title: Enhanced membrane-type 1 matrix metalloproteinase expression by hyaluronan             oligosaccharides in breast cancer cells facilitates CD44 cleavage and tumor cell             migration.
abstract: Hyaluronan (HA), a component of the extracellular matrix, plays an important role in cell-cell adhesion and cell migration. Membrane type 1-matrix metalloproteinase (MT1‑MMP) is often expressed in invasive cancer cells. CD44, a transmembrane receptor for HA, is implicated in various adhesion-dependent cellular processes including cell migration, tumor cell metastasis and invasion. Previous studies have shown that CD44 is highly expressed in cancer cells and may be proteolytically cleaved at the ectodomain by MT1-MMP; this process of inducing CD44 cleavage plays a critical role in cancer cell migration. We hypothesized that HA modulates MT1-MMP expression to facilitate breast cancer cell migration. Flow cytometry, real-time PCR, western blotting and immunofluorescence staining were used to quantify HA-induced MT1-MMP expression in breast cancer cells. In order to validate the relevance of cell migration and HA-induced MT1-MMP, we analyzed the cell migration via matrigel-coated transwell. We found that after HA oligosaccharide (6.5 kDA) stimulation, MT1-MMP expression in the membrane of breast cancer cells was increased. In response to HA oligosaccharide stimulation, significant upregulation of MT1-MMP mRNA occurred. Our data also provide evidence that HA oligosaccharide enhances MT1-MMP; the elevated expression of MT1-MMP confers enhanced CD44 cleavage and cell migration. In conclusion, we have identified a new function of HA in the induction of MT1-MMP expression in breast cancer cell lines and CD44 cleavage to increase cell migration during the invasion process. The HA oligosaccharide-induced MT1-MMP expression in breast cancer cells may be a critical step in the formation of metastatic colonies.
authors.affiliation: Institute of Anatomy and Cell Biology, School of Medicine, National Yang Ming University, Taipei, Taiwan, ROC.
authors.forename: Chang-I
authors.initials: CI
authors.lastname: Kung
authors.forename: Cheng-Yi
authors.initials: CY
authors.lastname: Chen
authors.forename: Chih-Chang
authors.initials: CC
authors.lastname: Yang
authors.forename: Cheng-Yu
authors.initials: CY
authors.lastname: Lin
authors.forename: Tien-Hua
authors.initials: TH
authors.lastname: Chen
authors.forename: Hwai-Shi
authors.initials: HS
authors.lastname: Wang
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000378:metabolism* / Q000494:pharmacology; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis; D009844:Oligosaccharides / Q000378:metabolism / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D018960:Hyaluronan Receptors; D009844:Oligosaccharides; D012333:RNA, Messenger; D006820:Hyaluronic Acid; D053511:Matrix Metalloproteinase 14