MAPK, NFκB, and VEGF signaling pathways regulate breast cancer liver metastasis

Abstract

In this study, we investigated the molecular pathways regulating breast cancer liver metastasis. We identified 48 differentially expressed genes (4 upregulated and 44 downregulated) by analyzing microarray dataset GSE62598 from Gene Expression Omnibus (GEO). We constructed a genetic interaction network with 84 nodes and 237 edges using the String consortium database. The network was reliably robust with a clustering coefficient (cc) of 0.598 and protein-protein interaction (PPI) enrichment p value of zero. Using the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases, we identified MAPK, NFκB and VEGF signaling pathways as the most critical pathways regulating breast cancer liver metastasis. These results indicate that the distinct breast cancer metastatic stages, including dissemination from the primary breast tumor, transit through the vasculature, and survival and proliferation in the liver, are regulated by the MAPK, NFκB, and VEGF signaling pathways.

Role of VEGFs/VEGFR-1 Signaling and Its Inhibition in Modulating Tumor Invasion: Experimental Evidence in Different Metastatic Cancer Models

“…A study based on bioinformatics and microarray gene expression analysis, comparing data from liver aggressive specimens and primary tumor specimens, revealed the differential expression of 48 genes. In particular, VEGF-A as well as the MAPK and NF-κB signaling pathways were identified as the key players in breast cancer liver metastases [227].…”

“…Breast Bone, lung, liver, and brain -The VEGF-A-stimulated-PKC pathway induces a pre-metastatic destabilization of pulmonary tight junctions, promoting vessel permeability and extravasation [225] -VEGF-A is involved in breast cancer liver metastases [227] -MiR-126 overexpression in human breast cancer inhibits cell proliferation by reducing VEGF-A levels [228] -Overexpression of COX-2-induced miR526b and miR655 in tumor cells upregulates VEGF-A [229] -VEGF-A signaling pathway and MMPs expression are positively regulated by cystathionine -γ-lyase, a key enzyme in the biosynthesis of the proangiogenic H 2 S [232] -PlGF stimulates cancer cell motility through activation of intracellular signaling cascades, including ERK1/2, and cytoskeletal remodeling [233] -PlGF favors CD34 + differentiation into tumor-mobilized bone marrow-derived CD11b + myeloid cells [235] -In breast cancer cells overexpression of COX-2-induced miR526b and miR655 results in upregulation of VEGFR-1 [229] -VEGFR-1 signaling, due to PlGF interaction, is associated with obesity-induced breast cancer progression [77] Ovary Peritoneum, liver, lymph nodes, bone, and brain -High expression of VEGF-A is considered a prognostic factor [239] -VEGF-A contributes to the recruitment and activation of myeloid-derived suppressor cells [242] -PlGF is overexpressed and increases MMP7 expression via downregulation of miR-543 [243] -PlGF overexpression increases ZEB2 expression in a p38 MAPK-dependent manner [245] -sVEGFR-1 induces cell death in a murine model of ovarian cancer [246] -VEGF-A is highly expressed in specimens from patients with post-radiotherapy relapsed/persistent cancer [250] -VEGF-A is coexpressed with a metabolism-related protein (MCT4 isoform) [251] -PlGF induces EMT, promoting migration and metastases, through activation of the ERK/MAPK signaling pathway [252] -VEGF-A in culture supernatants from cervical cancer cell lines induces an M2-like phenotype [254] -High VEGFR-1 expression is associated with distant metastases, poor OS and PFS [248] -VEGFR-1 is highly expressed in specimens from patients with post-radiotherapy relapsed/persistent cancer [250] Prostate Bone, lymph nodes, lung, liver, brain -VEGF-A expression and tumor invasiveness are favored by an acidic environment, through increased MMP9 secretion [256] -VEGF-A expression is higher in prostate cancer samples than in BPH and HGPIN samples [259] -VEGF-A decreases the expre...…”

Structure and function of vascular endothelial growth factor and its receptor system

“…In addition, the development of other anti-VEGF-VEGFR drugs such as VEGF-Trap and humanized anti-VEGFR antibodies is consistently ongoing to overcome adverse drug effects. Recent studies suggest that VEGF pathway appears to be useful for prognosis of several cancers patients including breast cancer and is also conducted as the most critical pathway regulating liver and lymph node metastasis of breast cancer ( 60 – 62 ). Therefore, we can use VEGF-VEGFR system as a potential target of new drugs, and more detailed structure-based insightful information regarding the VEGF-VEGFR system is essential to improve the anti-angiogenic therapy for the improved quality of life of cancer patients.…”

Weighted Gene Co-Expression Network Analysis Identifies Specific Modules and Hub Genes Related to Hyperlipidemia

“…When the STRING database [35] was analyzed, a total of 48 nodes and 266 protein pairs were got with a combined weight score > 0.25 in salmon module (Fig. 7A).…”