Expression of the wild-type insulin-like growth factor II receptor gene suppresses growth and causes death in colorectal carcinoma cells.
The insulin-like growth factor II receptor (IGFIIR) has been implicated as a tumor suppressor gene in human malignancy. Frequent mutation, loss of heterozygosity, and microsatellite instability (MSI) directly affecting the IGFIIR gene have been reported in several primary human tumor types. However, to our knowledge, dynamic functional evidence of a growth-suppressive role for IGFIIR has not yet been provided. We identified one MSI-positive colorectal carcinoma cell line, SW48, with monoallelic mutation in IGFIIR identical to that seen in primary colorectal carcinomas. A zinc-inducible construct containing the wild-type IGFIIR cDNA was stably transfected into SW48 cells. Growth rate and apoptosis were compared between zinc-treated, untreated, and untransfected cells. A twofold increase in IGFIIR protein expression was detected after zinc treatment in discrete clonal isolates of transfected SW48 cells. Moreover, zinc induction of exogenous wild-type IGFIIR expression reproducibly decreased growth rate and increased apoptosis. These data prove that wild-type IGFIIR functions as a growth suppressor gene in colorectal cancer cells and provide dynamic in vitro functional support for the hypothesis that IGFIIR is a human growth suppressor gene.
Souza
R F
RF
Department of Medicine, Dallas VA Medical Center and University of Texas-Southwestern Medical School, 75216, USA.
Wang
S
S
Thakar
M
M
Smolinski
K N
KN
Yin
J
J
Zou
T T
TT
Kong
D
D
Abraham
J M
JM
Toretsky
J A
JA
Meltzer
S J
SJ
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology*; D017209:Apoptosis / Q000235:genetics*; D002455:Cell Division / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology*; D018076:DNA, Complementary / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000502:physiology; D019656:Loss of Heterozygosity; D008668:Metallothionein / Q000235:genetics; D018895:Microsatellite Repeats; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000187:drug effects; D017527:Receptor, IGF Type 2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured; D015032:Zinc / Q000494:pharmacology
D018076:DNA, Complementary; D009363:Neoplasm Proteins; D017527:Receptor, IGF Type 2; D007335:Insulin-Like Growth Factor II; D008668:Metallothionein; D015032:Zinc