The Clinicopathological and Prognostic Significance of Foxp3 Expression in Gastric Cancer: A Meta-Analysis and TCGA Analysis

doi:10.21203/rs.3.rs-1602772/v1

Purpose：In gastric cancer (GC) patients, the relationship between Forkhead Box P3 (Foxp3) expression and clinicopathological parameters and prognosis is controversial. Our purpose was to study the association between Foxp3 expression and clinicopathological parameters and overall survival (OS) of GC patients.

Method：The data for this article was analyzed by Stata 15.1 software. The association between Foxp3 expression and clinicopathological data and OS was explored by pooled odds ratio (OR) with a 95% confidence interval (CI). We used deek’s plots to evaluate publication bias. By The Cancer Genome Altlas (TCGA) data, we detected that the association between Foxp3 expression and OS in stomach adenocarcinoma (STAD) patients.

Results：We obtained 12 articles including 1,583 GC patients. Our research observed that Foxp3 expression was not related to age (OR = 0.899, 95% CI = 0.549-1.472, p = 0.672), gender (OR = 0.836, 95% CI = 0.647-1.080, p = 0.171), differentiation (OR = 1.083, 95% CI = 0.616-1.904, p = 0.781), and TNM stage (OR = 0.967, 95% CI = 0.583-1.605, p = 0.898) in GC patients. We found that Foxp3 expression was related to tumor size (OR = 0.489, 95% CI = 0.2857-0.839, p = 0.009) and lymph node metastasis (OR = 0.514, 95% CI = 0.280-0.944, p = 0.032) in GC patients. Our studies showed that high Foxp3 expression of 1-year OS (OR = 0.606, 95% CI = 0.399-0.921, p = 0.019), 3-year OS (OR = 0.629, 95% CI = 0.436-0,908, p = 0.013), and 5-year OS (OR = 0.412, 95% CI = 0.231-0.734, p = 0.003) was better than low Foxp3 expression in GC patients. The OS of high Foxp3 expression group was better than low Foxp3 expression group by TCGA, but there was no different in statistic (p=0.34).

Conclusion：Foxp3 expression was relate to tumor sizes, lymph node metastasis and better OS in GC patients. Foxp3 expression was not related to age, sex, differentiation, and TNM stage. Foxp3 might be a prognosis maker in GC patients.

Forkhead Box P3

gastric cancer

clinicopathological parameters

prognosis

meta-analysis

It had been reported that gastric cancer (GC) is regarded as the fourth cancer-related deaths globally [1]. GC had a higher incidence rate in Asia, including China [2]. Although the development of endoscopic and surgical techniques is helpful to improve the diagnosis of GC, most GC patients were diagnosed with advanced disease with lymph node or distant metastasis, poor prognosis exists frequently as a result [3–5]. Subsequently, it is essential to find a maker to recognize the tumor diagnose and prognosis of GC patients.

Forkhead Box P3 (Foxp3) is a critical transcriptional factor in regulatory T cells (Tregs), which is expressed in Tregs and plays an imperative roles in the immunosuppressive capacities, proliferation, differentiation and regulation of Tregs [6, 7]. Recent studies indicated that Foxp3 was not only associated with Treg immune framework but also played a critical part in tumor development [8]. Studies showed that Foxp3 expression might predict prognosis in numerous sorts of cancers, including breast cancers, urinary bladder cancers, melanomas, non-small cell lung cancers and other cancers [9–12]. Similarly, some studies reported that Foxp3 expression may influence the prognosis and clinicopathological parameters in GC [13, 14]. However, the association between Foxp3 expression and prognosis and clinicopathological parameters in GC patients is controversial. Kyu et al. found that high expression of Foxp3 was associated with better overall survival (OS) in GC patients [15]. Yoshii et al. found that Foxp3 high expression may be associated with the poor OS in GC patients [16]. Li et al. found that Foxp3 was related to invasion degree and lymph node metastasis [17]. Wang et al. claimed that the Foxp3 expression was not associated with age, gender, differentiation, lymph node metastasis and tumor size in GC patients [18]. Currently, the associated between Foxp3 expression and clinicopathological parameters and OS of GC patients has not been reported. Hence, we explore the association between the expression of Foxp3 and clinicopathological parameters and prognosis by meta-analysis and The Cancer Genome Atlas (TCGA) in GC patients.

Search strategy

We obtained the databases from PubMed, EMBASE, Web of Science, Cochrane Library, and Chinese databases (CNKI), Wanfang, and VIP databases up to February 1, 2022. The language limits are English and Chinese. Search keywords were: “Foxp3” or “Forkhead box protein P3” and “carcinoma” or “cancer” and “gastric” or “stomach” and “survival” or “prognosis”. The included literature was checked. For the meta-analysis, we followed PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines.

Inclusion or exclusion criteria

Inclusion criteria identified in literature search: 1) to study the relationship between Foxp3 expression and clinicopathological parameters and prognosis in GC patients, 2) the Foxp3 expression was evaluated by immunohistochemistry (IHC) in GC patients, 3) the Foxp3 expression was divided into high / low or + / - groups.

The exclusion standards: 1) animal research, 2) repeated studies from the identical population or data, 3) lack of medical data, 4) radiotherapy or chemotherapy before operation.

Data extraction and assessment

Two independent reviewers (Jiacheng Gao and Zirui Jia) searched and detected the eligibility of the articles. Another author (Yuhang Wang) decided the disagreements of the two reviewers. The data have been extracted: first author, age, gender, number of patients, TNM stage, tumor sizes, lymph node metastasis, OS, and Foxp3 expression in GC patients.

The Newcastle-Ottawa Scale (NOS) (maximum score was 9) was used for methodological quality in systematic reviews of included research. In our article, we considered that NOS score ≥6 was high quality.

TCGA

We used Gene Expression Profiling Interactive Analysis (GEPIA), (http://gepia. cancer-pku.cn) to get the data of Foxp3 expression and OS of stomach adenocarcinoma (STAD) patients in TCGA, and 384 patients were included. Kaplan-Meier curve was used to analysis the survival of STAD patients.

Statistical Analysis

The data for this article was analyzed by Stata 15.1 software. The heterogeneity was measured by the Q test. A noteworthy Q test (p<0.05 orI²>50%) demonstrated heterogeneity among research. The association between Foxp3 expression and clinicopathological data and OS were explored by pooled odds ratio (OR) with a 95% confidence interval (CI). Publication bias was evaluated by deek’s plots, p less than 0.05 was considered significant.

Description of studies

In our meta-analysis, we searched for 350 relevant studies in the databases. 35 duplicated data from the same population were removed. Due to lack of statistical analysis and clinical data (N=265), reviews (N=7), case reports (N=5), editorial (N=15) and abstract (N=11), 303 articles were excluded. Finally, 12 articles were included [15-26] (Fig. 1). We listed the 12 articles in Table 1. Overall, the 12 articles included 1,583 GC patients were published between 2013 and 2021. 2 studies came from Korea, 1 study was from Japan, 1 study was from Brazil, 8 studies were from China.

Table 1. Clincal data included in the literature

No	First author	Year	No	Gender (M/F)	pNstage (N+/N-)	During	Country	Method	NOS
1	Wang	2021	115	90/25	79/36	2016-2018	China	IHC	7
2	Ouyang	2019	86	48/38	51/35	2014-2017	China	IHC	6
3	Neves	2018	33	20/13	-	-	Brazil	IHC	6
4	Deng	2013	90	64/26	-	2006-2007	China	IHC	6
5	Suh	2015	117	-	69/48	2006-2009	Korea	IHC	7
6	Yoshii	2012	92	44/48	34/58	2000-2010	Japan	IHC	7
7	Guo	2020	268	210/58	183/85	2009-2011	China	IHC	7
8	Geng	2014	100	61/39	68/32	2005-2006	China	IHC	6
9	Wang	2020	106	67/39	21/85	2005-2015	China	IHC	8
10	Li	2017	197	128/69	102/95	2007-2010	China	IHC	8
11	Ma	2014	197	130/67	86/101	-	China	INC	6
12	Won	2017	182	-	82/100	2006-2012	Korea	IHC	7

M,male;F,female;-,no data.

Foxp3 expression and clinicopathological data

To study the association between Foxp3 expression and clinicopathological parameters, we observed the association between Foxp3 expression and age, sex, tumor lymph node metastasis, tumor differentiation, TNM stage, and tumor size by meta-analysis. In our results, we found that Foxp3 expression was not related to age (OR = 0.899, 95% CI = 0.549-1.472, p = 0.672), gender (OR = 0.836, 95% CI = 0.647-1.080, p = 0.171), differentiation (OR = 1.083, 95% CI = 0.616-1.904, p = 0.781), and TNM stage (OR = 0.967, 95% CI = 0.583-1.605, p = 0.898) in GC patients. We observed that Foxp3 expression was related to tumor size (OR = 0.489, 95% CI = 0.2857-0.839, p = 0.009) and lymph node metastasis (OR = 0.514, 95% CI = 0.280-0.944, p = 0.032) in GC patients (Table 2 and Fig. 2).

Table 2. Results for the meta-analysis between Foxp3 expression and clinicopathological parameters of GC patients

Clinical parameters	No. of studies	Overall OR (95%CI)	Heterogeneity test (Q, I², P)
Age	14,15,16,18,19,20,22	0.899(0.549-1.472)	16.62,63%,0.2632 (random-effect)
Sex	13,14,15,16,18,19,20,22,23	0.836(0.647-1.080)	6.98,0.00%,0.538 (random-effect)
Lymph node metastasis (N0 vs N1-N3)	12,13,14,15,16,18,20,21,22,23	0.514(0.280-0.944)	63.20,85.8%,0.000 (random-effect)
Differentiation (Well/moderate vs poor)	12,14,15,17,18,19,20,21	1.083(0.616-1.904)	32.97,78.8%,0.000 (random-effect)
TNM stage (I II vs III IV)	12,14,15,16,17,18,22,23	0.967(0.583-1.605)	35.17,77.73%,0.000 (random-effect)
tumor size (≥5cm vs<5cm)	14,15,18,20	0.489(0.285-0.839)	6.06,50.05%,0.109 (random-effect)

Abbrebiation:OR,odds rates.

Publication bias between Foxp3 expression and clinicopathological parameters

We did not find any obvious publication bias in age, sex, tumor differentiation, tumor lymph node metastasis, TNM stage, and tumor size. p value was more than 0.05 in Begg’s test (p = 0.634, p = 0.054, p = 0.954, p = 0.954, p = 0.098, and p = 0.780, respectively) (Fig. 3).

Foxp3 expression and OS

To study the association between Foxp3 expression and OS of GC patients, we found that the association between Foxp3 expression and the OS of GC patients in Table 3 and Fig. 4. Compared with lower Foxp3 expression, high Foxp3 expression had a better 1-year OS (OR = 0.606, 95% CI = 0.399-0.921, p = 0.019), 3-year OS (OR = 0.629, 95% CI = 0.436-0.908, p = 0.013), and 5-year OS (OR = 0.412, 95% CI = 0.231-0.734, p = 0.003) of GC patients.

Publication bias between Foxp3 expression and OS

As shown in Fig. 5, there is no publication bias between Foxp3 expression and 1-year, 3-year, and 5-year OS (Bgger’s test, p = 0.637, p = 0.275, and p = 0.236) of GC patients.

Table3. Patient OS in relationship with expression of Foxp3

Author(year)	1-year OS		3-year OS		5-year OS
Author(year)	OR (95%CI)	Weight	OR (95%CI)	Weight	OR (95%CI)	Weight
Wang (2021)	0.39(0.04,3.82)	3.32%	0.47(0.09,2.43)	4.30%	-	-
Guo (2020)	1.07(0.43,2.67)	20.88%	0.92(0.52,1.64)	18.50%	0.66(0.37,1.16)	38.07%
Suh (2015)	0.45(0.17,1.16)	19.11%	0.56(0.24,1.29)	12.24%	-	-
Li (2017)	0.14(0.03,0.73)	6.56%	1.02(0.48,2.17)	13.84%	-	-
WON (2015)	0.43(0.13,1.45)	11.82%	0.43(0.18,1.00)	11.94%	0.23(0.10,0.52)	27.50%
Ouyang (2019)	0.48(0.09,2.63)	6.04%	-	-	-	-
Yoshii (2012)	1.52(0.34,6.75)	7.82%	1.01(0.43,2.38)	11.83%	-	-
Ma (2014)	0.69(0.30,1.62)	24.45%	0.65(0.34,1.24)	16.50%	0.39(0.23,0.73)	34.43%
Overall	0.61(0.40,0.92)	100%	0.63(0.44,0.91)	100%	0.41(0.23,0.73)	100%

Relative risks refer to no relationship in survival for patients with expression of Foxp3. One year: heterogeneity χ²= 6.97; p = 0.432; I² = 0.0%; z-test = 2.35; p = 0.019; Three years: heterogeneity χ² = 11.30; p = 0.126; I² = 38.1%; z-test = 2.48; p = 0.013; Five years: heterogeneity χ² = 4.48; p = 0.107; I² = 55.3%; z-test = 3.00; p = 0.003.

TCGA

By TCGA data, we explored the association between Foxp3 expression and prognosis in GC patients. The Gene Expression Profiling Interactive Analysis (GEPIA) included 384 patients who were equally divided into low Foxp3 group and high Foxp3 group, with 192 patients in each group (Fig.6). We found that the OS of the high Foxp3 expression group was higher than the low Foxp3 expression group, but it was not statistically significant (p=0.34).

GC is regarded as the fourth most cancer-related death globally. As the development of endoscopic and surgical technology, the diagnosis and treatment of GC have been improved significantly. However, most GC patients are still found at an advanced stage and the prognosis was poor. Therefore, early diagnosis and treatment of GC is becoming more and more urgent [27]. Recently, some studies found that transcriptional factors play an important role in clinicopathological parameters and OS of GC patients [28–30]. Foxp3 as a transcription factor, the association between Foxp3 and clinicopathological parameters and OS in GC patients had been studied. However, the association between Foxp3 expression and clinicopathological parameters and OS in GC patients is controversial. By meta-analysis, we found that: 1) Foxp3 expression is associated with lymph node metastasis and tumor size in GC; 2) the Foxp3 expression was not related to age, sex, differentiation and TNM stage in GC patients; 3) Foxp3 may be a prognosis maker in GC patients.

It has been reported that Foxp3 plays an important role in tumor proliferation of GC [31]. Li et al. found that mir-133a-3p is involved in proliferation of GC cells by directly binding the 3′-untranslated region of Foxp3 mRNA which inhibit the proliferation of GC cells [32]. Furthermore, Wang et al. found that high Foxp3 expression is related with the GC patients with tumor diameter < 5 cm [18]. However, Li et al. found that Foxp3 expression is not related with tumor size [17]. On the other hand, Geng et al. found that Foxp3 expression was associated with lymph node metasis [23]. Similarly, Wang et al. found that Foxp3 might have a relationship with the progress of lymph node metastasis, but the exact mechanisms are not clear [33]. However, Wang et al. found that Foxp3 expression is not related with lymph node metasis [25]. We included 12 articles with 1,583 GC patients, and our results indicated that Foxp3 expression was related to tumor size, and lymph node metastasis in GC patients.

Our results showed that the association between Foxp3 expression and tumor size, lymph node metastasis in GC patients. However, there is a controversy about Foxp3 expression and other clinicopathological parameters in GC patients. Ehc et al. observed that Foxp3 expression was associated with poorly differentiated tumors, diffuse and mixed tumors and vascular infiltration in GC patients [22]. Wang et al. claimed that Foxp3 expression was not related with tumor differentiation of GC patients [25]. Guo et al. found that Foxp3 expression was not related with age and gender and TNM stage [21]. However, Suh et al. found that Foxp3 expression was significantly related with lower T stage, and less neural invasion [24]. Our studies supported that Foxp3 expression was not related to age, gender, TNM stage and differentiation. However, it is necessary to take more clinical data with large sample to study the association between Foxp3 expression and clinicopathological parameters of GC patients in the future.

It had been reported that Foxp3 play a role in the development and maturation of regulatory T cells [6]. Tumor-infiltrating Foxp3⁺ regulatory T-cells promote GC progression and indicate poor prognosis of GC patients [34]. Recently, some articles have detected the association between Foxp3 expression and the OS of GC patients [35, 36]. However, it is still inconsistent between Foxp3 expression and OS of GC patients. Ma et al. found that Foxp3 high expression was associated with well prognosis of GC patients [23]. Yoshii et al. found that Foxp3 high expression might be related to poor prognosis in GC patients [13]. In our meta-analysis, we detected the association between Foxp3 expression and OS of GC patients, we found that high Foxp3 expression had a better 1-year OS, 3-year OS and 5-year OS of GC patients compared with lower Foxp3 expression. In addition, the TCGA database (included 384 STAD patients) was used to analysis the association between Foxp3 expression and OS of GC patients, and the results showed that the OS of the high Foxp3 expression STAD patients was better than that of the low Foxp3 expression STAD patients, but it was not significant statistically. Therefore, much large sample of GC patients including STAD and other pathological type should be performed to confirm the association between Foxp3 expression and OS of GC patients in the future.

Our meta-analysis has some limitations. Firstly, the studies we included were published in Chinese and English, this may cause bias. Secondly, the results were assessed subjectively by the inspectors, the expression of Foxp3 in GC was identified by IHC, and there was no unified standard to define the high or low Foxp3 expression in GC tissues. This may induce heterogeneity. Furthermore, some clinicopathological parameters of GC patients are included in our studies with small sample size, and more studies with much large sample are needed.

Our studies showed that Foxp3 may be relate to tumor size, tumor lymph node metastasis and well OS of GC patients. Foxp3 expression was not related to age, sex, differentiation, and TNM stage. Foxp3 might be a prognosis marker in GC patients, but more studies with much large sample of GC patients are needed to confirm it.

GC: Gastric cancer; Foxp3: Forkhead Box P3; OS: Overall survival; CI: Confidence interval; OR: Odds ratio; TCGA: The Cancer Genome Altlas; STAD: Stomach adenocarcinoma; Tregs: Regulatory T cells; IHC: Immunohistochemistry; NOS: Newcastle-Ottawa Scale; M: Male; F: Female; GEPIA: Gene Expression Profiling Interactive Analysis.

For the meta-analysis, we followed PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines. All methods were performed in accordance with the relevant guidelines and regulations.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

The meta-analysis data generated or analyzed during this study is included in this published article. We analyzed TCGA data by GEPIA website: http://gepia2.cancer-pku.cn/#analysis.

Competing interests

The authors declare no conflict of interests.

Funding

Not applicable.

Authors' contributions

GZ and XWZ designed the study; JCG, YHW and ZRJ set up the database; JCG and YHW screened the literature search, acquired reports of relevant trials, selected included studies and extracted data. JCG, YHW and ZRJ performed statistical analyses; analysed and interpreted the data. JCG, YHW ZRJ and TTZ wrote the draft and the final version of the manuscript. All authors critically revised the report for important intellectual content and approved the final manuscript.

Acknowledgements

Not applicable.

Author information

The Dalian Municipal Central Hospital Affiliated of Dalian Medical University, Dalian 116033, China.

Guo Zu and Xiangwen Zhang.

The Dalian Municipal Central Hospital Affiliated of Dalian Medical University, Dalian 116033, China. Dalian Medical University, Dalian 116044, China.

Jiacheng Gao, Zirui Jia and Yuhang Wang

The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.

Tingting Zhou.

Corresponding author

Correspondence to Guo Zu and Xiangwen Zhang.

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No competing interests reported.

The Clinicopathological and Prognostic Significance of Foxp3 Expression in Gastric Cancer: A Meta-Analysis and TCGA Analysis

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Abstract

Figures

Introduction

Methods

Statistical Analysis

Results

Discussion

Conclusion

Abbreviations

Declarations

Corresponding author

References

Additional Declarations

Status:

Version 1