Nuclear co-localization and functional interaction of COX-2 and HIF-1α characterize bone metastasis of human breast carcinoma

Abstract

The aim of the present paper was to identify nuclear co-localization of COX-2 and HIF-1α in human-bone metastasis of breast cancer, index of transcriptionally-activated cells and functional for gene expression. In particular, we verified whether hypoxia exerted a direct role on metastasis-gene expression or through COX-2 signaling, due to the relevance for clinical implications to individuate molecular targets for diagnosis and therapy. The experiments were performed in vitro with two autoregulatory loops triggered a specific array of transcription factors responsible for COX-2 transactivation. The novelty was that HGF and TGF-β1 biological signals were produced by hypoxic metastatic cells and, therefore, the microenvironment seemed to be modified by metastaticcell engraftment in the bone. In agreement, HIF-1α expression in bone-marrow supportive cells occurred in metastasis-bearing animals. Altogether, the data supported the pre-metastatic-niche theory. Our observations might be useful to design therapies against bone metastasis, by affecting the phenotype changes of metastatic cells occurring at the secondary growth site through COX-2-HIF-1 interaction.Keywords bone microenvironment · bone metastasis · breast cancer · COX-2 · HIF-1 3

Expression of PEBP4 protein correlates with the invasion and metastasis of colorectal cancer

“…Additionally, activated AKT up-regulates the expression of matrix metalloproteinase (MMP)-2 and increases the transcriptional activity of NF-κB, thereby increasing MMP-9 production. NF-κB also increases the expression of COX-2 [23,28], which induces the expression of several factors related to angiogenesis, such as vascular endothelial growth factor and MMP [29][30][31]. However, the specific mechanism of how PEBP4 is involved in the invasion and metastasis of colorectal cancer cells remains to be further verified.…”

PEBP4 gene expression and its significance in invasion and metastasis of non-small cell lung cancer

“…In addition, NF-κB can up-regulate COX-2 expression [30]. PEBP4 overexpression can also up-regulate the expression of COX-2, which induces the expression of angiogenesis-related factors such as vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP) and promotes tumor angiogenesis through the activation of the hypoxiainducible factor-1 (HIF-1) and inhibition of apoptosis [18,[31][32][33][34]. Furthermore, AKT can promote epithelial-mesenchymal transition, which causes the down-regulation of Ecadherin transcription, a reduction in cell adhesion, and an increase in cell motility and invasiveness [35,36].…”

Differences of osteoblastic bone metastases and osteolytic bone metastases in clinical features and molecular characteristics

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