CXCR3 expression as a prognostic factor in gastric cancer: a meta-analysis
Original Article

CXCR3 expression as a prognostic factor in gastric cancer: a meta-analysis

Hyun Min Koh1, Chang Lim Hyun2,3, Bo Gun Jang2,3, Hyun Ju Lee4,5

1Department of Pathology, Gyeongsang National University Changwon Hospital, Changwon, Republic of Korea; 2Department of Pathology, Jeju National University School of Medicine, Jeju, Republic of Korea; 3Department of Pathology, Jeju National University Hospital, Jeju, Republic of Korea; 4Department of Pathology, Soonchunhyang University College of Medicine, Cheonan, Republic of Korea; 5Department of Pathology, Soonchunhyang University Cheonan Hospital, Cheonan, Republic of Korea

Contributions: (I) Conception and design: All authors; (II) Administrative support: HM Koh, HJ Lee; (III) Provision of study materials or patients: HM Koh, CL Hyun; (IV) Collection and assembly of data: HM Koh, BG Jang; (V) Data analysis and interpretation: HM Koh, HJ Lee; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Hyun Ju Lee, MD, PhD. Department of Pathology, Soonchunhyang University Cheonan Hospital, Soonchunhyang University College of Medicine, 31 Soonchunhyang 6 gil, Dongnam-gu, Cheonan-si, Chungcheongnam-do, 330-721, Republic of Korea. Email: drlhjmd@daum.net.

Background: CXC chemokine receptor 3 (CXCR3) plays a critical role in tumorigenesis, and CXCR3 expression is associated with prognosis in many cancers. Recently, CXCR3 expression is recognized as a potential prognostic factor for patients with gastric cancer. In this study, we analyzed the prognostic significance of CXCR3 expression in gastric cancer.

Methods: We conducted a meta-analysis after selecting eligible studies through a literature search. We calculated pooled results to assess the associations between CXCR3 expression and overall survival (OS) and clinicopathological factors for gastric cancer.

Results: The pooled hazard ratio (HR) with 95% confidence interval (CI) between high expression of CXCR3 and OS was 0.46 (95% CI 0.30–0.71, P<0.001), suggesting that high expression of CXCR3 was associated with a favorable OS. High expression of CXCR3 was significantly correlated with younger age [odds ratio (OR) 0.67, 95% CI: 0.49–0.91, P=0.011], lower tumor grade (OR 0.46, 95% CI: 0.29–0.73, P=0.001), absence of lymph node metastasis (OR 0.47, 95% CI: 0.31–0.71, P<0.001), and lower Tumor-Node-Metastasis stage (OR 0.51, 95% CI: 0.35–0.74, P<0.001).

Conclusions: High expression of CXCR3 was associated with better survival and may be a potential prognostic factor for patients with gastric cancer patients.

Keywords: CXC chemokine receptor 3 (CXCR3); gastric cancer; meta-analysis; prognosis;


Submitted Sep 09, 2020. Accepted for publication Jan 08, 2021.

doi: 10.21037/tcr-20-2862


Introduction

Gastric cancer is the fourth most prevalent cancer, and the second most common cause of cancer-related mortality worldwide (1,2). The prognosis of gastric cancer is rather unfavorable, with a five-year survival rate below 30% (2). Genetically and biologically, gastric cancer is a heterogeneous disorder, and several prognostic factors have been suggested, but their use is limited (3).

CXC chemokine receptor 3 (CXCR3) is a G-protein-coupled receptor shown to influence immune responses, generation of the vascular system, and the repair of wounds (4). Recently, CXCR3 has been shown to play a crucial role in tumorigenesis, and the expression of CXCR3 is associated with the prognosis of many cancers, such as colorectal, breast and ovarian cancer, renal cell carcinoma, and glioblastoma (5-11).

Although CXCR3 expression as a prognostic factor has been studied in gastric cancer, it has been demonstrated in smaller samples and has not been systematically assessed (12-16). Therefore, we performed a meta-analysis to establish the prognostic significance of CXCR3 expression in gastric cancer.

We present the following article in accordance with the PRISMA reporting checklist (available at http://dx.doi.org/10.21037/tcr-20-2862).


Methods

Literature search

We searched the literature using the following keywords: (CXCR3) and (cancer or tumor or carcinoma) and (prognostic or prognosis or survival). The search was conducted on June 1, 2020 using PubMed, Embase, and the Cochrane library, and the manual search was performed at the same time.

Selection criteria

It was included in the analysis only if the following criteria were met in the literature: (I) CXCR3 expression was identified using immunohistochemistry in the human cancer tissue of the stomach, (II) the hazard ratio (HR) and 95% confidence interval (CI) were established between CXCR3 expression and patient survival. Excluded were duplicated literature, reviews, conference abstracts, case reports, and non-English articles.

Data collection and quality assessment

The entire literature contained in the analysis was reviewed to gather the primary data for each literature. The primary data collected included the following: first author, year of publication, country, sample size, sex of patients, study and follow-up period, and CXCR3 expression cut-off. Two authors compiled the data, and differences were revised through consensus.

Quality evaluation was conducted on the literature included in the analysis, and the Newcastle-Ottawa Scale was used for quality evaluation. Quality evaluation was also performed independently by two authors, and disagreement resolution was revised through consensus.

Statistical analysis

Mata-analysis was conducted using StataSE12 (Stata, College Station, TX, USA). Pooled HR with 95% CI: was calculated to evaluate the correlations between CXCR3 expression and patient survival, and the I2 value was used to determine the heterogeneity between the included literature. The funnel plot was plotted to verify publication bias visually. Egger’s test was performed to validate the funnel plot’s statistical significance. Sensitivity analysis was performed to determine the reliability of the pooled results. Pooled odds ratio (OR) with 95% CI: was calculated to assess the associations between CXCR3 expression and clinicopathological factors. Statistical significance was defined as a P<0.05.


Results

Search results and primary data of studies

Figure 1 illustrates the process of selecting the included literature. All studies were published in China, and the study period was from 2008 to 2013. For a total of 716, the number of samples varied from 96 to 192. The included studies’ quality evaluation score was between six and eight, indicating good quality (Table 1).

Figure 1 Flow diagram of the study selection process.
Table 1
Table 1 Basic data of the included studies
Full table

Association between high expression of CXCR3 and overall survival (OS)

The included studies’ heterogeneity was so considerable that the pooled HR was calculated using a random-effects model (I2=62.7%, P=0.030). The results revealed that the elevated expression of CXCR3 was associated with a favorable OS in gastric cancer (HR 0.46, 95% CI: 0.30–0.71, P<0.001) (Figure 2).

Figure 2 Forest plot of the association between CXCR3 expression and overall survival. CXCR3, CXC chemokine receptor 3.

Association between high expression of CXCR3 and clinicopathological factors

High CXCR3 expression was strongly associated with younger age (OR 0.67, 95% CI: 0.49–0.91, P=0.011), lower tumor grade (OR 0.46, 95% CI: 0.29–0.73, P=0.001), absence of lymph node metastasis (OR 0.47, 95% CI: 0.31–0.71, P<0.001), and lower Tumor-Node-Metastasis (TNM) stage (OR 0.51, 95% CI: 0.35–0.74, P<0.001). However, no substantial association was identified with sex, tumor size, Lauren classification, and tumor stage (Table 2) (Figure 3A,B,C,D,E,F,G,H).

Table 2
Table 2 The association between CXCR3 expression and clinicopathological factors in gastric cancer
Full table
Figure 3 Forest plot of the association between CXCR3 expression and clinicopathological factors. (A) Age, (B) sex, (C) tumor size, (D) tumor grade, (E) Lauren classification, (F) tumor stage, (G) lymph node metastasis, and (H) tumor-node-metastasis stage. CXCR3, CXC chemokine receptor 3.

Publication bias

According to the funnel plot, it appeared that there were small study effects, but Egger’s test did not prove it (P=0.232) (Figure 4A). The filled funnel plot also showed that the data did not change (HR 0.46, 95% CI: 0.30–0.71, P<0.001) (Figure 4B).

Figure 4 Funnel plot (A) and filled funnel plot (B) of the association between CXCR3 expression and overall survival. CXCR3, CXC chemokine receptor 3.

Sensitivity analysis

Sensitivity analysis indicated that the study published by Zhou et al. (15) affected the overall results (HR 0.38, 95% CI: 0.29–0.50) (Figure 5). However, the overall results were not substantially different (HR 0.44, 95% CI: 0.34–0.57), even after each study was excluded (Figure 5).

Figure 5 Sensitivity analysis of the association between CXCR3 expression and overall survival. CXCR3, CXC chemokine receptor 3.

Discussion

This study showed a strong association between high expression of CXCR3 and a better prognosis than low expression in gastric cancer. We also demonstrated a correlation between CXCR3 expression and clinicopathological factors, which revealed a significant association between high CXCR3 expression and younger age, lower tumor grade, absent lymph node metastasis, and lower TNM stage.

CXCR3 is an interferon-inducible chemokine receptor expressed in various cells (17). CXCR3 comprises three isoforms, CXCR3-A, CXCR3-B, and CXCR3-Alt, in humans with distinct roles in cell biology and tumorigenesis (17). Of these, CXCR3-A and CXCR3-B are two well-studied isoforms (18). Cancer cells can control the expression of CXCR3 isoforms in a way that benefits overall and can decrease their proliferation and survival by overexpressing CXCR3-B and suppressing CXCR-A (18). Indeed, Hu et al. (16) demonstrated that CXCR3-B mRNA was substantially higher than CXCR3-A mRNA in gastric cancer tissue. CXCR3-B mRNA was significantly lower in patients with metastasis than in patients without metastasis. Therefore, our findings that high expression of CXCR3 indicates a favorable prognosis may have been derived from increased CXCR3-B in gastric cancer tissue. However, the mechanism underlying CXCR3 isoform expression remains to be elucidated, so further research is needed.

This analysis has some limitations. First, the number of studies included was small, making it challenging to analyze in various ways, including subgroup analysis. Second, all the included studies were published in China, so we need to consider whether this could apply to other regions.

However, in this study, we first presented the significance of CXCR3 expression as a prognostic factor in gastric cancer.


Acknowledgments

Funding: This work was supported by the Soonchunhyang University Research Fund.


Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at http://dx.doi.org/10.21037/tcr-20-2862

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr-20-2862). 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.

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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Cite this article as: Koh HM, Hyun CL, Jang BG, Lee HJ. CXCR3 expression as a prognostic factor in gastric cancer: a meta-analysis. Transl Cancer Res 2021;10(3):1449-1456. doi: 10.21037/tcr-20-2862