Clinico-pathological and prognostic implications of Srx, Nrf2, and PROX1 expression in gastric cancer and adjacent non-neoplastic mucosa – an immunohistochemical study

Abstract

Introduction: Sulfiredoxin (Srx), which is an endogenous antioxidant substance which could, regulate the signaling pathways of reactive oxygen species. Nuclear factor erythroid 2-related factor 2 (Nrf2) is Cap-N-collar (CNC) transcription factors family member that have essential roles in regulation of antioxidant response. The transcription factor PROX1 is a transcription factor and a key regulatory protein in cancer development. Aim of the study: To analyze levels of tissue expression of Srx, Nrf2, and PROX1 in gastric cancer and adjacent non-neoplastic gastric mucosa to clarify the relationship between their expression levels, clinical, pathological parameters and patients' outcome. The results might lead to discovering novel targeted therapies to gastric cancers. Material and methods: We included 70 paraffin-embedded samples: 50 specimens from gastric carcinomas and 20 specimens from adjacent non-neoplastic gastric mucosa. All samples are stained with Srx, Nrf2, and PROX1 using immunohistochemistry, correlated their expression with clinicopathological and prognostic parameters of patients. Results: High levels of Srx and Nrf2 expression were positively associated with higher cancer grade (p = 0.006, 0.031 respectively), advanced stage (p < 0.001, 0.02 respectively), higher incidence of distant metastases (p = 0.029, 0.03 respectively) and dismal outcome (p < 0.001). High levels of PROX1 expression were associated with lower cancer grade (p = 0.005), absence of lymph nodes metastases (p = 0.023), early stage (p = 0.003), absence of relapse (p = 0.004), and favorable outcome (p < 0.001). Conclusions: Srx and Nrf2 expression increase gastric cancer invasiveness, suggesting their utility as poor prognostic markers, but PROX1 serves as a favorable prognostic marker of gastric cancer patients.

Lack of Relationship Between PROX1 Expression and Clinicopathological Parameters and Prognosis in Gastric Cancer Patients: A Meta-analysis and TCGA Analysis

“…Several studies support the correlation between high expression of PROX1 and shorter OS in GC patients (15)(16). But the other studies reported a total of 598 patients nding that PROX1 overexpression is associated with a longer OS (11)(12)(13). However, our meta-analysis reveals that PROX1 expression is not related with OS at 1, 3, or 5 years.…”

“…(16). According to Abeer M. Hafez et al (13) and KOJI UETA et al ( 16), PROX1 expression acts as a good prognostic predictor for GC patients. But Ueta K et al reported that PROX1 may be a bad promising prognostic biomarker (9).…”

Lack of relationship between PROX1 expression and clinicopathological parameters and prognosis in gastric cancer patients: a meta-analysis and TCGA analysis

“…However, the role of PROX1 in GC is controversial. Hafez AM et al also reported that high expression of PROX1 is relevant, but oppositely, to pathological stage, lymphatic metastasis and T stage [ 12 ]. Kasurinen A et al reported that the expression of PROX1 is not statistically correlated with the depth of invasion, lymph node metastasis and cancer stage by their study [ 11 ].…”

“…However, Alli Laitinen et al [ 10 ] reported that the high expression of PROX1 is irrelevant to pathological stage, lymphatic metastasis, T stage, and is correlated with a good prognosis. Hafez AM et al also reported that high expression of PROX1 is correlated with good prognosis but relevant to pathological stage, lymphatic metastasis and T stage [ 12 ]. The relationship between PROX1 expression and clinicopathological characteristics and prognosis in GC are widely disputed and remain controversial.…”

PROX1 Was Associated with LGR5 and Wnt Signaling and Contributed to Poor Prognosis in Gastric Cancer

“…There is no certainty regarding the significance of PROX1 expression in GC. While there are reports that PROX1 expression was a poor prognostic factor [8][9][10], there are various reports that it correlated with a good prognosis [11][12][13] or was not a prognostic factor [14]. The purpose of this study was to investigate and clarify whether PROX1 is a prognostic factor in GC.…”