Journal
PLOS BIOLOGY
Volume 16, Issue 1, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pbio.2003714
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Funding
- Ministry of Health and Welfare, Taiwan (Advance Medical Plan) [106-0324-01-10-07]
- Ministry of Science and Technology, Taiwan [105-2319-B-400-001]
- National Health Research Institutes, Taiwan [MG-105-PP-06]
- Ministry of Science and Technology, ROC [105-2314-B-400-031-MY2, 102-2311-B-007-008-MY3]
- Veterans General Hospitals University System of Taiwan [VGHUST 104-G6-1-1]
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Altered metabolism is one of the hallmarks of cancers. Deregulation of ribose-5-phosphate isomerase A (RPIA) in the pentose phosphate pathway (PPP) is known to promote tumorigenesis in liver, lung, and breast tissues. Yet, the molecular mechanism of RPIA-mediated colorectal cancer (CRC) is unknown. Our study demonstrates a noncanonical function of RPIA in CRC. Data from the mRNAs of 80 patients' CRC tissues and paired nontumor tissues and protein levels, as well as a CRC tissue array, indicate RPIA is significantly elevated in CRC. RPIA modulates cell proliferation and oncogenicity via activation of beta-catenin in colon cancer cell lines. Unlike its role in PPP in which RPIA functions within the cytosol, RPIA enters the nucleus to form a complex with the adenomatous polyposis coli (APC) and beta-catenin. This association protects beta-catenin by preventing its phosphorylation, ubiquitination, and subsequent degradation. The C-terminus of RPIA (amino acids 290 to 311), a region distinct from its enzymatic domain, is necessary for RPIA-mediated tumorigenesis. Consistent with results in vitro, RPIA increases the expression of beta-catenin and its target genes, and induces tumorigenesis in gut-specific promotor-carrying RPIA transgenic zebrafish. Together, we demonstrate a novel function of RPIA in CRC formation in which RPIA enters the nucleus and stabilizes beta-catenin activity and suggests that RPIA might be a biomarker for targeted therapy and prognosis.
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