Abstract
It is widely known that sporadic colorectal cancer (CRC) is age-related diseases with higher incidence rate among men. Transforming growth factor-β1 (TGF-β1) is a major immune regulatory cytokine with a great impact and dual role in gastrointestinal carcinogenesis. In this context, the aim of the study was to explore the role of circulating TGF-β1 and the -509C/T functional promoter polymorphism (rs1800469) within the TGF-β1 gene (TGFB1) in the susceptibility, progression, and prognosis of CRC among Bulgarian male and female patients. Patients with sporadic CRC and healthy controls were genotyped by polymerase-chain reaction–restriction fragment length polymorphism. Serum TGF-β1 levels before and after curative surgery were determined by ELISA. Total RNA was extracted from paired tumor, normal mucosa and distant metastasis samples and was used for quantitative detection of TGFB1 mRNA by TaqMan qPCR.We observed that TGF-β1 serum levels depend on the -509C/T genotype in combination with gender. TGF-β1 serum levels in CRC patients were decreased compared to controls, but statistical significance was reached only for men. In the stratified analysis by gender and genotype, a significant association was found for the CC genotype. Overall, our results indicate that the -509C allele increased the cancer risk, particularly for advanced stages (OR = 1.477; p = 0.029). The results from the relative mRNA quantification showed a significant upregulation of TGFB1 in distant metastases compared to primary tumor tissues and higher TGFB1 mRNA levels in men (RQ = 4.959; p = 0.022). In conclusion, we present data that diminished circulating TGF-β1 due to the CC genotype could be a possible risk factor for tumor susceptibility and progression. This association is more pronounced in males than in females. Colorectal cancer tissue expression of TGFB1 gene mRNA correlates with tumor progression and metastasis.
Highlights
Transforming growth factor-β1 (TGF-β1) is a major immune regulatory cytokine with a great impact on gastrointestinal tumorigenesis
TGF-β1 serum levels depend on the TGFB1 -509C/T polymorphism as well as age and gender in healthy controls
When healthy males and females were subdivided into two groups, under and over 50 years, we calculated a significant difference for only the CC genotype in both men (19.43±6.2 vs. 60.95±11.6ng/ml; p = 0.009, U-test) and women (24.49±1.9 vs. 42.54±7.6ng/ml; p = 0.0236, Utest) (Fig 2)
Summary
Transforming growth factor-β1 (TGF-β1) is a major immune regulatory cytokine with a great impact on gastrointestinal tumorigenesis. The cellular response to TGF-β1 includes transmembrane serine/threonine kinase receptors (TGF-βRI and TGF-βRII), which upon ligand binding recruit and phosphorylate a specific subset of Smad proteins in a cascade manner [3]. This canonical signalling cascade, known as the Smad-dependent pathway, leads to the transcription of particular genes. One of the mechanisms by which TGF-β1 is able to maintain tolerance is to support survival and regulatory functions through the upregulation of Foxp expression in peripheral CD4+CD25+ regulatory T cells [6] Another function of Tregs is to suppress host anti-tumor response and promote tumor development [7]
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