Insulin-like growth factor I, IGF-binding protein 3, and lung cancer risk in a prospective study of men in China.
ABSTRACT Insulin-like growth factor I (IGF-I) stimulates cell proliferation and inhibits apoptosis in the lung and other tissues by interacting with the IGF-I receptor. The major binding protein for IGF-I, insulin-like growth factor-binding protein 3 (IGFBP-3), modulates the effects of IGF-I but also inhibits cell growth and induces apoptosis independent of IGF-I and its receptor. In a prospective study of men in Shanghai, China, we examined the association between serum levels of IGF-I and IGFBP-3 and the subsequent risk of lung cancer.
From 1986 to 1989, serum was collected from 18,244 men aged 45-64 years living in Shanghai without a history of cancer. We analyzed IGF-I and IGFBP-3 levels in serum from 230 case patients who developed incident lung cancer during follow-up and from 740 control subjects.
Among 230 case patients and 659 matched control subjects, increased IGF-I levels were not associated with increased risk of lung cancer. However, for subjects in the highest quartile relative to the lowest quartile of IGFBP-3, the odds ratio (OR) for lung cancer, adjusted for smoking and IGF-I, was 0.50 (95% confidence interval [CI] = 0.25 to 1.02). When the analysis was restricted to ever smokers (184 case patients and 344 matched control subjects), the OR for lung cancer in men in the highest quartile of IGFBP-3 relative to those in the lowest quartile, adjusted for smoking and IGF-I, was 0.41 (95% CI = 0.18 to 0.92).
In this prospective study of Chinese men, higher serum levels of IGF-I did not increase the risk of lung cancer. However, subjects with higher serum levels of IGFBP-3 were at reduced risk of lung cancer. This finding is consistent with experimental data that indicate that IGFBP-3 can inhibit cellular proliferation and induce apoptosis independent of IGF-I and the IGF-I receptor.
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ABSTRACT: Recent studies have identified a negative correlation between serum levels of insulin-like growth factor binding protein-3 (IGFBP-3) and the risk of lung cancer. In this study, polymorphisms present at the -1590 site of the IGFBP-3 promoter were evaluated in relation to lung cancer risk in a Chinese Han population. A total of 248 nonsmall cell lung cancer (NSCLC) cases and 29 small cell lung cancer cases were compared with 252 matched, healthy controls. Polymerase chain reaction-based restriction fragment length polymorphism assays were used to detect polymorphisms present. The A/A genotype and an A allele were both associated with an increased risk of NSCLC after being adjusted for age and gender (adjusted odds ratio = 2.296, 95% confidence interval = 1.133-4.655; and adjusted odds ratio = 1.390, 95% confidence interval = 1.042-1.854, respectively). In conclusion, the A/A genotype and A allele of the IGFBP-3 promoter -1590 site may represent a genetic risk factor for NSCLC, with the A/A genotype being associated with a higher risk for squamous cell carcinoma than adenocarcinoma.Genetic Testing and Molecular Biomarkers 05/2011; 15(5):301-6. DOI:10.1089/gtmb.2010.0176 · 1.15 Impact Factor
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ABSTRACT: Lung cancer leads all other cancers in both incidence and mortality. Recent advances in underlying molecular pathogenesis have validated a panel of protein tyrosine kinases as new targets in lung cancer treatment. Insulin-like growth factor-1 receptor (IGF-1R) is an important tyrosine kinase receptor involved in cell proliferation, differentiation, metabolism, apoptosis, and angiogenesis. Aberrant activation of IGF-1R is frequently found in patients with lung cancer and contributes to malignant transformation and poor prognosis for patients with lung cancer. In this review, we focused on recent progress in the research of IGF-1R's role in lung cancer development and progression, including its structure and biological function, potential mechanisms of aberrant activation, and related oncogenic effects. We also discussed effective IGF-1R antagonists that are currently registered for clinic trials or are undergoing preclinical study with special emphasis on their antibodies and small molecule tyrosine kinase inhibitors.American Journal of Translational Research 01/2009; 1(2):101-14. · 3.23 Impact Factor
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ABSTRACT: The IGF system performs a fundamental role in the regulation of cellular proliferation, differentiation and apoptosis. These diverse biological actions are mediated primarily by IGF association with the type I IGF receptor (IGF-IR), which is in turn regulated by a group of high-affinity IGF-binding proteins (IGFBP-1 to -6). All of the IGFBPs can have growth-inhibitory effects by competitively binding IGFs and preventing their association with the IGF-IR. IGFBP-3 is the most abundant binding protein in the circulation and controls the actions of the IGFs by regulating their distribution and bioavailability to target tissues. Disruptions in the balance of IGF system components leading to excessive proliferation and survival signals have been implicated in the development of different tumor types. Epidemiological evidence indicates that increased levels of IGF-I, reduced levels of IGFBP-3 or an increased ratio of IGF-I to IGFBP-3 in the circulation are associated with an increased risk for the development of several common cancers, including those of the breast, prostate, lung and colon. The results of preclinical studies indicate that a diversity of interventions which antagonize IGF-IR signaling or augment IGFBP-3 function inhibit tumor cell growth in models of human cancers. A more comprehensive understanding of the interplay between cellular targets of the IGF system and antineoplastic agents will facilitate the development of novel strategies for the prevention and treatment of cancer.Endocrine Related Cancer 01/2004; 10(4):561-78. · 4.91 Impact Factor