ABSTRACT
Metastasis-associated C4.4A, which becomes upregulated during wound healing and, in some tumors, during tumor progression, is known to be frequently associated with hypoxia. With the function of C4.4A still unknown, we explored the impact of hypoxia on C4.4A expression and functional activity. Metastatic rat and human tumor lines upregulate C4.4A expression when cultured in the presence of CoCl(2). Although hypoxia-inducible factor 1α (HIF-1α) becomes upregulated concomitantly, HIF-1α did not induce C4.4A transcription. Instead, hypoxia-induced C4.4A up-regulation promoted in vivo and in vitro wound healing, where increased migration on the C4.4A ligands laminin-111 and -332 was observed after a transient period of pronounced binding. Increased migration was accompanied by C4.4A associating with α(6)ß(4), MT1-MMP1, and TACE and by laminin fragmentation. Hypoxia also promoted the release of C4.4A in exosomes and TACE-mediated C4.4A shedding. The association of C4.4A with α(6)ß(4) and MT1-MMP1 was maintained in exosomes and exosomal α(6)ß(4)- and MT1-MMP1-associated C4.4A but not shed C4.4A sufficient for laminin degradation. Hypoxia-induced recruitment of α(6)ß(4) toward raft-located C4.4A, MT1-MMP, and TACE allows for a shift from adhesion to motility, which is supported by laminin degradation. These findings provide the first explanation for the C4.4A contribution to wound healing and metastasis.
Subject(s)
Cell Adhesion Molecules/physiology , Cell Movement , Exosomes/metabolism , Integrin alpha6beta4/metabolism , Matrix Metalloproteinase 14/metabolism , Neoplasm Proteins/physiology , Animals , Cell Adhesion , Cell Adhesion Molecules/genetics , Cell Adhesion Molecules/metabolism , Cell Hypoxia , Cell Line, Tumor , GPI-Linked Proteins/genetics , GPI-Linked Proteins/metabolism , GPI-Linked Proteins/physiology , Gene Expression , Gene Expression Regulation , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Keratinocytes/metabolism , Keratinocytes/physiology , Neoplasm Metastasis , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Protein Binding , Rats , Response Elements , Wound Healing , KalininABSTRACT
Germ cell tumors (GCTs) are among the most common malignancies in young men. We have previously documented that patients with GCT frequently produce serum antibodies directed against proteins encoded by human endogenous retrovirus (HERV) type K sequences. Transcripts originating from the env gene of HERV-K, including the rec-relative of human immunodeficiency virus rev, are highly expressed in GCTs. We report here that mice that inducibly express HERV-K rec show a disturbed germ cell development and may exhibit, by 19 months of age, changes reminiscent of carcinoma in situ, the predecessor lesion of classic seminoma in humans. This provides the first direct evidence that the expression of a human endogenous retroviral gene previously established as a marker in human germ cell tumors may contribute to organ-specific tumorigenesis in a transgenic mouse model.
