Suppressing the TF-fVII pathway at the gene expression level: A strategy to inhibit aberrant signaling cascades associated with cancer cells

Abstract

Normal human tissues widely synthesize tissue factor (TF), also known as coagulation factor III, on their surface. Coagulation factor VII (fVII) is a serine protease precursor, primarily produced by hepatocytes in the liver and secreted into the bloodstream. Upon injury, fVII in the blood can bind its cellular receptor, TF, converting to its active form, fVIIa. This TF-fVIIa complex initiates a downstream extrinsic coagulation cascade. Cancer cells are known to overexpress TF. Formation of a protein complex between cell surface TF and plasma fVII can trigger aberrant cellular signaling via multiple pathways, resulting in malignant phenotypes. In addition, the TF-fVIIa complex may underlie a common complication associated with particular cancer types, venous thromboembolism, suggesting that TF-fVIIa signaling may be an attractive therapeutic target. Basal transcription of TF ( F3 ) and fVII ( FVII ) genes in normal and cancer cells is regulated by the ubiquitous transcription factor, Sp1, and other tissue-specific transcription factors. Furthermore, the F3 gene may be activated in cancer cells in response to various stimuli associated with the tumor microenvironment. Intriguingly, FVII can be constitutively activated in non-hepatocytic cancer cells. Hypoxia, characteristic of the tumor microenvironment, can enhance expression of both F3 and FVII genes, but via distinct molecular mechanisms. In this short review, we will discuss strategies to suppress this aberrant transcription based on our current knowledge of the molecular mechanisms regulating gene expression. We will further discuss how these strategies are beneficial compared with those targeting the cell surface TF-fVIIa complex.