Original article
Micro-RNA profiling in kidney and bladder cancers

https://doi.org/10.1016/j.urolonc.2007.01.019Get rights and content

Abstract

Objectives

Micro-RNAs are a group of small noncoding RNAs with modulator activity of gene expression. Recently, micro-RNA genes were found abnormally expressed in several types of cancers. To study the role of the micro-RNAs in human kidney and bladder cancer, we analyzed the expression profile of 245 micro-RNAs in kidney and bladder primary tumors.

Methods and materials

A total of 27 kidney specimens (20 carcinomas, 4 benign renal tumors, and 3 normal parenchyma) and 27 bladder specimens (25 urothelial carcinomas and 2 normal mucosa) were included in the study. Total RNA was used for hybridization on an oligonucleotide microchip for micro-RNA profiling developed in our laboratories. This microchip contains 368 probes in triplicate, corresponding to 245 human and mouse micro-RNA genes.

Results

A set of 4 human micro-RNAs (miR-28, miR-185, miR-27, and let-7f-2) were found significantly up-regulated in renal cell carcinoma (P < 0.05) compared to normal kidney. Human micro-RNAs miR-223, miR-26b, miR-221, miR-103-1, miR-185, miR-23b, miR-203, miR-17-5p, miR-23a, and miR-205 were significantly up-regulated in bladder cancers (P < 0.05) compared to normal bladder mucosa. Of the kidney cancers studied, there was no differential micro-RNA expression across various stages, whereas with increasing tumor-nodes-metastasis staging in bladder cancer, miR-26b showed a moderate decreasing trend (P = 0.082).

Conclusions

Our results show that different micro-RNAs are deregulated in kidney and bladder cancer, suggesting the involvement of these genes in the development and progression of these malignancies. Further studies are needed to clarify the role of micro-RNAs in neoplastic transformation and to test the potential clinical usefulness of micro-RNAs microarrays as diagnostic and prognostic tool.

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.

Section snippets

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.

References (31)

  • G. Kovacs

    Molecular differential pathology of renal cell tumours

    Histopathology

    (1993)
  • R. Baffa et al.

    Molecular genetics of bladder cancer: Targets for diagnosis and therapy

    J Exp Clin Cancer Res

    (2006)
  • G.A. Calin et al.

    Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers

    Proc Natl Acad Sci USA

    (2004)
  • L. Zhang et al.

    microRNAs exhibit high frequency genomic alterations in human cancer

    Proc Natl Acad Sci USA

    (2006)
  • G.A. Calin et al.

    MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias

    Proc Natl Acad Sci USA

    (2004)
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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.

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