title: IGF2 promotes growth of adrenocortical carcinoma cells, but its overexpression does not modify phenotypic and molecular features of adrenocortical carcinoma.
abstract: Insulin-like growth factor 2 (IGF2) overexpression is an important molecular marker of adrenocortical carcinoma (ACC), which is a rare but devastating endocrine cancer. It is not clear whether IGF2 overexpression modifies the biology and growth of this cancer, thus more studies are required before IGF2 can be considered as a major therapeutic target. We compared the phenotypical, clinical, biological, and molecular characteristics of ACC with or without the overexpression of IGF2, to address these issues. We also carried out a similar analysis in an ACC cell line (H295R) in which IGF2 expression was knocked down with si- or shRNA. We found no significant differences in the clinical, biological and molecular (transcriptomic) traits between IGF2-high and IGF2-low ACC. The absence of IGF2 overexpression had little influence on the activation of tyrosine kinase pathways both in tumors and in H295 cells that express low levels of IGF2. In IGF2-low tumors, other growth factors (FGF9, PDGFA) are more expressed than in IGF2-high tumors, suggesting that they play a compensatory role in tumor progression. In addition, IGF2 knock-down in H295R cells substantially impaired growth (>50% inhibition), blocked cells in G1 phase, and promoted apoptosis (>2-fold). Finally, analysis of the 11p15 locus showed a paternal uniparental disomy in both IGF2-high and IGF2-low tumors, but low IGF2 expression could be explained in most IGF2-low ACC by an additional epigenetic modification at the 11p15 locus. Altogether, these observations confirm the active role of IGF2 in adrenocortical tumor growth, but also suggest that other growth promoting pathways may be involved in a subset of ACC with low IGF2 expression, which creates opportunities for the use of other targeted therapies.
authors.affiliation: Paris Cardiovascular Center, Institut National de la Santé et de la Recherche Médicale U970, Université Paris Descartes, Paris, France; Département de Biologie Hormonale, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Guillaud-Bataille
authors.affiliation: Institut Cochin, Institut National de la Santé et de la Recherche Médicale U1016, Centre National de la Recherche Scientifique UMR8104, Université Paris Descartes, Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Ragazzon
authors.affiliation: Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre le Cancer, Paris, France.
authors.forename: Aurélien
authors.initials: A
authors.lastname: de Reyniès
authors.affiliation: Paris Cardiovascular Center, Institut National de la Santé et de la Recherche Médicale U970, Université Paris Descartes, Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Chevalier
authors.affiliation: Paris Cardiovascular Center, Institut National de la Santé et de la Recherche Médicale U970, Université Paris Descartes, Paris, France; Département de Biologie Hormonale, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Francillard
authors.affiliation: Institut Cochin, Institut National de la Santé et de la Recherche Médicale U1016, Centre National de la Recherche Scientifique UMR8104, Université Paris Descartes, Paris, France; Département d'Endocrinologie, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France.
authors.forename: Olivia
authors.initials: O
authors.lastname: Barreau
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U938, Université Pierre et Marie Curie, Paris, France; Laboratoire d'explorations fonctionnelles endocriniennes, Assistance Publique Hôpitaux de Paris, Hôpital Armand Trousseau, Paris, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Steunou
authors.affiliation: Paris Cardiovascular Center, Institut National de la Santé et de la Recherche Médicale U970, Université Paris Descartes, Paris, France.
authors.forename: Johann
authors.initials: J
authors.lastname: Guillemot
authors.affiliation: Institut Cochin, Institut National de la Santé et de la Recherche Médicale U1016, Centre National de la Recherche Scientifique UMR8104, Université Paris Descartes, Paris, France; Service d'Anatomie Pathologique, Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpétrière, Université Pierre et Marie Curie, Paris, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Tissier
authors.affiliation: Institut Cochin, Institut National de la Santé et de la Recherche Médicale U1016, Centre National de la Recherche Scientifique UMR8104, Université Paris Descartes, Paris, France.
authors.forename: Marthe
authors.initials: M
authors.lastname: Rizk-Rabin
authors.affiliation: Institut Cochin, Institut National de la Santé et de la Recherche Médicale U1016, Centre National de la Recherche Scientifique UMR8104, Université Paris Descartes, Paris, France.
authors.forename: Fernande
authors.initials: F
authors.lastname: René-Corail
authors.affiliation: Département de Biologie et Pathologie Médicales, Institut Gustave Roussy, Villejuif, France.
authors.forename: Abir
authors.initials: A
authors.lastname: Al Ghuzlan
authors.affiliation: Institut Cochin, Institut National de la Santé et de la Recherche Médicale U1016, Centre National de la Recherche Scientifique UMR8104, Université Paris Descartes, Paris, France; Département d'Endocrinologie, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Assié
authors.affiliation: Institut Cochin, Institut National de la Santé et de la Recherche Médicale U1016, Centre National de la Recherche Scientifique UMR8104, Université Paris Descartes, Paris, France; Département d'Endocrinologie, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Bertagna
authors.affiliation: Département d'Imagerie Médicale, Médecine nucléaire, Institut Gustave Roussy, Villejuif, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Baudin
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U938, Université Pierre et Marie Curie, Paris, France; Laboratoire d'explorations fonctionnelles endocriniennes, Assistance Publique Hôpitaux de Paris, Hôpital Armand Trousseau, Paris, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Le Bouc
authors.affiliation: Institut Cochin, Institut National de la Santé et de la Recherche Médicale U1016, Centre National de la Recherche Scientifique UMR8104, Université Paris Descartes, Paris, France; Département d'Endocrinologie, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bertherat
authors.affiliation: Paris Cardiovascular Center, Institut National de la Santé et de la Recherche Médicale U970, Université Paris Descartes, Paris, France; Département de Biologie Hormonale, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Clauser
mesh_terms: D000293:Adolescent; D018268:Adrenocortical Carcinoma / Q000235:genetics* / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D056426:Genetic Loci; D018392:Genomic Imprinting; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D055815:Young Adult
chemical_list: D012333:RNA, Messenger; D007335:Insulin-Like Growth Factor II
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