
MOLECULAR CHARACTERIZATION OF MICRORNA
INTERFERENCE AND ARISTOLOCHIC ACID
INTOXICATION FOUND IN UPPER TRACT UROTHELIAL
CARCINOMA IN PATIENTS WITH BALKAN ENDEMIC
NEPHROPATHY: A SYSTEMATIC REVIEW
OF THE CURRENT LITERATURE Bašić D1*, Ignjatović I1, Janković Veličković Lj2, Veljković A3 *Corresponding Author: *Corresponding Authors: Dragoslav Bašić, Urology Clinic, University Clinical Center Niš, Faculty of
Medicine, University of Niš, Niš, Serbia, Puškinova 2, 18000 Niš, Serbia, Email: basicdr@gmail.com page: 8 download article in pdf format
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Abstract
The term “aristolochic acid nephropathy” (AAN) is
used to include any form of toxic interstitial nephropathy
that is caused either by ingestion of plants containing aristolochic
acids (AA) or by the environmental contaminants
in food such as in Balkan endemic nephropathy (BEN).
Aristolochic acid (AA) intoxication is strongly associated
with the development of upper tract urothelial carcinoma
(UTUC); however, the underlying molecular mechanism
remains to be defined. MicroRNAs (miRNA) regulate
several biological processes, including cell proliferation,
differentiation, and metabolism, acting as oncogenes or
tumor suppressors. A unique miRNA expression profile
suggested that miRNAs could function as regulators in
UTUC developmental processes.
This review aimed to summarize data available in the
literature about underlying molecular mechanisms leading
to the expression of miRNAs in AA-UTUC patients with
BEN. Strong correlation in AA-UTUC has a distinctive
gene alteration pattern, AL-DNA adducts, and a unique
tumor protein (TP53) mutational spectrum AAG to TAG
(A: T→T: A) transversion in codon 139 (Lys → Stop) of
exon 5 activates the p53 tumor suppressor protein. Further,
p53 protein is responsible not only for the expression of
miRNAs but also acts as a target molecule for miRNAs and
plays a crucial function in the AA-UTUC pathogenicity
through activation of cyclin-dependent kinase (CyclinD1)
and cyclin protein kinase 6(CDK6) to support cell cycle
arrest. This study, proposed a molecular mechanism that
represented a possible unique relationship between AA
intoxication, miRNAs expression, and the progression of
UTUC in patients with BEN.
Key words: aristolochic acids; Balkan endemic nephropathy;
microRNA, upper tract urothelial carcinoma
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