio=1.794; 95% confidence interval=1.186-2.712; p=0.006). Conclusion: Expression of EREG mRNA in cancer tissue from patients with pStage II/III GC may be a useful prognostic marker after curative surgery.

Key Words:

Gastric cancer (GC) is the fifth most commonly diagnosed cancer worldwide and the fourth most common cause of cancer death (1). The standard treatment for pathological (p) Stage II/III GC is curative resection and postoperative adjuvant chemotherapy (2-6). However, the clinical outcome of pStage II/III GC has not been satisfactory. Several studies have identified prognostic biomarkers of GC using quantitative reverse transcription PCR (RT-PCR) or immunohistochemistry (7-9), and personalized postoperative adjuvant chemotherapy treatments using these biomarkers are expected to be developed. Therefore, the identification of novel prognostic biomarkers for pStage II/III GC is an important area of research.

Epiregulin (EREG) is a ligand for the ErbB receptor family (ErbB1/EGFR/HER1, ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4) (10), which contributes to processes including angiogenesis, vascular remodelling, cell proliferation, and inflammation (11). EREG is rarely expressed in normal tissues, but it has been reported to be over-expressed in several cancers (12-14). EREG over-expression is also involved in tumour cell proliferation, invasion, and metastasis and is associated with poor prognosis in various cancers (15). However, the correlation between EREG expression and clinicopathological features and cancer outcomes in patients with pStage II/III GC who have undergone curative surgery has not been fully elucidated. In this study, we aimed to clarify the clinical significance of EREG expression in cancer tissues from patients with pStage II/III GC who have undergone curative surgery.

Patients and Methods

Patients and samples. We collected specimens of GC tissue and adjacent normal mucosa from 253 patients with pStage II/III GC who underwent curative surgery at Kanagawa Cancer Center and Yokohama City University between 2002 and 2010. Each tissue specimen was immediately embedded in an optimal cutting temperature compound (Sakura Finetech Co., Ltd., Tokyo, Japan) and stored at –80°C. The tissue specimens were stained with haematoxylin and eosin before histopathological examination. Tissue sections consisting of more than 80% cancer cells were defined as cancer tissue for RNA extraction and synthesis of complementary DNA (cDNA).

Total RNA was extracted from GC tissue and adjacent normal mucosal specimens using TRIzol™ Reagent (Gibco, Grand Island, NY, USA). Synthesis of a cDNA from total RNA was performed using the iScript cDNA Synthesis Kit (Bio-Rad Laboratories, Hercules, CA, USA).

Quantitative reverse transcription PCR. Quantitative reverse transcription PCR (RT-qPCR) was performed using iQ SYBR Green Supermix (Bio-Rad Laboratories, Inc.). The oligonucleotide primers used for EREG were: sense primer 5’-CGTGTGGCTCAAGTGT CAATAAC-3’, antisense primer 5’-TTCACATCGGACACCAGTA TAACC-3’. As an internal control, β-actin was used. The oligonucleotide primers used for β-actin were sense primer 5’-AGTTGCGTTACACCCTTTCTTGAC-3’, antisense primer 5’-GCTCGCTCCAACCGACTGC-3’. PCRs were carried out in a total volume of 15 μl composed of 200 ng of cDNA; 0.4 μM of each primer; 7.5 μl of iQ SYBR Green Supermix containing dCTP, dATP, dTTP, and dGTP at a concentration of 0.4 mM each and 50 U/ml of iTag DNA polymerase. Reactions were conducted under the following conditions: 3 min at 95°C, denaturation of cDNA at 90°C for 10 s for EREG and 15 s for β-actin, annealing at 58°C for 10 s for EREG and at 60°C for 15 s for β-actin, primer extension at 72°C for 20 s for EREG and 30 s for β-actin, repeated for 40 cycles, followed by a 10 min hold at 72°C. Melting curve analysis was used to distinguish specific products from non-specific products and primer dimers. A standard curve was produced for each run, and three points corresponding to human control cDNA (Clontech Laboratories, Inc., Mountain View, CA, USA) were measured to evaluate the expression of specific mRNA in the samples. The concentration of each sample was calculated based on the intersection points with the standard curve.

Statistical analyses. The expression levels of EREG mRNA in gastric cancer tissues and adjacent normal mucosa were compared using the Wilcoxon test. The relationship between the expression of EREG mRNA and the values of explanatory variables was analysed using the Χ2 test. The relationship between EREG mRNA expression levels and overall survival (OS) was evaluated using the Kaplan–Meier method and analysed using the log-rank test. Univariate and multivariate analyses were performed using the Cox proportional hazards model to identify prognostic risk factors for OS. Statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan) and a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). Two-sided p-values were calculated, and a p-value <0.05 was considered statistically significant.

Results

Differences in EREG mRNA expression. Expression levels of EREG mRNA were significantly higher in GC tissues compared to normal adjacent gastric mucosa (p=0.002; Figure 1).

Figure 1.
Figure 1.

Comparison of EREG expression levels in gastric cancer tissues and normal adjacent gastric mucosa (p=0.002). The Wilcoxon test was used to calculate p-values (n=143).

Relationships between EREG mRNA expression and clinicopathological features. Patients were divided into EREG mRNA expression and non-expression groups. The relationships between EREG mRNA expression and clinicopathological features are summarized in Table I. No association was found between EREG mRNA expression levels and these features.

View this table:
Table I.

Relation between EREG mRNA expression and clinicopathological features.

Survival analyses. The high-expression EREG mRNA group displayed significantly poorer OS than the low-expression group (55.0% vs. 73.0%, respectively; p=0.005; Figure 2).

Figure 2.
Figure 2.

Kaplan-Meier survival curves for overall survival in patients with and without EREG expression. The 5-year OS rate was 55.0% for patients in the EREG expression group and 73.0% for those in the non-expression group (p=0.005).

Univariate and multivariate analyses of EREG mRNA expression and clinicopathological factors for overall survival. Univariate analysis indicated that serosal invasion, lymph-node metastasis, lymphatic invasion, and EREG mRNA expression levels were significant prognostic factors for OS (Table II). Multivariate analysis indicated that serosal invasion [hazard ratio (HR)=1.603; 95% confidence interval=1.052-2.443; p=0.028], lymphatic invasion (HR=1.669; 95% confidence interval=1.005-2.773; p=0.048), and EREG mRNA expression (HR=1.794; 95% confidence interval=1.186-2.712; p=0.006) were significant independent prognostic factors for OS (Table II).

View this table:
Table II.

Univariate and multivariate Cox proportional hazards analyses of the clinicopathological features for overall survival.

Discussion

In this study, we evaluated the clinical significance of EREG mRNA expression in cancer tissues from patients with pStage II/III GC who underwent curative resection. We showed that 5-year OS was significantly poorer in the high-expression group compared to that in the low-expression group. Furthermore, we showed that expression of EREG mRNA in GC tissue may be a useful prognostic factor.

First, we compared EREG mRNA expression levels in cancer tissue with those in adjacent normal mucosa. Previous studies had reported that EREG mRNA was rarely expressed in normal mucosa, while its expression in cancer tissues had been reported in various cancer types such as gastric, cervical, lung, pancreatic, colon, and oesophageal cancers (12-14, 16, 17). Our results are consistent with previous reports and showed that EREG mRNA expression in 143 GC tissue samples was significantly higher when compared to that in paired adjacent normal mucosa.

Second, we examined the relationship between EREG mRNA expression levels and clinicopathological features. Previous GC studies have reported that increased EREG expression is significantly associated with TNM stage, tumour size, depth of invasion, lymph node metastasis, distant metastasis, and differentiation (16, 18). In other cancers, EREG expression is associated with depth of invasion in oral squamous cell carcinomas (14), lymph node metastasis, and differentiation in oesophageal cancer (13), lymph node metastasis in non-small cell lung cancer (19), and disease progression in bladder cancer (20). However, in our study, there was no association between EREG mRNA expression levels and clinicopathological features in tissue samples from patients with pStage II/III GC.

Finally, we investigated the relationship between EREG mRNA expression levels and outcomes in patients with pStage II/III GC who have undergone curative surgery. Previous studies have reported that high expression of EREG is associated with poor outcomes in various cancers, including gastric, colorectal, lung, and oesophageal cancers (13, 14, 16, 17, 21, 22). However, some studies have shown that EREG expression is not significantly associated with outcomes (18, 23). In this study, we demonstrated that 5-year OS was significantly poorer in the high-expression group than in the low-expression group. In addition, the results of univariate and multivariate analyses showed that EREG mRNA expression levels may be a useful prognostic factor in patients with pStage II/III GC who have undergone curative surgery.

It is unclear how increased EREG expression levels contribute to poor GC prognosis. Previous reports suggest that EREG stimulates ErbB signalling pathways involved in cancer progression. Accelerated ErbB signalling activates the downstream MEK/ERK and PI3K/Akt signalling pathways, contributing to cancer cell proliferation and differentiation (15, 22, 24). Some studies have reported that activation of the MEK/ERK and PI3K/Akt pathways is also associated with GC progression (25-27). Therefore, EREG may promote cancer cell proliferation, invasion, and metastasis by acting as a ligand for ErbB receptors, leading to a poor prognosis. In recent years, EREG has been reported as a therapeutic biomarker for several EGFR inhibitors. Previous reports have shown that EREG over-expression is a biomarker of EGFR-targeted therapies (cetuximab or panitumumab) for colorectal cancer patients (28-30). High expression of EREG mRNA has been used as a treatment biomarker of an EGFR and HER2 inhibitor (lapatinib) in patients with HER2-positive breast cancer (31). A previous study used gene expression analysis of GC cell lines to show that EREG over-expression is a treatment biomarker for cetuximab and afatinib (32). Moreover, EREG expression levels have been shown to correlate significantly with EGFR and ErbB2 expression levels in clinical GC samples (18). Therefore, EREG expression levels might be associated with increased EGFR receptors signalling, thus contributing to cancer progression and resulting in poor outcomes.

There are several limitations to this study. First, we only examined the mRNA expression of EREG in gastric cancer tissues, not the protein expression. In order to determine the clinical usefulness of the protein as a biomarker, both mRNA and protein expression should be examined in the same tissue specimens. Second, there is the issue of heterogeneity of the cancer tissues examined. mRNA was extracted from 5 mm2 of gastric cancer tissue, including that from the deepest part of the tumour; however, it does not represent the entire tumour. Thus, we were unable to ascertain whether there is tumor heterogeneity between different parts of the tumour, which could have influenced our results.

In conclusion, EREG gene expression in GC tissues may be a useful prognostic biomarker for patients with pStage II/III GC who have undergone surgery. Our results may aid further clinical trials of biomarker-oriented adjuvant chemotherapy.

Acknowledgements

The Authors thank all the patients, their families, and the site staff for their participation in this study.

Footnotes

  • ↵* These Authors contributed equally to this study.

  • Authors’ Contributions

    Concept and study design were conducted by HS, IH, YH, YM, and TO. Data collection and literature search were performed by HS, IH, HW, KK, and TO. Data analysis and interpretation were performed by HS, IH, YH, TA, YT, and TO. The manuscript and figures were drafted by HS, IH, and TO. Finally, the manuscript was revised and approved by all investigators. Thus, all the Authors actively participated in this study.

  • Conflicts of Interest

    The Authors declare that there are no conflicts of interest regarding this study.

  • Received June 1, 2022.
  • Revision received June 23, 2022.
  • Accepted June 24, 2022.

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Clinical Significance of EREG Gene Expression in Gastric Cancer Tissue After Curative Surgery
HIDEAKI SUEMATSU, ITARU HASHIMOTO, YUKIHIKO HIROSHIMA, HAYATO WATANABE, KAZUKI KANO, KOSUKE TAKAHASHI, TORU AOYAMA, TAKANOBU YAMADA, HIROSHI TAMAGAWA, TAKASHI OGATA, NORIO YUKAWA, YASUSHI RINO, MUNETAKA MASUDA, YOHEI MIYAGI, TAKASHI OSHIMA
Anticancer Research Aug 2022, 42 (8) 3873-3878; DOI: 10.21873/anticanres.15880
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