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

Author(s)

Teixeira Rossi, Ana Flavia ^[1] ; Contiero, Julia Cocenzo ^[1] ; Manoel-Caetano, Fernanda da Silva ^[1] ; Severino, Fabio Eduardo ^[2] ; Silva, Ana Elizabete ^[1]

Affiliation

^[1] Sao Paulo State Univ UNESP, Dept Biol, Rua Cristovao Colombo 2265, BR-15054000 Sao Jose Do Rio Preto, SP - Brazil

^[2] Sao Paulo State Univ UNESP, Fac Med, Dept Surg & Orthoped, BR-18618687 Botucatu, SP - Brazil

• Document type: Journal article
• Source: WORLD JOURNAL OF GASTROINTESTINAL ONCOLOGY; v. 11, n. 4, p. 281-294, APR 15 2019.
• Web of Science Citations: 1

Abstract

BACKGROUND Gastric carcinogenesis can be induced by chronic inflammation triggered by Helicobacter pylori (H. pylori) infection. Tumor necrosis factor (TNF)-alpha 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-alpha signaling pathway in gastric cancer (GC) tissues and its relationship. METHODS Quantitative polymerase chain reaction (qPCR) by TaqMan (R) assay was used to quantify the RNA transcript levels of TNF-a 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-alpha 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. (AU)

• FAPESP's process: 15/21464-0 - Evaluation of effect of inflammaton on mediators in the signaling pathway TNF-a, on DNA damage response and interaction with network miRNAs in gastric carcinogenesis
• Grantee: Ana Elizabete Silva
• Support Opportunities: Regular Research Grants
• FAPESP's process: 15/23392-7 - Assessment of mediators of tumor necrosis factor-± signaling pathway and microRNAs in gastric carcinogenesis associated with Helicobacter pylori
• Grantee: Ana Flávia Teixeira Rossi Freire
• Support Opportunities: Scholarships in Brazil - Doctorate