title: Inverse relationship between insulin receptor expression and progression in renal cell carcinoma.
abstract: We investigated the relationship among serum insulin level, insulin receptor (IR) expression in renal cell carcinoma (RCC), and outcomes in patients with RCC who underwent nephrectomy. We also explored the role of insulin signaling in RCC progression in a murine RCC allograft RENCA model using metformin to treat hyperinsulinemia induced by a high-carbohydrate diet. Clinically, the IR expression level in RCC tissue was significantly lower in patients with tumor stage pT2-4 and/or distant metastases. The IR expression level in RCC tissue was significantly lower in patients with preoperative serum C-peptide levels greater than or equal to the median than in patients with levels less than the median. High IR expression level was significantly associated with better disease-free and overall survival after nephrectomy. The IR expression level was significantly higher in murine subcutaneous flank tumors of the low-carbohydrate diet group and high-carbohydrate diet plus metformin group than of the high‑carbohydrate diet group. In vivo progression of murine tumors was not significantly enhanced by hyperinsulinemia induced by a high-carbohydrate diet and was significantly inhibited by metformin in both the low- and high‑carbohydrate diet groups. IR expression in RCC tissue was inversely associated with cancer progression in the clinical and murine experimental model studies. The clinical and murine allograft model study results suggested that hyperinsulinemia does not promote RCC progression. Decreased IR expression in high‑stage RCC tumors with poor prognosis may be the result of downregulation induced by the host's hyperinsulinemia.
authors.affiliation: Department of Urology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Department of Urology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Urology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Mingguo
authors.initials: M
authors.lastname: Huang
authors.affiliation: Department of Urology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Numakura
authors.affiliation: Department of Urology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tsuruta
authors.affiliation: Department of Urology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Saito
authors.affiliation: Department of Urology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Maeno
authors.affiliation: Laboratory for Malignancy Control Research, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Eijiro
authors.initials: E
authors.lastname: Nakamura
authors.affiliation: Department of Urology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Narita
authors.affiliation: Department of Urology, Yamagata University Faculty of Medicine, Yamagata, Japan.
authors.forename: Norihiko
authors.initials: N
authors.lastname: Tsuchiya
authors.affiliation: Department of Urology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Habuchi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism / Q000601:surgery*; D000070601:Diet, Carbohydrate Loading / Q000009:adverse effects*; D018450:Disease Progression; D005260:Female; D006801:Humans; D006946:Hyperinsulinism / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D007328:Insulin / Q000097:blood*; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000601:surgery*; D008297:Male; D008687:Metformin / Q000008:administration & dosage* / Q000627:therapeutic use; D051379:Mice; D008875:Middle Aged; D009368:Neoplasm Transplantation; D011972:Receptor, Insulin / Q000378:metabolism*; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D015703:Antigens, CD; D007328:Insulin; D008687:Metformin; C435941:INSR protein, human; D011972:Receptor, Insulin