All-trans-retinoic acid and hexamethylene bisacetamide (HMBA) regulate TGF-α and Hst-1/kFGF expression in differentiation sensitive but not in resistant human teratocarcinomas Journal Article

  

Authors:	Miller, W. H. Jr; Maerz, W. J.; Kurie, J.; Moy, D.; Baselga, J.; Lucas, D. A.; Grippo, J. F.; Masui, H.; Dmitrovsky, E.
Article Title:	All-trans-retinoic acid and hexamethylene bisacetamide (HMBA) regulate TGF-α and Hst-1/kFGF expression in differentiation sensitive but not in resistant human teratocarcinomas
Abstract:	The multipotent human teratocarcinoma (TC) cell NTera-2 clone D1 (abbreviated NT2/D1) differentiates into a neuronal lineage after retinoic acid (RA) treatment and a distinct phenotype after hexamethylene bisacetamide (HMBA) treatment. We previously reported that RA treatment of NT2/D1 cells reduces cellular cloning efficiency and nude mouse tumorigenicity. This accompanied a loss of mRNA expression of transforming growth factor-α (TGF-α) and the fibroblast growth factor kFGF, also known as hst-1 (abbreviated hst-1/kFGF). This study extends prior work by reporting that the distinct phenotype induced by HMBA also decreases cloning efficiency, tumorigenicity, and TGF-α and hst-1/kFGF mRNA expression in NT2/D1 cells. These RNA findings were confirmed by measurements of growth factor protein in the conditioned media of inducer-treated and untreated NT2/D1 cells. In two established human TC lines refractory to the actions of RA, N2102ep and Tera-1, RA fails to decrease expression of either growth factor despite induction of its nuclear receptor, RAR-β. However, HMBA induces morphologic maturation and down-regulation of these growth factors in N2102ep cells. This indicates that the loss of TGF-α and hst-1/kFGF expression serves as a new marker of differentiation in human TCs. To explore the effects of these growth factors on growth and differentiation of NT2/D1 cells, TGF-α or hst-1/kFGF protein was added following inducer treatment or no treatment. Neither growth factor blocked immunophenotypic differentiation, but both promoted the growth of uninduced NT2/D1 cells in cloning assays. Growth factor expression studies were extended from cultured TCs to germ cell tumor biopsies, where TGF-α was expressed in all and hst-1/kFGF was expressed in a subset of examined tumors. Together, these findings reveal that TGF-α and hst-1/kFGF are differentiation markers in human teratocarcinomas that appear to promote tumor cell growth without blocking differentiation. © 1994, International Society of Differentiation. All rights reserved.
Keywords:	controlled study; human tissue; human cell; proto-oncogene proteins; antineoplastic agents; comparative study; biological marker; cell division; gene expression; embryo; cell line; cell differentiation; drug resistance; tumor cells, cultured; gene expression regulation; messenger rna; carcinogenicity; immunophenotyping; tumor growth; cell nucleus receptor; germ cell tumor; nerve cell; retinoic acid; clone cells; fibroblast growth factor; fibroblast growth factors; transforming growth factor alpha; cell cloning; tretinoin; teratocarcinoma; hexamethylenebisacetamide; acetamides; human; priority journal; article; support, non-u.s. gov't; support, u.s. gov't, p.h.s.
Journal Title:	Differentiation
Volume:	55
Issue:	2
ISSN:	0301-4681
Publisher:	International Society of Differentiation
Date Published:	1994-01-01
Start Page:	145
End Page:	152
Language:	English
DOI:	10.1046/j.1432-0436.1994.5520145.x
PROVIDER:	scopus
PUBMED:	8143931
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-0028174917&doi=10.1046%2fj.1432-0436.1994.5520145.x&partnerID=40&md5=418a11d9706561be17e4cf78dd1e1b7b
Notes:	Export Date: 14 January 2019 -- Article -- Source: Scopus

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