title: Tissue-specificity of heparan sulfate biosynthetic machinery in cancer.
abstract: Heparan sulfate (HS) proteoglycans are key components of cell microenvironment and fine structure of their polysaccharide HS chains plays an important role in cell-cell interactions, adhesion, migration and signaling. It is formed on non-template basis, so, structure and functional activity of HS biosynthetic machinery is crucial for correct HS biosynthesis and post-synthetic modification. To reveal cancer-related changes in transcriptional pattern of HS biosynthetic system, the expression of HS metabolism-involved genes (EXT1/2, NDST1/2, GLCE, 3OST1/HS3ST1, SULF1/2, HPSE) in human normal (fibroblasts, PNT2) and cancer (MCF7, LNCaP, PC3, DU145, H157, H647, A549, U2020, U87, HT116, KRC/Y) cell lines and breast, prostate, colon tumors was studied. Real-time RT-PCR and Western-blot analyses revealed specific transcriptional patterns and expression levels of HS biosynthetic system both in different cell lines in vitro and cancers in vivo. Balance between transcriptional activities of elongation- and post-synthetic modification- involved genes was suggested as most informative parameter for HS biosynthetic machinery characterization. Normal human fibroblasts showed elongation-oriented HS biosynthesis, while PNT2 prostate epithelial cells had modification-oriented one. However, cancer epithelial cells demonstrated common tendency to acquire fibroblast-like elongation-oriented mode of HS biosynthetic system. Surprisingly, aggressive metastatic cancer cells (U2020, DU145, KRC/Y) retained modification-oriented HS biosynthesis similar to normal PNT2 cells, possibly enabling the cells to keep like-to-normal cell surface glycosylation pattern to escape antimetastatic control. The obtained results show the cell type-specific changes of HS-biosynthetic machinery in cancer cells in vitro and tissue-specific changes in different cancers in vivo, supporting a close involvement of HS biosynthetic system in carcinogenesis.
authors.affiliation: a Institute of Molecular Biology and Biophysics SD RAMS ; Novosibirsk , Russia.|b Novosibirsk State University ; Novosibirsk , Russia.
authors.forename: Anastasia V
authors.initials: AV
authors.lastname: Suhovskih
authors.affiliation: a Institute of Molecular Biology and Biophysics SD RAMS ; Novosibirsk , Russia.
authors.forename: Natalya V
authors.initials: NV
authors.lastname: Domanitskaya
authors.affiliation: a Institute of Molecular Biology and Biophysics SD RAMS ; Novosibirsk , Russia.
authors.forename: Alexandra Y
authors.initials: AY
authors.lastname: Tsidulko
authors.affiliation: a Institute of Molecular Biology and Biophysics SD RAMS ; Novosibirsk , Russia.
authors.forename: Tatiana Y
authors.initials: TY
authors.lastname: Prudnikova
authors.affiliation: c MTC; Karolinska Institute ; Stockholm , Sweden.
authors.forename: Vladimir I
authors.initials: VI
authors.lastname: Kashuba
authors.affiliation: a Institute of Molecular Biology and Biophysics SD RAMS ; Novosibirsk , Russia.|b Novosibirsk State University ; Novosibirsk , Russia.|c MTC; Karolinska Institute ; Stockholm , Sweden.
authors.forename: Elvira V
authors.initials: EV
authors.lastname: Grigorieva
mesh_terms: D063646:Carcinogenesis; D045744:Cell Line, Tumor; D060833:Cellular Microenvironment / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006497:Heparan Sulfate / Q000096:biosynthesis* / Q000378:metabolism; D006801:Humans; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009928:Organ Specificity
chemical_list: D006497:Heparan Sulfate; D009363:Neoplasm Proteins
keywords: biosynthesis; breast cancer; colon cancer; expression pattern; extracellular matrix; heparan sulfate; prostate cancer; proteoglycan; tissue-specificity