Does RNA Editing Play A Role In The Development Of Urinary Bladder Cancer?

Main Category: Urology / Nephrology
Also Included In: Cancer / Oncology;  Genetics
Article Date: 30 Mar 2009 - 4:00 PDT

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UroToday.com - RNA editing is a site-specific modification of one or more molecules in the RNA which results in a difference between the RNA and the sequence of the DNA it is transcribed from. Currently two types of RNA editing are recognized: C-to-U RNA editing and A-to-I RNA editing. Editing is essential to normal life and for the development of both vertebrates and invertebrates.

Altered editing patterns were found in epileptic mice, suicide victims suffering chronic depression, Amyotrophic Lateral Sclerosis, Systemic Lupus Erythematosus, malignant gliomas and certain pigmentation defects in humans.

To date, very few studies explored altered RNA editing in tumoral tissues. Significant under editing in RNA encoding for the beta sub-unit of glutamate receptor (GluB) was demonstrated in malignant glioma cells.

With regard to adenocarcinoma of colon, there is an editing site in RNA encoding for K protein, which plays a part in tumorigenesis.

Editing event in this site results in a single amino acid change (Ala to Thr) hence in the appearance of a new variant K protein seen uniquely in large bowel adenocarcinoma cells but not in normal cells.

In brain tumoral tissue significant global hypoediting of Alu repetitive elements within MED13 transcripts was identified compared to their normal counterparts.

Hypoediting in MED 13 and Breast Cancer 1 (BRCA1) repetitive elements was also identified in prostate, lung, kidney and testis tumors, though that effect was found to be most significant in the brain.

As RNA editing has not been systematically explored with regard to urinary tract malignancies, despite experimental proofs for its existence there, we were aimed to find a potential role of A-to-I RNA editing in the development of urinary bladder malignancies.

Editing sites chosen for analysis represent all known coding regions, where editing has been shown to alter coding sequence (i.e: BLCAP, Cyfip2, FLNA, GluB Q/R) as well as non-coding sequences of transcripts relevant to cancer (i.e.: RBBBP9, CARD11, FANCCN MDM4, BRCA1).

We focused on patients diagnosed as having space-occupying lesion (SOL) in their urinary bladder and as a result were booked for endoscopic trans-urethral resection of their tumor (TUR-T). Informed consent was obtained from each patient for taking tumor sample as well as 1 mm of normal bladder mucosa. Samples were not obtained in case of previous bladder instillations of either Bacillus Calmette Gue'rin (BCG) or Mitomycin C (MMC), in case of previous pelvic/bladder irradiation treatment or in those cases where lesions were smaller than 8 mm, what would have negatively influenced ultimate pathological results.

Overall, 32 patients were recruited to this study: 26 males (81%) and 6 females (19%) at a median age of 69 years (range: 46-90 years).

For analyzing editing levels we used SEQUENOM® MassARRAY Compact Analyzer and MassARRAY Assay Design 2 software. Since we were specifically interested in BLCAP RNA editing changes for its potential role in the development of urinary bladder transitional cell carcinoma, we further explored editing in this site in a different manner and independent of the former method. Comparing RNA editing levels in normal tissue to either tumoral or inflammatory tissue revealed no significant difference. Similar results were obtained using both methods of analysis.

Given the ultimate negative results for nine different editing sites we used an editing site database to further explore editing phenomenon in or around genes specifically known to contribute bladder cancer development, such as: p53, COX2, TGFBR1, FEZ1/LZTS1, p63, H19, BCL2, CDC91L1, c-MET.

Unfortunately, no editing was found in their transcribed mRNA or adjacent Alu repeats, and when there was evidence for editing like in the case of p53 gene, its quantity was too small for further evaluation.

In summary, despite the relatively small sample study, we managed to prove the negative linkage between RNA editing and the development of urinary bladder cancer.

Yet, this epigenetic mechanism may play a role in the development of other genito-urinary tract tumors, such as kidney, testis and prostate and therefore requires further investigation preferably on a larger study group.

Written by Dorit E. Zilberman, MD as part of Beyond the Abstract on UroToday.com

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