engleski

Cancer related genes and their posttranscriptional regulation in aritolochiac acid associated urothelial cancer.

ntroduction and Aims: Upper urinary tract urothelial cancers(UUC) are rare in general population but occur in almost 50% of patients with endemic nephropathy(EN)/aristolochic acid nephropathy (AAN). Aristolochic acid(AA) was proven as the etiological factor both for EN/AAN and UUC. The goal of this study was to identify tumor suppressor genes(TSG) and oncogenes(OG) involved in AA induced carcinogenesis and their posttranscriptional regulation mehanisms by microRNAs. Methods: Paired samples of tumors and adjacent normal urothelial tissues of 13 patients from Croatian and Bosnian endemic regions were analyzed. MiRNA profiling was performed by high- capacity quantitative PCR, while mRNA expression profiling of the same RNAs was done using microarray technology. Immunohistochemistry was performed on tissue microarrays. Results: The broad involvement of known cancer genes in the process of UUC tumorigenesis was revealed by expression profiling analysis of the tumors, implicating on many OG(35 up-regulated ; 54 down- modulated), and TSG(17 up-regulated ; 3 down- modulated). We studied whether the upregulation of specific OG (MYC, FGFR3, HRAS and KRAS) and down regulation of TSG (PTEN and PTCH1) might be augmented in UUC by coordinated action of miRNAs. Figure 1. shows a correlative network implicating numerous down-modulated miRNAregulators of these OG, including tumor suppressor miRNAs miR-23b, miR-143 and miR-145, and also a broad inhibition of PTCH1 by increased oncogenic miRNAs including miR-21, miR-18a and miR-9, and of PTEN by oncogenic miRNAs of the miR- 17-92 family. Both PTEN and PTCH1 appear commonly inhibited by essentially all the members of the miR-200 family. The elevated MYC then represents a central node in these processes, functioning as the activator of miR-17, miR-20 and miR-9 and inhibitor of miR-23b, the repressor of FGFR3 and KRAS, and the tumor- suppressor miRNA let-7c. By means of immunohistochemistry a trend of lower expression of PTEN protein was observed in tumor versus the normal tissue. Conclusions: AAN-associated UTUC carcinogenesis is characterized by a major deregulation of oncogenes and tumor suppressor genes, whose activity may be broadly and modulated by coordinate action of miRNAs.

urothelial cancer ; aristolochiac acid

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