Abstract
The angiogenesis is an important component of tumor growth and tightly associated with hypoxia. The expression level of genes related to regulation of angiogenesis ( BAI2, SPARC, TIMP1, TIMP2, TIMP3, TIMP4, THBS1, THBS2, ADAMTS5 and FGF2 ) in glioma U87cells and cells with suppressed function of signaling enzyme ERN1, a major mediator of the endoplasmic reticulum stress by qPCR, was studied. We have shown that the expression of genes encoding BAI2, SPARC, TIMP2, TIMP3, THBS1 and THBS2 is strongly increased in glioma cells with ERN1 signaling enzyme loss of function, being more intense for TIMP2, TIMP3 and THBS1 genes. At the same time, the expression of genes encoding TIMP1, TIMP4, ADAMTS5 and FGF2 is significantly decreased with more strong effect for ADAMTS5 and TIMP4 genes. At hypoxia, the expression of most of studied genes in both glioma cell types is affected. Hypoxia induced the expression of TIMP1, TIMP3 and ADAMTS5 genes both in control glioma cells and cells with ERN1 enzyme loss of function. However, the effect of hypoxia towards TIMP2 gene expression was observed only in control glioma cells. At the same time, the expression of genes encoding BAI2, SPARC, THBS1, THBS2, ADAMTS5 and FGF2 is decreased under hypoxia action, but its expression mostly depended on ERN1 signaling enzyme function. The results of this study provide strong evidence that suppression of ERN1 signaling enzyme function, as well as hypoxia, changes the expression of genes related to regulation of angiogenesis in glioma cells. It is possible that changes in the expression of these genes contribute to the suppression of glioma cells’ proliferation by blockade of ERN1 signaling enzyme functioning. Keywords : gene expression, BAI2, SPARC, TIMP1, TIMP2, TIMP3, TIMP4, THBS1, THBS2, ADAMTS5, FGF2, ERN1, glioma cells, hypoxia.
Highlights
The endoplasmic reticulum stress plays an important role in tumor growth
We have shown that the expression of genes encoding brain-specific angiogenesis inhibitor 2 (BAI2), SPARC, TIMP2, tissue inhibitor of matrix metalloproteinase 3 (TIMP3), THBS1 and THBS2 is strongly increased in glioma cells with ERN1 signaling enzyme loss of function, being more intense for TIMP2, TIMP3 and THBS1 genes
We found that genes related to the regulation of angiogenesis and proliferation are expressed in human glioma cell line U87, and the levels of their expression were dependent upon the ERN1 signaling enzyme functioning
Summary
The endoplasmic reticulum stress plays an important role in tumor growth. It is an obligatory component of tumorigenesis, as well as hypoxia and angiogenesis. Different factors, including hypoxia, have been shown to induce complex intracellular signaling events known as the unfolded protein response which is mainly mediated by endoplasmic reticulum to nuclei-1 signaling enzyme (ERN1; named as inositol requiring enzyme-1alpha, IRE1) in order to adapt cells for survival or, alternatively, to enter cell death programs through the endoplasmic reticulum-associated machineries [3,4,5] As such, it participates in the early cellular response to the accumulation of misfolded proteins in the lumen of the endoplasmic reticulum [2]. The endoplasmic reticulum stress is contributed to the expression profile of many regulatory genes resulting in proliferation, angiogenesis and apoptosis [6, 7]
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