Unusual retention of introns in CD44 gene transcripts in bladder cancer provides new diagnostic and clinical oncological opportunities

Abstract

Increased and disorganised expression of CD44 variant exons has been demonstrated in biopsy samples of several types of human malignancy by many groups. This abnormality can be used to detect exfoliated tumour cells in the urine of bladder cancer patients. The present report demonstrates that the deranged activity of this gene in neoplasia also results in the accumulation of immature mRNA transcripts containing non-coding sequences (introns) from this gene in cancer tissues and cells. There is simultaneous overexpression of a newly identified 437 bp exon (coding sequence) located in the variably active region of the gene and of many abnormal variant exon combinations. This is the first report describing the specific retention of introns in gene transcripts in clinical diagnostic samples of tumour tissues and cells. The phenomenon was seen repeatedly in samples from cancer patients and in a cancer cell line, and thus could form the basis for a unique new and specific method of cancer diagnosis.

Expression of CD44 variant exons in acute myeloid leukemia is more common and more complex than that observed in normal blood, bone marrow or CD34+ cells

“…18,[36][37][38] The complex patterns of variant exon expression combined with the detection of retained introns in some malignant tissues raises the possibility that CD44 variant expression in malignant cells indicates a general loss of regulation of the splicing mechanism within these cells. [39][40][41][42] Although not directly tested for, there was no evidence for the presence of retained introns in AML in our study. Aside from the possible biological consequence of CD44 variant expression the complex patterns obtained may prove to be of diagnostic, prognostic or even therapeutic value.…”

Prostate cancer invasion is influenced more by expression of a CD44 isoform including variant 9 than by Muc18

“…5,22 Of 61 patients whose malignancy was missed on cytology (false negative), 11 had it diagnosed by RT-PCR for CD44v8-v10. 21 Overexpression of CD44v8-v10 containing mRNA has been used as a serum, urinary, and tissue marker for bladder cancer 21,22,38 and is an independent prognostic factor for colon cancer. 23 Furthermore, RT-PCR-enzyme linked immunosorbent assay has been used for detection of abnormal and overexpressed CD44 transcripts in colon cancer.…”

Relationship of Cytokeratin 20 and CD44 Protein Expression with WHO/ISUP Grade in pTa and pT1 Papillary Urothelial Neoplasia

“…A selective few include altered oncogene and tumor suppressor genes (9 -11), growth factors and growth factor receptors (12)(13)(14)(15), intermediate filament expression (8), and cell proliferation markers (8,11). Recently, CD44 and cytokeratin 20 (CK20) expression have been studied in bladder carcinoma, and the data suggest that they may be useful in the diagnosis of urothelial carcinoma on the basis of tumor immunoreactivity (IR; 16 -21) or by using reverse transcription-polymerase chain reaction in urine cytology (22)(23)(24). CK20 belongs to the epithelial subgroup of cytoskeleton-associated intermediate filaments (25) and has restricted expression in the gastrointestinal and urinary tracts, in Merkel cells, and in their respective neoplasms (25,26).…”