Urologic Oncology: Seminars and Original Investigations
Original articleMicro-RNA profiling in kidney and bladder cancers☆
Introduction
Kidney cancer accounts for 3% of adult malignancies [1]. It represents a nonhomogeneous entity, although between 80% and 95% of the malignancies of the adult kidney can be classified as clear-cell or papillary renal cell carcinomas (RCCs). The histopathology of these tumors has been correlated with distinctively different genetic changes, indicating that unrelated molecular mechanisms underlie the development of each type of tumor [2].
Urothelial carcinoma, previously designated as transitional cell carcinoma (TCC), is the second most common malignancy of the genitourinary tract [1]. No specific and exclusive cytogenetic aberration has been identified for urothelial carcinoma, but various nonrandom deletions, gain of chromosomes, polyploidization, and formation of isochromosomes have been observed [3].
Micro-RNAs are an abundant class of small noncoding RNAs of about 22 nucleotides in length, which function as negative regulators (cleavage or translational repression) of gene expression by antisense complimentarily to specific messenger RNAs [4], [5]. Increasing evidence shows that expression of micro-RNA genes are deregulated in human cancer [5], [6]. Micro-RNA genes show high-frequency genomic alterations in tumors [7], and a high proportion of known micro-RNAs are located at fragile sites or in cancer-associated genomic regions, including minimal regions of loss of heterozygosity, minimal amplicons, or breakpoint cluster regions [6].
Specific overexpression or underexpression has been correlated with particular tumor types [8], [9], [10], [11]. Micro-RNA overexpression could also result in down-regulation of tumor suppressor genes, whereas their underexpression could lead to oncogene up-regulation [5], [6]. This permits micro-RNAs to act both as tumor suppressors and oncogenes [12], [13]. Most importantly, micro-RNA expression signatures have been described to predict the outcome in several tumors, including lung cancer and chronic lymphocytic leukemia [14], [15], [16], and it may also predict response to chemotherapy [17]. Micro-RNAs might prove to be new therapeutic targets for a wide range of diseases, including cancer [13].
In this study, we analyzed the micro-RNA expression profiles in human bladder and kidney cancer, and detected that different micro-RNAs are involved in these 2 common malignancies that appear so different in their molecular biology and clinical behavior. We further evaluated micro-RNA expression pattern across different tumor stages to determine if different micro-RNAs could be implicated in tumor progression. Our results confirm that micro-RNA expression profiles could be used in the future together with other biomolecular markers to classify, diagnose, and predict the behavior of human bladder and renal cancers.
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Patients
Normal and pathologically diagnosed biopsy specimens were obtained from patients with kidney masses who underwent partial or radical nephrectomy and patients with bladder tumors who underwent radical cystectomy or endoscopic resection for primary or recurrent TCC. Tissue samples from bladder and kidney specimens were collected between 1998 and 2000 at Department of Urology at Thomas Jefferson University, with informed consent and approval by the internal review board.
Pathologic studies
A total of 27 kidney (RCC =
Results
We compared RCC to normal kidney micro-RNA expression profiles and identified 4 human micro-RNAs (miR-28, miR-185, miR-7-2, and let-7f-2) that significantly up-regulated in RCC (1.2-fold change cutoff; P < 0.05) (Fig. 1A;Table 1). The analysis of 4 benign kidney tumors (oncocytomas = 2 and angiomyolipomas = 2) showed a pattern of micro-RNA expression more similar to the normal parenchyma (data not shown).
Categorizing RCC samples according to the TNM stage included the following subgroups: T1 (n
Discussion
The recent discovery of micro-RNAs has resulted in a better comprehension of organism development and differentiation. Growing evidence suggests that expression of micro-RNA genes is deregulated in human cancer, and several studies pointed out the existence of a functional micro-RNA network that interacts with well-recognized oncogenes-oncosuppressors players [5], [6], [12].
In this study, we analyzed micro-RNA expression patterns in bladder and kidney cancers, 2 common malignancies of the
Conclusions
Our report identifies for the first time the possible role of micro-RNAs in bladder and kidney cancer development and progression. Further studies of in vitro and in vivo models are necessary to elucidate micro-RNAs’ targets and role in these malignancies. A larger series of human kidney and bladder cancers will need to be studies to define if micro-RNAs represent a clinically useful tool in the classification, diagnosis, and prognosis of human bladder and renal cancers.
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This work was supported by a grant from the Commonwealth of Pennsylvania Project IV Aerodigestive and Bladder Cancer Commonwealth Universal Research Enhancement (CURE), the Benjamin Perkins Bladder Cancer Fund, and the Martin Greitzer Fund.