Up-regulation of tumor necrosis factor-α pathway survival genes and of the receptor TNFR2 in gastric cancer

Abstract

BACKGROUND Gastric carcinogenesis can be induced by chronic inflammation triggered by Helicobacter pylori ( H. pylori ) infection. Tumor necrosis factor (TNF)-α and its receptors (TNFR1 and TNFR2) regulate important cellular processes, such as apoptosis and cell survival, and the disruption of which can lead to cancer. This signaling pathway is also modulated by microRNAs (miRNAs), altering gene expression. AIM To evaluate the mRNA and miRNAs expression involved in the TNF-α signaling pathway in gastric cancer (GC) tissues and its relationship. METHODS Quantitative polymerase chain reaction (qPCR) by TaqMan ® assay was used to quantify the RNA transcript levels of TNF-α signaling pathway ( TNF, TNFR1, TNFR2, TRADD, TRAF2, CFLIP, NFKB1 , NFKB2, CASP8, CASP3) and miRNAs that targets genes from this pathway (miR-19a, miR-34a, miR-103a, miR-130a, miR-181c) in 30 GC fresh tissue samples. Molecular diagnosis of H. pylori was performed by nested PCR for gene HSP60 . A miRNA:mRNA interaction network was construct using Cytoscape v3.1.1 from the in silico analysis performed using public databases. RESULTS Up-regulation of cellular survival genes as TNF, TNFR2, TRADD, TRAF2 , CFLIP , and NFKB2 , besides CASP8 and miR-34a was observed in GC tissues, whereas mediators of apoptosis such as TNFR1 and CASP3 were down-regulated. When the samples were stratified by histological type, the expression of miR-103a and miR-130a was significantly increased in the diffuse-type of GC compared to the intestinal-type. However, no influence of H. pylori infection was observed on the expression levels of mRNA and miRNAs analyzed. Moreover, the miRNA:mRNA interaction network showed several interrelations between the miRNAs and their target genes, highlighting miR-19a and miR-103a, which has as predicted or validated target a large number of genes in the TNF-α pathway, including TNF, TNFR1, TNFR2, CFLIP, TRADD, CASP3 and CASP8 . CONCLUSION Our findings show that cell survival genes mediated by TNF/TNFR2 binding is up-regulated in GC favoring its pro-tumoral effect, while pro-apoptotic genes as CASP3 and TNFR1 are down-regulated, indicating disbalance between apoptosis and cell proliferation processes in this neoplasm. This process can also be influenced by an intricate regulatory network of miRNA:mRNA.

The Pathogenic Effects of Fusobacterium nucleatum on the Proliferation, Osteogenic Differentiation, and Transcriptome of Osteoblasts

“…These genes, which have been reported to participate in the occurrence, development, and metastasis of tumors, were also the core genes in osteoblasts whose expression changed significantly under stimulation with F. nucleatum , as shown by RNA-seq analysis. NFKB2 has been observed to be upregulated in gastric cancer tissues ( Rossi et al, 2019 ), and its altered expression can collaborate with heterozygous Kras MUT to drive tumorigenesis but decreases the metastatic potential of pancreatic ductal adenocarcinoma ( Mueller et al, 2018 ). The upregulation of Tnfrsf1b, which belongs to the TNF receptor superfamily, has also been found in gastric cancer tissues ( Rossi et al, 2019 ), and Tnfrsf1b can promote colorectal carcinogenesis ( Liu et al, 2018 ).…”

“…NFKB2 has been observed to be upregulated in gastric cancer tissues ( Rossi et al, 2019 ), and its altered expression can collaborate with heterozygous Kras MUT to drive tumorigenesis but decreases the metastatic potential of pancreatic ductal adenocarcinoma ( Mueller et al, 2018 ). The upregulation of Tnfrsf1b, which belongs to the TNF receptor superfamily, has also been found in gastric cancer tissues ( Rossi et al, 2019 ), and Tnfrsf1b can promote colorectal carcinogenesis ( Liu et al, 2018 ). Fbln5 can inhibit epithelial cell proliferation and carries out tumor-promoting and tumor-protective functions in breast lesions ( Karanis et al, 2019 ).…”

Identification of Key Genes and MicroRNAs in Gastric Cancer via miRNA-mRNA Regulatory Network

“…Moreover, related studies indicated that miR-130a-3p was upregulated in GC and promoted the invasion of GC cells [63]. Rossi et al [64] indicated that the miR-130a in diffuse GC was higher than that in intestinal type GC. In addition, some studies suggested that miR-130a was downregulated in GC and was related to the migration and metastasis of GC [65].…”

Role of miRNA-19a in Cancer Diagnosis and Poor Prognosis

“…Many studies [ 51 , 52 , 53 ] have shown that miR-19a is involved in the proliferation of human gastric cancer (GC). Yuan et al [ 51 ] demonstrated that miR-17-92a-1 Cluster Host Gene (MIR17HG)-derived miR-18a and miR-19a-3p coordinately mediate GC cell metastasis by directly inhibiting mothers against decapentaplegic homolog 2 (SMAD2) expression and upregulating Wingless-related integration site (Wnt)/β-catenin signaling.…”