previous network
next network
Proteolysis in human hepatocellular cancer
This network was generated using Cytoscape V2.2, yFiles/circular layout with a lexically-driven XML plug-in to the Agilent Literature Search, curated and color coded in Adobe Illustrator CS2.
A marked activation of genes involved in the IL-6 signaling pathway, including IL-6 and Stat3, is observed in human hepatocellular cancer (HCC)suggesting that HCC could arise from an IL-6-driven transformed stem cell with inactivated TGF-beta signaling (nodes in orange). Deregulation of TGF-beta signaling may contribute to impaired differentiation and allow for the development of cancers, linking the differentiation of stem cells with suppression of carcinogenesis.
It is suspected that inter-alpha-trypsin inhibitor-heavy chain-4 (ITIH4, node in red), an acute-phase protein, might be associated in a positive-feedback loop with IL-6. In turn, increased ITIH4, an IL-6 target, appears to be a critical mediator of hepatocarcinogenesis. The inter-alpha-trypsin inhibitors (ITI) are a family of plasma protease inhibitors, assembled from a light chain and five homologous heavy chains (encoded by ITIH1, ITIH2, ITIH3, ITIH4, and ITIH5), contributing to extracellular matrix stability by covalent linkage to hyaluronan. Plasma hyaluronan binding protein (PHBP) is a novel serine protease which consists of three epidermal growth factor (EGF, node in gray) domains, a kringle domain, and a serine protease domain, which is similar to that of urinary plasminogen activator (u-PA, node in gray. PHBP is present as the 70-kDa inactive single chain precursor in human plasma. It transforms to the active two chain form, 50-kDa heavy chain and 27-kDa light chain, which are linked by a disulfide bond, by auto-cleavage (see positions of cleavage above the node in green).
Altogether ITIH molecules have been shown to play a particularly important role in inflammation and carcinogenesis, as well as being down-regulated in multiple human solid tumors. They are also linked to HCC by IL-6, whose serum concentrations are significantly higher in HCC patients than in controls, as well as being positively correlated with the size of the tumor.
It is suspected that inter-alpha-trypsin inhibitor-heavy chain-4 (ITIH4, node in red), an acute-phase protein, might be associated in a positive-feedback loop with IL-6. In turn, increased ITIH4, an IL-6 target, appears to be a critical mediator of hepatocarcinogenesis. The inter-alpha-trypsin inhibitors (ITI) are a family of plasma protease inhibitors, assembled from a light chain and five homologous heavy chains (encoded by ITIH1, ITIH2, ITIH3, ITIH4, and ITIH5), contributing to extracellular matrix stability by covalent linkage to hyaluronan. Plasma hyaluronan binding protein (PHBP) is a novel serine protease which consists of three epidermal growth factor (EGF, node in gray) domains, a kringle domain, and a serine protease domain, which is similar to that of urinary plasminogen activator (u-PA, node in gray. PHBP is present as the 70-kDa inactive single chain precursor in human plasma. It transforms to the active two chain form, 50-kDa heavy chain and 27-kDa light chain, which are linked by a disulfide bond, by auto-cleavage (see positions of cleavage above the node in green).
Altogether ITIH molecules have been shown to play a particularly important role in inflammation and carcinogenesis, as well as being down-regulated in multiple human solid tumors. They are also linked to HCC by IL-6, whose serum concentrations are significantly higher in HCC patients than in controls, as well as being positively correlated with the size of the tumor.
Other Networks
Below are links to NCBI by PMID supporting this network.
© The PMAP Web Site is managed by The Center on Proteolytic Pathways at the Burnham Institute for Medical Research through a grant from the NIH Roadmap.
Copyright 2008. All rights reserved.
The Burnham Institute for Medical Research 10901 N. Torrey Pines Rd., La Jolla, CA 92037.
With problems, comments, or suggestions please contact: pmap_info@burnham.org