Clinical implications and characteristics of factor forkhead box protein 3 in gastric cancer

Abstract

Abstract. Transcription factor forkhead box protein 3 (FOXP3) is a specific marker of naturally occurring regulatory T cells (Tregs). Recently, various reports have suggested that FOXP3 may represent a tumor escape mechanism in cancer cells apart from its roles in Tregs. In the present study, the clinical and biological characteristics of FOXP3 were evaluated in human gastric cancer. The expression and localization of FOXP3 in gastric cancer cell lines was analyzed to evaluate its cellular biological features. Sections of human gastric cancer specimens were stained using immunohistochemistry (IHC) to assess the relationship between FOXP3 expression and tumor differentiation, in order to identify its clinical characteristics in gastric cancer. Expression of FOXP3 mRNA and protein was found in four gastric cancer cell lines (AGS, SGC-7901, . IHC of the gastric cancer sections revealed that more than 56% of gastric cancers displayed nuclear or cytoplasmic FOXP3 staining. Furthermore, a linear relationship between the differentiation of the gastric cancer tissues and FOXP3 expression intensity was shown. IHC and confocal analysis showed that the expression of FOXP3 was mainly present in the nucleus of tumor cells in the tissues and cell lines. Thus, FOXP3 nuclear staining may be associated with the risk of poor tumor differentiation. Apart from the lymphocytes, no FOXP3 staining was noted in the normal gastric tissues and para-tumor tissues. The high frequency of FOXP3 expression in gastric cancer tissue is a significant finding in the investigation of tumor differentiation and immune escape. This mechanism provides a further understanding of gastric cancer and a novel therapeutic strategy is presented. IntroductionGastric cancer is the second most common cause of cancerrelated death in the world (1). Gastric cancer is difficult to cure, mainly because most patients present with advanced disease at diagnosis. Patients with gastric cancer conventionally exhibit a poorly functioning immune system, such as decreased T-cell proliferation, a low CD4 + /CD8 + ratio and a deficient production of T-helper cytokines (2-4). This condition of poor response does not improve significantly after surgery (5).Gastric adenocarcinoma often begins at a site where the stomach lining is inflamed. Numerous experts believe that an infection with the bacterium Helicobacter pylori is the cause of most stomach cancers (6-8). It has been reported that H. pylori-infected individuals have increased levels of regulatory T cells (Tregs) in the gastric and duodenal mucosa that express factor forkhead box protein 3 (foxp3) mRNA. The induction of the Treg response contributes to an equilibrium between the host and the bacterium, allowing H. pylori to survive, while also preventing the risk of destructive inflammation (9). These reports suggest that FOXP3 expression may play an important role in gastric cancer development.FOXP3 is a member of the forkhead/winged-helix family of transcriptional regulators and is considered to be an important gene whic...

The Role of Tumoral FOXP3 on Cell Proliferation, Migration, and Invasion in Gastric Cancer

“…We also observed FOXP3 expression in both GC and para-carcinoma tissues. Expression of FOXP3 in GC tissues was higher as compared to that in para-carcinoma tissues, which was consistent with previous studies [31, 35]. Additionally, expression levels of FOXP3 was associated with pathological grading of GC, which was also consistent with results from a previous study by Jiang et al [35].…”

“…Expression of FOXP3 in GC tissues was higher as compared to that in para-carcinoma tissues, which was consistent with previous studies [31, 35]. Additionally, expression levels of FOXP3 was associated with pathological grading of GC, which was also consistent with results from a previous study by Jiang et al [35]. This suggested that FOXP3 expression is associated with the degree of GC differentiation, No correlation was found between FOXP3 expression and lymph node metastasis in our study.…”

“…Although the role of Treg-derived TGF-β on immune response is well known, the exact role of tumor-derived TGF-β is not very clear. Xue and Jiang suggested that FOXP3 expression may be an important mechanism of immune escape in gastric cancer [35, 39]. Here we hypothesized that FOXP3 can increase TGF-β expression and secretion, which can further exhibit an inhibitory role on anti-tumor immune responses via the TGF-β pathway; in-depth work is needed to verify our hypothesis.…”

Progesterone receptor gene serves as a prognostic biomarker associated with immune infiltration in gastric cancer: a bioinformatics analysis

“…FOXP3+Tregs are reported to be closely related to the incidence and development of GC, and increase FOXP3+Tregs infiltration in GC tissues can predict poor prognosis ( 55 ). FOXP3, a key protein in Treg differentiation and function, may influence tumor differentiation and immune escape in GC patients ( 56 ). In this study, we found that PGR expression was positively related to markers of Tregs, such as FOXP3, CCR8, STAT5B, and TGFB1 ( Tables 2,3 ).…”