title: Clinical significance of insulin receptor substrate-I down-regulation in non-small cell lung cancer.
abstract: Insulin receptor substrate-1 (IRS-1) is an adaptor protein for insulin-like growth factor (IGF) signaling and it is presumed associated with cancer development, progression or clinical outcome of patients harboring solid tumors. Therefore, we investigated by immunohistochemistry, the expression of IRS-1 in the tumor tissues from 94 patients who were diagnosed as stage I non-small cell lung cancer (NSCLC) and had undergone a curative lung resection. The relationships between its intratumoral expression and various clinical parameters were explored. IRS-1 is consistently expressed in the cytoplasm of intrapulmonary bronchial and bronchiolar epithelial cells comprising normal appearing adjacent lung tissues. Forty-one (43.6%) of 94 specimens showed loss of IRS-1 expression. In a subset analysis, IRS-1 was more frequently lost in stage IB than in IA tumors (50.0 vs. 22.7%, p=0.024, chi(2) test), which was reflected by the facts that tumors which showed down-regulation of IRS-1 had larger area than those with IRS-1 expression (18.1 vs. 12.1 cm(2), p=0.044, t-test). Down-regulation of IRS-1 is more frequently observed in squamous cell carcinoma than other cell type lung cancer (p=0.002, chi(2) test) and its expression was not affected by histological grade of differentiation. Comparing pack-years (P.Y.) between groups of smokers whose tumor expressed IRS-1 and those that did not, smokers whose tumor showed loss of IRS-1 expression had higher P.Y. than those whose tumor did express IRS-1 (39.2+/-23.67 vs. 25.6+/-26.61 P.Y., p=0.034, t-test). Intratumoral expression of IRS-1 did not influence disease-free survival, disease-specific survival or overall survival of stage I NSCLC patients, whose median follow-up duration is 7.5 years (95% CI; 7.21-7.86 years). These results suggest that loss of IRS-1 might rather be an early event in NSCLC development than a prognostic factor and that it is more strongly related with squamous cell carcinoma and with smoking.
authors.affiliation: Department of Internal Medicine, National Health Insurance Corporation Ilsan Hospital, Koyang, Korea.
authors.forename: Chang Hoon
authors.initials: CH
authors.lastname: Han
authors.forename: Jae Yong
authors.initials: JY
authors.lastname: Cho
authors.forename: Jong Tae
authors.initials: JT
authors.lastname: Moon
authors.forename: Hyung Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Se Kyu
authors.initials: SK
authors.lastname: Kim
authors.forename: Dong Hwan
authors.initials: DH
authors.lastname: Shin
authors.forename: Joon
authors.initials: J
authors.lastname: Chang
authors.forename: Chul Min
authors.initials: CM
authors.lastname: Ahn
authors.forename: Sung Kyu
authors.initials: SK
authors.lastname: Kim
authors.forename: Yoon Soo
authors.initials: YS
authors.lastname: Chang
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D055504:Insulin Receptor Substrate Proteins; D008175:Lung Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010750:Phosphoproteins / Q000096:biosynthesis*; D011379:Prognosis; D012907:Smoking; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins