title: HMGI(Y) and HMGI-C genes are expressed in neuroblastoma cell lines and tumors and affect retinoic acid responsiveness.
abstract: HMGI-C and HMGI(Y) are architectural DNA-binding proteins that participate in the conformational regulation of active chromatin. Their pattern of expression in embryonal and adult tissues, the analysis of the "pygmy" phenotype induced by the inactivation of the HMGI-C gene, and their frequent qualitative or quantitative alteration in experimental and human tumors indicate their pivotal role in the control of cell growth, differentiation, and tumorigenesis in several tissues representative of the epithelial, mesenchymal, and hematopoietic lineages. In contrast, very little information is available on their expression and function in neural cells. Here, we investigated the expression of the HMGI(Y) and HMGI-C genes in neuroblastoma (NB), a tumor arising from an alteration of the normal differentiation of neural crest-derived cells and in embryonal and adult adrenal tissue. Although HMGI(Y) is constitutively expressed in the embryonal and adult adrenal gland and in all of the NB cell lines and ex vivo tumors examined, its regulation appears to be associated to growth inhibition and differentiation because we observed that HMGI(Y) expression is reduced by retinoic acid (RA) in several NB cell lines that are induced to differentiate into postmitotic neurons, whereas it is up-regulated by RA in cells that fail to differentiate. Furthermore, the decrease of HMGI(Y) expression observed in RA-induced growth arrest and differentiation is abrogated in cells that have been made insensitive to this drug by NMYC overexpression. In contrast, HMGI-C expression is down-regulated during the development of the adrenal gland, completely absent in the adult individual, and only detectable in a subset of ex vivo NB tumors and in RA-resistant NB cell lines. We provide evidence of a causal link between HMGI-C expression and resistance to the growth arrest induced by RA in NB cell lines because exogenous HMGI-C expression in HMGI-C-negative and RA-sensitive cells is sufficient to convert them into RA-resistant cells. Therefore, we suggest that HMGI-C and HMGI(Y) may participate in growth- and differentiation-related tumor progression events of neuroectodermal derivatives.
authors.affiliation: Department of Experimental Medicine and Pathology, University La Sapienza, Rome, Italy. g.giannini@caspur.it
authors.forename: G
authors.initials: G
authors.lastname: Giannini
authors.forename: L
authors.initials: L
authors.lastname: Di Marcotullio
authors.forename: E
authors.initials: E
authors.lastname: Ristori
authors.forename: M
authors.initials: M
authors.lastname: Zani
authors.forename: M
authors.initials: M
authors.lastname: Crescenzi
authors.forename: S
authors.initials: S
authors.lastname: Scarpa
authors.forename: G
authors.initials: G
authors.lastname: Piaggio
authors.forename: A
authors.initials: A
authors.lastname: Vacca
authors.forename: F A
authors.initials: FA
authors.lastname: Peverali
authors.forename: F
authors.initials: F
authors.lastname: Diana
authors.forename: I
authors.initials: I
authors.lastname: Screpanti
authors.forename: L
authors.initials: L
authors.lastname: Frati
authors.forename: A
authors.initials: A
authors.lastname: Gulino
mesh_terms: D000311:Adrenal Glands / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle; D002454:Cell Differentiation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D025741:HMGA1a Protein; D025743:HMGA2 Protein; D006609:High Mobility Group Proteins / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics*; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D014158:Transcription, Genetic; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D025743:HMGA2 Protein; D006609:High Mobility Group Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D014157:Transcription Factors; D025741:HMGA1a Protein; D014212:Tretinoin