Reactivation of rat insulin-like growth factor II gene during hepatocarcinogenesis

Abstract

The insulin-like growth factor II (rIGFII) is a mitogenic polypeptide, the expression of which is high in most rat tissues during embryonic development, yet is barely detectable in adult tissues except for some of neurogenic origin. The gene is present as a single copy in the genome but has three alternative leader exons, E1, E2 and E3, thereby with three independent transcriptional promoters. We analysed the expression of rIGFII and the relative efficiency of each promoter in hepatocarcinogen-treated livers, primary hepatomas and established hepatoma lines. The E3-specific product was first detected after 6 weeks of 3'-methyl-4-dimethylaminoazobenzene treatment and those of E1 and E2 also after 9 weeks. The levels gradually increased according to the sum of the treatment period, but reactivation was nil in the regenerating liver. Consistently high levels of expression were observed in all primary tumors, but the relative promoter activity varied with the tumor. The significance of rIGFII reactivation was discussed in the light of the hepatocarcinogenesis.

Autonomous growth of a human neuroblastoma cell line is mediated by insulin-like growth factor II.

“…These include Wilms' tumor (10,16,54), rhabdomyosarcoma (10, 1 1), liposarcoma (55), 40% of colon carcinomas (55), leiomyomas/leiomyosarcomas (41), breast carcinomas (56), and 20% of hepatic carcinomas (57). IGF-II RNA also is increased in rat medullary thyroid carcinomas (58) and hepatocellular carcinomas (59,60), and in woodchuck hepatocellular carcinomas that develop after chronic infection with woodchuck hepatitis virus (61). These studies do not address the question of whether the expression of IGF-II mRNA is an epiphenomenon or consequence of tumorigenesis, or whether IGF-II is involved in the initiation or propagation ofthe tumors.…”

“…Fractions 48-65 contained IGF activity, as recognized by the inhibition of 1251I-IGF-II tracer binding to rat placental IGF-II receptors and coelution with a 7.5-kD 1251I-IGF-II marker included in the gel filtration sample, and were well resolved from IGF binding proteins (fractions [31][32][33][34][35][36][37][38][39][40]. Fractions in the IGF peak (fractions [48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65] were pooled and examined in a radioimmunoassay and a radioreceptor assay that are specific for IGF-II. Dilutions of the pooled IGF fractions inhibited 12511…”

Reactivation of the insulin-like growth factor-II signaling pathway in human hepatocellular carcinoma

“…Therefore, the selection for cells with high IGF-Ⅱ levels may rescue a more unfavorable tumor phenotype and therefore promote tumor progression. Lastly, a reactivation of IGF-Ⅱ expression in experimentally induced liver tumors using different chemical substances (3'-Me-DAB, 2-AAF, DENA) has been described in rats [82][83][84] .…”

The H19 endodermal enhancer is required for Igf2 activation and tumor formation in experimental liver carcinogenesis

“…IGF2 expression is frequently activated in human cancers and its overexpression has been implicated in the pathogenesis of overgrowth diseases (Toretsky and Helman, 1996;Li et al, 1998;Reik and Maher, 1997;Morison et al, 1996;Sperandeo et al, 2000). In the mouse, Igf2 is activated in experimental liver and pancreas carcinogenesis and its deletion a ects tumor formation (Ueno et al, 1988;Norstedt et al, 1988;Takagi et al, 1992;Casola et al, 1995;Haddad and Held, 1997;Christofori et al, 1994).…”

“…Di erential activation of these promoters has been observed in human and experimental cancers (Ueno et al, 1988;Zarrilli et al, 1994). Although several transcription factors involved in neoplastic transformation have been reported to bind and regulate in vitro-transfected IGF2 promoter fragments, no information has been obtained so far on the mechanisms responsible for the activation of this gene during in vivo carcinogenesis (Zhang et al, 1996(Zhang et al, , 1998Lee et al, 1998;Caricasole and Ward, 1993;Drummond et al, 1992;Kim et al, 1992).…”