Investigation of the early-response genes in chemical-induced renal carcinogenicity for the prediction of chemical carcinogenicity in rats

Abstract

-This study was designed to identify early-response genes of chemical-induced renal carcinogenicity for the prediction of chemical carcinogenicity in rats. We conducted a 28-day repeated-dose test in male Crl:CD (SD) rats with 12 carcinogens and 10 non-carcinogens as the training dataset, and five carcinogens and five non-carcinogens as the validation dataset. Renal gene expression profiles were analyzed by using a microarray. Fifteen candidate genes were selected from the gene expression profiles of the training dataset as genes that showed specific expression in response to carcinogens. To assess the prediction performance of the candidate genes for renal carcinogenicity, a prediction formula was developed on the basis of the gene expression data. When this formula was applied to the training dataset to check its predictive performance, all of the carcinogens and non-carcinogens were predicted correctly; the prediction formula was then applied to the validation dataset, and five carcinogens and four non-carcinogens were correctly predicted. However, 4-Hydroxy-m-phenylenediammonium dichloride (AMIDOL), a known non-renal carcinogen, was judged as positive. Therefore, the accuracy of the prediction formula for renal carcinogenicity was 100% for the training dataset and 90% for the validation dataset. Among the predictive genes, Hamp and Ranbp1 are known to be important for cell growth and cell cycle regulation, which are important events in carcinogenesis. Given our current limited knowledge of the genes responsible for renal carcinogenesis, the identification of candidate genes of chemical-induced renal carcinogenicity by use of this gene expression-based prediction method represents a promising advance in renal carcinogen identification.

Key sunitinib‐related biomarkers for renal cell carcinoma

“…But unfortunately, there were not any laboratory experiments evidence conducted in RCC. HAMP is famous for the maintenance of iron homeostasis 57,58 and the regulation of cell growth and cycle 59 . Studies have showed iron metabolism was correlated with inflammation 60 and malignant tumor, such as multiple myeloma, 61 hepatocellular carcinoma, 62 and renal carcinoma 63 .…”

“…Moreover, conventional dendritic cells can secrete hepcidin, the product of HAMP, which is noticeable in the inflamed intestine of humans. HAMP has been uncovered to be associated with the prognosis of urothelial carcinoma of the upper urinary tract and RCC 64 and to contribute to the early stage of carcinogenesis 59 . HAMP has a strong correlation with immune and carcinoma.…”

Mechanism-Based Evaluation System for Hepato- and Nephrotoxicity or Carcinogenicity Using Omics Technology

“…A total of 100 chemicals, consisting of 68 chemicals used in prediction systems examining hepatic carcinogenicity and 32 chemicals commonly used in prediction systems examining renal carcinogenicity and detection systems for hepatotoxicity and nephrotoxicity, were selected from among chemicals used in previous studies [11][12][13]. The number of test compounds used in each experiment is shown in Fig.…”

“…Recently, we reported a renal carcinogenicity prediction system to predict chemical carcinogenicity in rats; a 28-day repeated-dose test was performed using male Crl:CD (SD) rats with 12 carcinogens and 10 non-carcinogens as the training dataset and five carcinogens and five non-carcinogens as the validation dataset [13]. In this prediction system, the prediction accuracies for the training and the validation datasets were calculated to be 100% and 90%, respectively, while 4-hydroxy-m-phenylenediammonium dichloride (AMIDOL), a known non-renal carcinogen, was judged as being positive.…”

“…Among the predictive genes, Hamp and Ranbp1 are known to be important for cell growth and cell cycle regulation, which are important events in carcinogenesis. Given our current limited knowledge of the genes responsible for renal carcinogenesis, the identification of candidate genes for chemical-induced renal carcinogenicity using this gene expression-based prediction method represents a promising advance in renal carcinogen identification [13].…”