PD33-04 INVERSE RELATIONSHIP BETWEEN INSULIN RECEPTOR EXPRESSION AND CANCER PROGRESSION IN RENAL CELL CARCINOMA: CLINICAL AND EXPERIMENTAL EVALUATION

Abstract

You have accessJournal of UrologyKidney Cancer: Basic Research III1 Apr 2015PD33-04 INVERSE RELATIONSHIP BETWEEN INSULIN RECEPTOR EXPRESSION AND CANCER PROGRESSION IN RENAL CELL CARCINOMA: CLINICAL AND EXPERIMENTAL EVALUATION Makoto Takahashi, Takamitsu Inoue, Mingguo Huang, Hiroshi Tsuruta, Mitsuru Saito, Shintaro Narita, Norihiko Tsuchiya, and Tomonori Habuchi Makoto TakahashiMakoto Takahashi More articles by this author , Takamitsu InoueTakamitsu Inoue More articles by this author , Mingguo HuangMingguo Huang More articles by this author , Hiroshi TsurutaHiroshi Tsuruta More articles by this author , Mitsuru SaitoMitsuru Saito More articles by this author , Shintaro NaritaShintaro Narita More articles by this author , Norihiko TsuchiyaNorihiko Tsuchiya More articles by this author , and Tomonori HabuchiTomonori Habuchi More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.2102AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Insulin is not only a key regulator in the glucose metabolism pathway but also a strong growth factor in cell proliferation pathways. It has been reported that obesity increases the risk of renal cell carcinoma (RCC). However, epidemiological studies have suggested that obese patients with RCC have better prognosis. We investigated the relationship between insulin receptor (IR) expression and outcomes in patients who underwent radical nephrectomy for RCC and explored the role of insulin signaling in the progression of a murine RCC model using metformin to treat hyperinsulinemia induced by a high-carbohydrate diet. METHODS pT1-T4 tumor specimens from 99 patients with RCC were evaluated for IR expression by immunohistochemistry. Serum insulin and C-peptide levels were measured. The association between biomarker expression and serum concentration, prognostic factors, and clinical outcomes were assessed. C57BL/6 mice were randomized into four groups: low-carbohydrate diet, high-carbohydrate diet, low-carbohydrate diet + metformin, and high-carbohydrate diet + metformin groups. RENCA cells were injected subcutaneously. Body weight, glucose tolerance test, serum insulin level, and tumor volume were evaluated. Immunoblotting was performed to assess the insulin signaling pathway in the murine RCC model. RESULTS The IR expression level was significantly lower in patients with tumor stage pT2-4 and with a preoperative serum C-peptide level more than 5.14 ng/mL. High IR expression was an independent predictor of favorable progression-free survival after radical nephrectomy. In vivo progression of RENCA in the murine model was not significantly stimulated by hyperinsulinemia induced by a high-carbohydrate diet. However, in vivo progression of RENCA was significantly inhibited by metformin in both the low- and high-carbohydrate diet groups. IR expression was significantly higher in the tumors from the low-carbohydrate diet group and high-carbohydrate diet plus metformin group than that from the high-carbohydrate diet group. CONCLUSIONS IR expression in RCC was inversely associated with cancer progression and serum insulin levels in both clinical and murine models. The anticancer effect of metformin in the murine RCC model might be derived from the direct effect of the agent on cancer cells rather than the effect of the lower insulin level. The lower expression of IR in the tumor from patients with a poor outcome might be the result of a higher serum insulin level, which is not strong cause of cancer progression. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e710-e711 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Makoto Takahashi More articles by this author Takamitsu Inoue More articles by this author Mingguo Huang More articles by this author Hiroshi Tsuruta More articles by this author Mitsuru Saito More articles by this author Shintaro Narita More articles by this author Norihiko Tsuchiya More articles by this author Tomonori Habuchi More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...