Loss of function of the candidate tumor suppressor prox1 by RNA mutation in human cancer cells

Meiko Takahashi, Takanobu Yoshimoto, Masayuki Shimoda, Tomoya Kono, Masayuki Koizumi, Shujiro Yazumi, Yutaka Shimada, Ryuichiro Doi, Tsutomu Chiba, Hajime Kubo

    Research output: Contribution to journalArticle

    40 Scopus citations

    Abstract

    The importance of genetic mutations in carcinogenesis has been recognized, and it has been proposed that aberrant mutation of mRNA may represent a novel oncogenic principle. Here we report that the mRNA of a homeobox gene prox1, a candidate tumor suppressor, suffers adenosine-to-inosine nucleotide conversion and loses tumor-suppressive functions in a subset of human cancers. Expression of Prox1 was reduced in pancreatic cancers, and the extent of reduction correlated with progression of tumor differentiation. A-to-G base change was found in prox1 cDNA taken from human cancer cells, but not in corresponding genomic DNA. We mapped four common mutation sites in prox1 gene, and the same four sites were mutated in human clinical samples from several cancers. Tetracycline-induced wild-type (wt) Prox1 in tumor cells inhibited transforming activity and cellular proliferation. However, mutant Prox1 with the four common sites altered from A to G lost these inhibitory functions. In mice, xenografts of tumor cells with tetracycline-induced wt-Prox1 formed tumor masses significantly more slowly than control tumors, whereas mutated Prox1 had no effect. These findings may point to a pivotal role of the RNA mutation of prox1 gene in the pathogenesis of human cancer progression.

    Original languageEnglish (US)
    Pages (from-to)1003-1010
    Number of pages8
    JournalNeoplasia
    Volume8
    Issue number12
    DOIs
    StatePublished - Dec 2006

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    Keywords

    • Asymmetrical cell division
    • Cancer
    • Prox1
    • RNA mutation
    • Tumor-suppressor gene

    ASJC Scopus subject areas

    • Cancer Research

    Cite this

    Takahashi, M., Yoshimoto, T., Shimoda, M., Kono, T., Koizumi, M., Yazumi, S., Shimada, Y., Doi, R., Chiba, T., & Kubo, H. (2006). Loss of function of the candidate tumor suppressor prox1 by RNA mutation in human cancer cells. Neoplasia, 8(12), 1003-1010. https://doi.org/10.1593/neo.06595