Complex alternative splicing of the hKLK3 gene coding for the tumor marker PSA (prostate-specific-antigen)

PSA (prostate-specific antigen), the most useful serum marker for prostate cancer, is encoded by the hKLK3 gene and is present in the serum as a mixture of several molecular species. This work was performed to identify the hKLK3 transcripts in order to determine how many proteins resembling PSA are synthesized from the hKLK3 gene and secreted in blood. Combined Northern blotting, molecular cloning and database searching showed that the hKLK3 gene produces at least 15 transcripts ranging in size from 0.7 to 6.1 kb. Polysomal distribution analysis revealed that the transcripts shorter than 3.1 kb are efficiently translated in prostate cell line. A total of 12 hKLK3 transcripts have been completely or partially cloned. They result from alternative splicing or/and alternative polyadenylation involving complex regulation. They code for eight proteins: PSA, a truncated form of PSA (PSA-Tr), five PSA variants (PSA-RPs) and one protein (PSA-LM) unrelated to PSA. Using a specific antibody, we detected the PSA-RP2 variant in prostate tissue. All the variants share the same signal peptide and could contribute to the diversity of hKLK3 proteins in prostate fluid and blood.