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Inverse relationship between insulin receptor expression and progression in renal cell carcinoma
Makoto Takahashi1, Takamitsu Inoue1, Mingguo Huang1
1Department of Urology, Akita University Graduate School of Medicine, Akita, Japan.
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.
Insights
In renal cell carcinoma (RCC), lower insulin receptor (IR) expression correlates with advanced cancer and poorer survival. Hyperinsulinemia did not promote RCC progression in mice, suggesting IR downregulation may be a host response.
Area of Science:
- Oncology
- Endocrinology
- Molecular Biology
Background:
- Insulin signaling plays a role in various cancers.
- The relationship between insulin levels, insulin receptor (IR) expression, and renal cell carcinoma (RCC) outcomes requires further elucidation.
- Hyperinsulinemia is increasingly prevalent and may influence cancer development and progression.
Purpose of the Study:
- To investigate the association between serum insulin levels, IR expression in RCC tissues, and patient outcomes.
- To explore the role of insulin signaling in RCC progression using a murine allograft model.
- To evaluate the effect of metformin on hyperinsulinemia-induced changes in RCC progression.
Main Methods:
- Analysis of IR expression in RCC tissues from patients undergoing nephrectomy.
- Correlation of IR expression with tumor stage, metastasis, and preoperative serum C-peptide levels.
- Assessment of disease-free and overall survival in relation to IR expression.
- Utilizing a murine RCC allograft model (RENCA) with varying dietary interventions (low-carbohydrate, high-carbohydrate) and metformin treatment.
- Evaluating tumor progression and IR expression in murine models.
Main Results:
- Lower IR expression in RCC tissues was observed in patients with advanced tumor stage (pT2-4) and/or distant metastases.
- Patients with higher preoperative serum C-peptide levels exhibited significantly lower IR expression in RCC tissues.
- High IR expression was significantly associated with improved disease-free and overall survival post-nephrectomy.
- In the murine model, hyperinsulinemia induced by a high-carbohydrate diet did not significantly enhance tumor progression.
- Metformin treatment inhibited tumor progression in both low- and high-carbohydrate diet groups and increased IR expression in tumors.
Conclusions:
- IR expression in RCC tissue is inversely associated with cancer progression.
- Hyperinsulinemia does not appear to promote RCC progression.
- Decreased IR expression in high-stage RCC may result from host hyperinsulinemia-induced downregulation.
- Targeting insulin signaling pathways, potentially with metformin, may offer therapeutic strategies for RCC.