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

Expression of the CD44 molecule has been linked to tumor growth and metastases in both human and rodent cancers. Alternatively spliced variants expressed in rat and mouse tumors have been shown to confer metastatic potential to non-metastatic carcinoma cell lines, and human homologues of rat variant mRNA sequences are expressed in human tumors. In the present study matched sets of RNA from adenocarcinomas of the colon and distant normal mucosa were assayed for CD44 expression by quantitative RT-PCR. Retrospective analysis revealed that colonic tumor cells 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 transcripts with inserts >400 bases and 4) the primary alternatively spliced CD44 isoform in colonic adenocarcinomas in all cases is CD44R. Interestingly, two patterns of CD44 isoform expression termed ''variant dominant'' or ''balanced'' patterns of expression, based on the ratio of variant to standard CD44 transcripts (R+V's/H),could be differentiated. An unfavorable prognosis was suggested for tumors expressing increased levels of CD44 variant exons previously associated with tumor metastasis. Specifically, patients with tumors expressing the ''variant dominant'' pattern of expression irregardless of Dukes classification and Dukes C and D staged tumors of both patterns exhibited a poorer prognosis. (C) 1994 Academic Press, Inc.