PYGO2 regulates IL10 and plays immunosuppressive role through ESCC progression

Abstract

Background: Esophageal squamous cell carcinoma (ESCC), one of the most aggressive carcinomas of the gastrointestinal tract, is the sixth most common cause of cancer-related death. Wnt pathway plays a pivotal role in cell proliferation and differentiation. PYGO2 and IL10 are involved in this pathway. Our aim in this study was to examine the correlation between PYGO2 and IL10 expression in ESCC patients and cell lines.

Methods: Relative-comparative real time-PCR (RT-qPCR) was used to evaluate the PYGO2 and IL10 mRNA expression profile in 58 non-treated ESCC compared to their margin normal tissues. Expression of PYGO2 was induced in KYSE-30 and YM1 ESCC lines and IL10 expression was analyzed.

Results: The results revealed the significant overexpression of PYGO2 and IL10 mRNA in 31.0% and 51.7% of ESCCs, respectively. The PYGO2 and IL10 overexpression was significantly correlated to each other (p = 0.007). Concomitant overexpression of the genes was significantly associated to grade of tumor differentiation (p < 0.01), and tumor depth of invasion (p < 0.05). Induced expression of PYGO2 caused a meaningful change in IL10 expression in ESCC cells.

Conclusion: PYGO2 may regulate IL10 through Wnt/β-catenin signaling pathway, suggesting a possible oncogenic role for PYGO2/IL10 axis in ESCC tumorigenesis. Considering the involvement of IL10 as an anti-inflammatory cytokine and PYGO2 role in elevated tumor invasion and metastasis, possible functional interaction between these factors may promote a process which induces invasion and malignant phenotype in ESCC.

Keywords: IL10; PYGO2; Co-overexpression; Quantitative real-time PCR; Wnt/β-catenin pathway.

Fig. 1

(a) The predicted protein-protein interaction network generated using GeneMANIA, illustrating the predicted relationships between PYGO2-IL10 through Wnt signaling pathway genes. (b) The protein-protein interaction network for PYGO2. (c) The protein-protein interaction network for IL10. (d) The predicted protein-protein interaction network in the context of ESCC, based on predictions from Phenolyzer

Fig. 2

Descriptive analysis of PYGO2 and IL10 gene expression pattern in ESCC patients as scatter plot. The Y-axis represents the log 2 fold change of gene expression, and the X-axis indicates the number of patients. Relative mRNA expression of more than two-fold in tumor tissue is considered as overexpression; less than minus two-fold as underexpression and the range in between is defined as normal or no change

Fig. 3

Regression plot representing correlation between PYGO2 and IL10 mRNA expression (p = 0.007). X and Y axises show log 2 fold change of gene expression

Fig. 4

Potential correlation between PYGO2 and IL10 expression through the Wnt/β-catenin signaling pathway in ESCC progression. Binding of Wnt ligand to FZD and LRP induces inactivation of the AXIN-APC-GSK3β destruction complex via DVL, leading to β-catenin accumulation and transition to the nucleus. Then, PYGO2 as a coactivator of the transcriptional complex (LEF/TCF/β-catenin), may directly activate transcription of target genes such as IL10. Furthermore, IL10 expression manifests direct correlation with FZD, WNT, LRP expression, β-catenin accumulation, and augmentation of EGFR levels in this pathway