Cross-sectional associations of diet and insulin-like growth factor levels in 7- to 8-year-old children.

BACKGROUND: The insulin-like growth factors (IGF) are polypeptide hormones which are associated with several adult diseases including cancer and coronary heart disease. The dietary determinants of circulating levels of components of the IGF system are of interest, as these may mediate some of the effects of diet on later health. However, few studies have examined the relationship between diet and IGF levels in children.OBJECTIVE: To investigate associations between diet and IGF-I and IGFBP-3 levels in 7- to 8-year-old children.METHODS: This study used subjects participating in the Avon Longitudinal Study of Parents and Children. Diet was assessed using a 3-day unweighed food diary. Confounding variables considered were maternal education, housing tenure, birthweight, and body mass index.RESULTS: Complete information on dietary intakes, IGF levels, and all confounding variables were available for 521 children (287 boys). IGF-I was positively associated with intakes of protein, magnesium, zinc, calcium, potassium, and phosphorus, and IGFBP-3 was positively associated with energy. The IGF-I/IGFBP-3 ratio was positively associated with intakes of protein, zinc, and phosphorus. There was some evidence that the dietary determinants of the IGF system differed between the sexes. None of the foods examined were strongly associated with IGF levels, in particular, there was no association with red meat or vegetable intake.CONCLUSION: These data suggest that the IGF axis in children is affected by diet. This may provide a mechanism whereby childhood diet could have a long-term effect on risk of chronic disease.     

Reduced expression of insulin-like growth factor binding protein-3 and its promoter hypermethylation in human hepatocellular carcinoma.

Insulin-like growth factor binding protein-3 (IGFBP-3) is postulated to be a mediator of growth suppression signals. Reduced expression of the IGFBP-3 was observed in nine out of 12 human hepatocellular carcinomas (HCC) (75%). Promoter hypermethylation of the IGFBP-3 was detected in four out of 12 HCCs (33%) although mutations were not identified. The expression of IGFBP-3 was restored by the demethylating agent 5-aza-2'-deoxycytidine in HCC cell line with promoter hypermethylation (HepG2). As IGFBP-3 functions like a tumor suppressor gene, it may be used as a therapeutic target for HCC.     

Molecular significance of excess body weight in postmenopausal breast cancer patients, in relation to expression of insulin-like growth factor I receptor and insulin-like growth factor II genes.

A number of epidemiological and clinical studies have revealed that excess body weight increases the risk of postmenopausal breast cancer and also adversely affects subsequent malignant progression. To elucidate the molecular mechanisms underlying these observations, we examined mRNA expression of various genes in normal (non-cancerous) mammary gland and cancer tissue of Japanese patients with primary breast cancer, in association with their body mass index (BMI). On the basis of analysis of 106 breast cancer patients, we found that mRNA expression of insulin-like growth factor I receptor (IGF-IR) and insulin-like growth factor II (IGF-II) in the normal mammary gland showed a significant and positive association with increased BMI among postmenopausal patients. Furthermore, the positive association of increased BMI with IGF-IR mRNA expression was also found in postmenopausal breast cancer tissue, while this association was not observed among premenopausal patients. In addition, increased mRNA expression of cyclin D1 and bcl-2 was observed in association with increased mRNA levels of IGF-IR among the patients regardless of menopausal status. These findings suggest that the molecular consequence of the increased BMI is the increased expression of IGF-II and IGF-IR, resulting in development of postmenopausal breast cancer and its progression mediated through modulation of the cell cycle and apoptosis.     

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.     

EXPRESSION OF INSULIN-LIKE GROWTH FACTOR Ⅱ(IGF-Ⅱ)IN HUMAN HEPATOCELLULAR CARCINOMA AND LIVER CIRRHOSIS:ITS RELATIONSHIP WITH HEPATITIS B VIRUS X PROTEIN EXPRESSION

Sixty cases of hepatocellular carcinoma (HCC) and47 cases of liver cirrhosis (LC) were examined withimmunocytochemistry method using antibodies againstIGF-II and HBxAg on formalin-fixed, paraffin-embeddedtissue sections. 32 HCC and 37 LC were found to bepositive to HBxAg, in which the positive rates of IGF-IIwere 100% (32/32) and 94.6% (35/37) respectively. 28HCC and 10 LC were found to be HBxAg negative, IGF-IIwas positive in 23 HCC (83.1%) and 6 LC:(60%) Thepositive expression rates of IGF-II in HBxAg positivetissues were significanfly higher than those in HBxAgnegative tissues (P<0.05). There were three types ofdistribution of IGF-II expression in HCC and LC (1)perinucleus: (2) diffuse in cytoplasm; (3) inside nucleus.IGF-II was highly expressed in most of hyperplastic andneoplastic nodules hepatocytes and some of regenerationnodules. Small polygonal liver cells (SPLCs) were foundin the liver tissues surrounding the tumor and cirrhosisand they were positive to both IGF-II and HBxAg. Thepositive rates     

Angiotensin-I-converting enzyme inhibitors may be an alternative anti-angiogenic strategy in the treatment of liver fibrosis and hepatocellular carcinoma. Possible role of vascular endothelial growth factor.

The renin-angiotensin system (RAS) is frequently activated in patients with chronic liver diseases. Angiotensin-II (AT-II), which is produced by angiotensin-converting enzyme (ACE), has many physiological effects, including strong pro-angiogenic activity. AT-II induces the potent angiogenic factor, vascular endothelial growth factor (VEGF). Recent studies have revealed that angiogenesis is an essential process in many pathological events, such as tumor growth including hepatocellular carcinoma (HCC), and even in liver fibrogenesis. ACE inhibitors are currently widely used as anti-hypertensive agents in clinical practice. Studies have found that the ACE inhibitor, perindopril (PE), which is a potent inhibitor of experimental HCC growth and angiogenesis, is associated with the suppression of VEGF at a clinically comparable dose. PE also markedly suppressed the hepatocarcinogenesis step. In liver fibrogenesis, AT-II is known to stimulate proliferation and production of tissue inhibitor of metalloproteinases-1 (TIMP-1) in activated hepatic stellate cells (Ac-HSC), which play a pivotal role in liver fibrosis development. PE markedly inhibited liver fibrogenesis associated with suppression of Ac-HSC proliferation and TIMP-1 expression via protein kinase-C, which serves as an intracellular signaling pathway. Since ACE inhibitor is used widely in clinical practice without serious side effects, it may provide an alternative new strategy for the treatment of liver fibrosis and HCC.