Expression of insulin-like growth factors (IGFs) and IGF signaling: molecular complexity in uterine leiomyomas.
OBJECTIVE
To study whether dysregulation of insulin-like growth factors (IGFs) and IGF signaling are common molecular changes in symptomatic leiomyomas (fibroids) and whether IGFs are associated with large fibroids.


METHODS
Examination of IGFs and IGF pathway genes in a large cohort of fibroids at transcriptional and translational levels. Mechanisms leading to alterations of IGFs and related genes were also analyzed.


METHODS
University clinical research laboratory.


METHODS
Hysterectomies for symptomatic fibroids were collected: 180 cases from paraffin-embedded tissues and 50 cases from fresh-frozen tissues.


METHODS
Tissue microarray and immunohistochemistry, DNA methylation analysis, reverse-transcriptase polymerase chain reaction, and Western blot.


METHODS
Transcription and translation analyses of IGF-1/2, p-AKT, p-S6K, and TSC1/2 in fibroids and matched myometrium.


RESULTS
Insulin-like growth factors and downstream effectors were dysregulated in approximately one third of fibroids. All except for IGF-2 seemed to be abnormally regulated at translation levels. Up-regulation of IGF-2 messenger RNAs was contributed by all four alternating slicing promoters. There was a positive correlation of IGF-1 and p-AKT over-expression with fibroid size. Insulin-like growth factor 1 but not IGF-2 levels directly correlated with activation of p-AKT and p-S6K.


CONCLUSIONS
Altered expressions of IGFs and their related downstream proteins were found in one third of fibroids. Large fibroids show high levels of IGF-1 and p-AKT activity compared with small ones.
Peng
Lan
L
Department of Pathology, New York University School of Medicine, New York, New York 10016, USA.
Wen
Yong
Y
Han
Yulong
Y
Wei
Anran
A
Shi
Guizhi
G
Mizuguchi
Masashi
M
Lee
Peng
P
Hernando
Eva
E
Mittal
Khush
K
Wei
Jian-Jun
JJ
D015331:Cohort Studies; D017931:DNA Primers; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D007044:Hysterectomy; D007889:Leiomyoma / Q000235:genetics* / Q000503:physiopathology / Q000601:surgery; D020411:Oligonucleotide Array Sequence Analysis; D014176:Protein Biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013002:Somatomedins / Q000235:genetics* / Q000502:physiology; D014158:Transcription, Genetic; D014594:Uterine Neoplasms / Q000235:genetics* / Q000503:physiopathology / Q000601:surgery
D017931:DNA Primers; D013002:Somatomedins