thromboplastin and Carcinogenesis

Tissue factor (TF) and its isoforms play an important role in a variety of physiologic and pathophysiologic functions, such as initiation of blood coagulation, vessel wall hemostasis, angiogenesis, and tumorigenesis. Micro(mi)RNAs are crucial for post-transcriptional control of protein generation by regulating the expression of one-third of all human genes. In recent years, miRNAs were shown to modulate the expression and biologic function of TF in different physiologic- and pathophysiologic-relevant settings, such as in autoimmune diseases and in different types of cancer. In the present review, we will summarize and discuss the latest findings regarding the impact of miRNAs on the generation of TF and its isoforms as well as on regulation of TF biology under normal and pathophysiologic conditions.

Topics: Blood Coagulation; Carcinogenesis; Humans; MicroRNAs; Protein Isoforms; Thromboplastin; Thrombosis

Metastasis results from a complex set of traits acquired by tumor cells, distinct from those necessary for tumorigenesis. Here, we investigate the contribution of enhancer elements to the metastatic phenotype of osteosarcoma. Through epigenomic profiling, we identify substantial differences in enhancer activity between primary and metastatic human tumors and between near isogenic pairs of highly lung metastatic and nonmetastatic osteosarcoma cell lines. We term these regions metastatic variant enhancer loci (Met-VELs). Met-VELs drive coordinated waves of gene expression during metastatic colonization of the lung. Met-VELs cluster nonrandomly in the genome, indicating that activity of these enhancers and expression of their associated gene targets are positively selected. As evidence of this causal association, osteosarcoma lung metastasis is inhibited by global interruptions of Met-VEL-associated gene expression via pharmacologic BET inhibition, by knockdown of AP-1 transcription factors that occupy Met-VELs, and by knockdown or functional inhibition of individual genes activated by Met-VELs, such as that encoding coagulation factor III/tissue factor (F3). We further show that genetic deletion of a single Met-VEL at the F3 locus blocks metastatic cell outgrowth in the lung. These findings indicate that Met-VELs and the genes they regulate play a functional role in metastasis and may be suitable targets for antimetastatic therapies.

Topics: Carcinogenesis; Cell Line, Tumor; Enhancer Elements, Genetic; Epigenomics; Gene Expression Regulation, Neoplastic; Genome, Human; Humans; Lung Neoplasms; Neoplasm Metastasis; Osteosarcoma; Proteins; Selection, Genetic; Thromboplastin; Transcription Factor AP-1; Tumor Microenvironment

The aim of the study was to further investigate the role of fibrinogen-like protein 2 (FGL-2), a transmembrane prothrombinase that directly cleaves prothrombin to thrombin, in angiogenesis and tumor development and the mechanism(s) underlying these processes. To study angiogenesis HUVEC clones with decreased fgl-2 mRNA were generated by specific siRNA. To study tumorigenesis SCID mice were implanted with intact (wild type) and fgl-2-silenced PC-3 clones. IFN-γ treated HUVEC expressing increased fgl-2 mRNA exhibited significant capillary sprouting that was not inhibited by hirudin, whereas fgl-2 silencing completely inhibited blood-vessel formation. Tumors (poorly differentiated carcinoma) developed in all 12 mice injected with wild type PC-3 compared with 8/12 mice injected with the fgl-2-silenced PC-3 clone. The tumors developed by fgl-2-silenced PC-3 clones were smaller and less aggressive and contained significantly fewer blood vessels (p<0.05). All tumors' sections were negative for thrombin staining, indicating that FGL-2-induced tumorigenesis was not mediated by thrombin. In fgl-2-silenced tumors there was a decrease in fgl-2 mRNA (p=0.02) and ERK1/2 phosphorylation (p<0.05) by 80% and a 20%, respectively. The mechanism underlying these processes, studied in PC-3 clones, revealed that fgl-2 silencing was associated with a 65% decrease in FGF-2 mRNA (p<0.01) and a 30% down regulation of ERK1/2 phosphorylation (p<0.05). Together, these results suggest that FGL-2 mediates angiogenesis and tumorigenesis not by thrombin-mediated mechanism but rather through FGF-2/ERK signaling pathway. FGL-2 may serve as a valuable therapeutic target in the future.

Topics: Animals; Carcinogenesis; Cell Line, Tumor; Cell Proliferation; Fibrinogen; Human Umbilical Vein Endothelial Cells; Humans; Male; MAP Kinase Signaling System; Mice, SCID; Neovascularization, Pathologic; Prostate; Prostatic Neoplasms; RNA Interference; RNA, Small Interfering; Thrombin; Thromboplastin

Topics: Animals; Carcinogenesis; Fibrinogen; Humans; Male; MAP Kinase Signaling System; Neovascularization, Pathologic; Prostatic Neoplasms; Thromboplastin