Insulin-like growth factor binding protein 3 (IGFBP-3) is an important regulator of normal and malignant cell growth. It modulates the mitogenic effects of
insulin-like growth factors (IGFs) by inhibiting growth through mechanisms both dependent on and independent of IGF binding.
IGF-I and
IGF-II levels are regulated by binding to the
IGF-II receptor, which is inactivated by mutation in human gastrointestinal (GI)
tumors. We have previously demonstrated elevated
IGF-II ligand expression in
IGF-II receptor-mutant GI
tumors, implicating the IGF signaling system in GI
tumorigenesis. Therefore, to investigate the potential involvement of
IGFBP-3 in human GI
carcinogenesis, direct
DNA sequencing of exons 1-4 and intron-exon boundaries of the
IGFBP-3 gene was performed in 10
colorectal cancers, 10
gastric cancers, and 10
esophageal cancers. Four distinct sequence alterations were identified: (a) in one gastric and one esophageal
tumor, an A to C transversion occurred at
nucleotide 5795 (CAC-->CCC), leading to a
His-->Pro substitution at
codon 179; (b) a second esophageal
tumor had a C to T transition at
nucleotide 8291 (ACC-->ATC), leading to a Thr-->Ile substitution at
codon 277 of
IGFBP-3; (c) one alteration comprised a G to C transversion in exon 1 at
nucleotide 2132 (GGG-->GCG), leading to a
Gly-->Ala substitution at
codon 32 in two
gastric cancers, seven
esophageal cancers, and nine
colon cancers; and (d) a C to G transversion located 17
nucleotides from the
3' splice site in intron 1 was observed in three
colon cancers and four
esophageal cancers. All of these DNA sequence alterations were present in matched normal
DNA from the same subjects, which suggests that some or all of them may represent polymorphisms. However, we cannot exclude the possibility that the germ-line nonconservative amino acid substitutions predicted to occur as a result of these alterations result in subtle changes to
IGFBP-3 protein function and a predisposition to developing GI
malignancy.