A novel autocrine loop involving IGF-II and the insulin receptor isoform-A stimulates growth of thyroid cancer.
The insulin receptor (IR) occurs in two isoforms (IR-A and IR-B) resulting from alternative splicing of exon 11 of the gene. The IR-A isoform is predominantly expressed in fetal tissues and malignant cells and binds IGF-II with high affinity. We previously observed that IRs are overexpressed in thyroid cancer cells; now we evaluated whether these cells preferentially express IR-A and produce IGF-II, which would activate a growth-promoting autocrine loop. The IR content ranged 6.0-52.6 ng/100 microg cell membrane protein in thyroid cancer primary cultures (n = 8) and permanent cell lines (n = 6) vs. 1.2-1.7 in normal thyroid cells (n = 11 primary cultures; P < 0.0001). IR-A isoform relative abundance ranged from 36-79% in cancer cells (with the highest values in undifferentiated cancers) vs. 27-39% in normal cells. Similar results were obtained in normal vs. cancer thyroid tissue specimens. IGF-II caused IR autophosphorylation with an ED(50) of 1.5-40.0 nM in cancer cells vs. more than 100 nM in normal cells; IGF-II affinity correlated with the relative abundance of IR-A (r = 0.628; P < 0.0001). IGF-II was expressed in all cancer cells, highly expressed in anaplastic cells, and less expressed in normal cells. In conclusion, malignant thyrocytes, especially when poorly differentiated, produce IGF-II and overexpress IR, predominantly as IGF-II-sensitive isoform A. A growth-promoting autocrine loop is activated, therefore, and may affect thyroid cancer biology.
Vella
Veronica
V
Istituto di Medicina Interna e di Malattie Endocrine e del Metabolismo, Cattedra di Endocrinologia, University of Catania, Ospedale Garibaldi, 95123 Catania, Italy.
Pandini
Giuseppe
G
Sciacca
Laura
L
Mineo
Rossana
R
Vigneri
Riccardo
R
Pezzino
Vincenzo
V
Belfiore
Antonino
A
D015703:Antigens, CD; D019898:Autocrine Communication; D002454:Cell Differentiation; D002455:Cell Division; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D011972:Receptor, Insulin / Q000032:analysis / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D007335:Insulin-Like Growth Factor II; C435941:INSR protein, human; D011972:Receptor, Insulin