ALTERNATIVE SPLICING OF CD44 PRE-MESSENGER-RNA IN HUMAN COLORECTAL TUMORS

Expression of the CD44 molecule has been linked to tumor growth and me tastases in both human and rodent cancers. Alternatively spliced varia nts expressed in rat and mouse tumors have been shown to confer metast atic potential to non-metastatic carcinoma cell lines, and human homol ogues of rat variant mRNA sequences are expressed in human tumors. In the present study matched sets of RNA from adenocarcinomas of the colo n and distant normal mucosa were assayed for CD44 expression by quanti tative RT-PCR. Retrospective analysis revealed that colonic tumor cell s had both quantitative and qualitative differences in CD44 expression when compared to normal mucosa. These were: 1) an increase in levels of CD44 transcripts, 2) an increase in levels of alternatively spliced transcripts, 3) the presence of larger alternatively spliced transcri pts with inserts >400 bases and 4) the primary alternatively spliced C D44 isoform in colonic adenocarcinomas in all cases is CD44R. Interest ingly, two patterns of CD44 isoform expression termed ''variant domina nt'' or ''balanced'' patterns of expression, based on the ratio of var iant to standard CD44 transcripts (R+V's/H),could be differentiated. A n unfavorable prognosis was suggested for tumors expressing increased levels of CD44 variant exons previously associated with tumor metastas is. Specifically, patients with tumors expressing the ''variant domina nt'' pattern of expression irregardless of Dukes classification and Du kes C and D staged tumors of both patterns exhibited a poorer prognosi s. (C) 1994 Academic Press, Inc.