title: Identification of an alternatively spliced isoform of carbonic anhydrase XII in diffusely infiltrating astrocytic gliomas.
abstract: Carbonic anhydrase XII (CA XII) is a transmembrane enzyme that is associated with neoplastic growth. CA XII has been proposed to be involved in acidification of the extracellular milieu, creating an appropriate microenvironment for rapid tumor growth. Because RNA sequence databases have indicated that two isoforms of CA XII might exist in human tissues, and because alternatively spliced protein forms have been linked to aggressive behavior of cancer cells, we designed a study to evaluate the presence of the two forms of CA XII in diffuse astrocytomas, a tumor type known for its aggressive and often noncurable behavior. Reverse transcription PCR of tumor samples surprisingly revealed that CA XII present in diffuse astrocytomas is mainly encoded by a shorter mRNA variant. We further showed by Western blotting that anti-CA XII antibody recognized both isoforms in the glioblastoma cell lines, and we then evaluated the expression of CA XII in astrocytomas using immunohistochemistry and correlated the results with various clinicopathological and molecular factors. Of 370 diffusely infiltrating astrocytomas, 363 cases (98%) showed immunoreactions for CA XII. Importantly, CA XII expression correlated with poorer patient prognosis in univariate (p = 0.010, log-rank test) and multivariate survival analyses (p = 0.039, Cox analysis). From these results, we conclude that CA XII is commonly expressed in diffuse astrocytomas and that it might be used as a biomarker of poor prognosis. The absence of 11 amino acids in the shorter isoform, which seems to be common in astrocytomas, may affect the normal quaternary structure and biological function of CA XII.
authors.affiliation: Institute of Medical Technology, University of Tampere, Biokatu 6, FI-33520 Tampere, Finland.
authors.forename: Joonas
authors.initials: J
authors.lastname: Haapasalo
authors.forename: Mika
authors.initials: M
authors.lastname: Hilvo
authors.forename: Kristiina
authors.initials: K
authors.lastname: Nordfors
authors.forename: Hannu
authors.initials: H
authors.lastname: Haapasalo
authors.forename: Seppo
authors.initials: S
authors.lastname: Parkkila
authors.forename: Alise
authors.initials: A
authors.lastname: Hyrskyluoto
authors.forename: Immo
authors.initials: I
authors.lastname: Rantala
authors.forename: Abdul
authors.initials: A
authors.lastname: Waheed
authors.forename: William S
authors.initials: WS
authors.lastname: Sly
authors.forename: Silvia
authors.initials: S
authors.lastname: Pastorekova
authors.forename: Jaromir
authors.initials: J
authors.lastname: Pastorek
authors.forename: Anna-Kaisa
authors.initials: AK
authors.lastname: Parkkila
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D001254:Astrocytoma / Q000201:enzymology*; D014408:Biomarkers, Tumor / Q000032:analysis*; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000201:enzymology*; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D008969:Molecular Sequence Data; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D014408:Biomarkers, Tumor; D007527:Isoenzymes; C483903:CA13 protein, human; D002256:Carbonic Anhydrases