AP-2alpha, interleukin-4 (IL-4), E-cadherin, fibulin 1D, p16(INK4alpha), PTEN, RKIP, and S100A4 are determinants (suppressors, except for S100A4) of cancer cell invasiveness and other traits of cancer progression, which are located upstream of matrix metalloproteinases (MMPs) in cell signaling pathways. We will refer to them as upstream cancer-progression determinants (UCPDs, for brevity). MMP-1, MMP-2, MMP-9, MMP-11, MMP-13, MMP-14, MMP-16, and MMP-19 are enhancers of cancer cell invasiveness and other traits of cancer progression, in MDA-MB-231 breast cancer cells. We are interested in pathway links from UCPDs to gene expression of cancer cell MMPs in MDA-MB-231 cells. To test models about these links, wild-type copies of UCPDs were transiently overexpressed and then MMP mRNAs were measured by reverse transcription real-time PCR. The present results show that each of eight UCPDs is linked to the gene expression of a unique set of MMPs. This indicates that the effects are sequence-specific and that each UCPD reaches these MMP expressions through different sets of signaling pathways. We have detected 20 new pathway links, 11 are downregulatory and nine are upregulatory; 15 are new links in any cell, and five are new links in breast cancer. In seven links, three cancer-progression suppressing UCPDs unexpectedly enhance the gene expression of five cancer-progression promoting MMPs.

We isolated a human cDNA by expression cloning and characterized its gene product as a new human protein that enables entry and infection of herpes simplex virus (HSV). The gene, designated hfl-B5, encodes a type II cell surface membrane protein, B5, that is broadly expressed in human primary tissue and cell lines. It contains a high-scoring heptad repeat at the extracellular C terminus that is predicted to form an ␣-helix for coiled coils like those in cellular SNAREs or in some viral fusion proteins. A synthetic 30-mer peptide that has the same sequence as the heptad repeat ␣-helix blocks HSV infection of B5-expressing porcine cells and human HEp-2 cells. Transient expression of human B5 in HEp-2 cells results in increased polykarocyte formation even in the absence of viral proteins. The B5 protein fulfills all criteria as a receptor or coreceptor for HSV entry. Use by HSV of a human cellular receptor, such as B5, that contains putative membrane fusion domains provides an example where a pathogenic virus with broad tropism has usurped a widely expressed cellular protein to function in infection at events that lead to membrane fusion.Herpes simplex virus type 1 (HSV-1) and HSV-2 are prevalent human pathogens that infect a broad range of animal cells. They establish lifelong latency in human neurons from which reactivation to lytic replication leads to recurrent herpes lesions. Entry into cells involves attachments of viral glycoproteins to multiple alternative cellular receptors (2,10,30). However, the molecular mechanisms of entry have not yet been defined.The human proteins identified as receptors for HSV include heparan sulfate (HS) proteoglycans and several integral membrane proteins that are members of well-characterized families (30). Herpesvirus entry mediator HVEM (HveA) is a member of the tumor necrosis factor receptor family (20). Nectin 2 (HveB) and nectin 1 (HveC) or herpes immunoglobulin-like receptor are adhesion molecules in the immunoglobulin superfamily (7,12,35). D-Glucosaminyl 3-O-sulfotransferase (3-OS) modifies specific sites in cellular HS to generate binding sites for the essential HSV attachment glycoprotein D (gD) (27). Nectin 1, which was originally isolated as poliovirus receptorrelated protein, allows entry of most HSV-1 and HSV-2 strains and is broadly expressed on a range of human tissues. HVEM and nectin 2 are more limited by either tissue distribution or strain specificity for transfer of HSV susceptibility. HVEM does not support entry of mutant virus HSV-1(Rid-1) that has a point mutation in gD (20). Nectin 2 is reported to allow entry of HSV-2 strains and HSV-1(Rid-1), but not most HSV-1 strains (35). Isolation of animal homologs for nectin 1 and HVEM raises the possibility that they may engage HSV during infection of animal cells.With the exception of HS, HSV gD is a viral ligand for these receptors. Some regions of gD involved in receptor interactions have been defined (3,8). How the cellular proteins interact with other viral proteins (each other or other cellular proteins) ...

Previously we detected new signaling pathways, some downregulatory and others upregulatory, from seven known suppressors of cancer progression to the expression of eight cancer-promoting matrix metalloproteinases (MMPs) in breast cancer cells. The goals of the present study were to test whether the preceding observations occur only in breast cancer cells and, if not, whether the same downregulatory and upregulatory signaling pathways are active in cells of other human cancers, focusing on activator protein-2alpha, E-cadherin, fibulin1D, interleukin 4, p16(INK4alpha), p53, PTEN, and RKIP, and on MMP1, MMP2, MMP7, MMP13, MMP14, MMP16, MMP19, and MMP25. To this end, in the present study we tested the effects of raising the cellular levels of wild-type copies of these known suppressors of cancer progression on the expression of these MMPs. This study yielded several unexpected results. We have detected 53 new signaling pathways in cells of prostate, brain, lung, ovarian and breast human cancers, with an abundance of signaling pathways as high as approximately 40% of the cancer progression regulator/MMP pairs tested in cells of prostate and breast cancers. Cells of various cancers differed widely and sequence-specifically in the identity of their signaling pathways, so that almost 90% of the pathways were different in cells from one cancer to another. In each of 18 out of 51 signaling pathways, a known suppressor of cancer progression stimulated, rather than inhibited, the expression of a cancer-promoting MMP. Ten signaling pathways were upregulatory in cells of some cancers and downregulatory in cells of other cancers.

Cell invasiveness is essential for cancer metastasis. Many proteins, and more recently also non-coding RNAs, particularly microRNAs (miRNAs), have been reported to affect the cell invasiveness of various cancers. There is an apparent gap between the high number of these macromolecules and the low number of signaling pathways experimentally verified to control cancer invasiveness. We have brought together these various proteins and RNAs because we could not find any publication that filled this important gap. We have noted 589 proteins, 28 miRNAs, and 1 long non-coding RNA that are reported to modulate invasiveness in cells of various cancers. Interestingly, 44 proteins enhance invasiveness in cells of some cancers, but suppress it in cells of others. Almost all of the proteins that show experimentally verified activation/inhibition effects on, or binding interactions with, each other are linked together in a single network, in a "hub-and-spoke" architecture. The accumulated data show trends that point to anticipated future results and highlight gaps in what is known about invasiveness signaling. Identification of cancer invasiveness signaling networks is important for combination and personalized targeted therapies of cancers.

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