RPL22L1 induction in colorectal cancer is associated with poor prognosis and 5-FU resistance

• Published in: PloS one Vol. 14; no. 10; p. e0222392
• Main Authors: Rao, Shuyun, Peri, Suraj, Hoffmann, Jens, Cai, Kathy Q, Harris, Bryan, Rhodes, Michele, Connolly, Denise C, Testa, Joseph R, Wiest, David L
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 03-10-2019; Public Library of Science (PLoS)
• Subjects: 5-Fluorouracil; Animal models; Animals; Biology and Life Sciences; Blood; Cancer; Cancer therapies; Care and treatment; Cell Proliferation; Chemotherapy; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Deactivation; Deoxyribonucleic acid; DNA; DNA methylation; DNA Modification Methylases - metabolism; DNA repair; DNA Repair Enzymes - metabolism; Drug resistance; Drug Resistance, Neoplasm; Ectopic expression; Fluorouracil; Fluorouracil - therapeutic use; Gene expression; Genes; Genetic aspects; Homology; Humans; Inactivation; Laboratory animals; Leukemia; Lymphoma; Medical prognosis; Medical research; Medicine and Health Sciences; Metastasis; Mice; MLH1 protein; MutL Protein Homolog 1 - metabolism; Oncology; Prognosis; Proteins; Proto-Oncogene Proteins - metabolism; Research and Analysis Methods; Ribosomal Proteins - metabolism; RNA-Binding Proteins - metabolism; Solid tumors; Statistics; Tumor Suppressor Proteins - metabolism; Tumors; Xenografts; Xenotransplantation; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0222392

We have previously demonstrated that loss of the tumor suppressive activity of ribosomal protein (RP) RPL22 predisposes to development of leukemia in mouse models and aggressive disease in human patients; however, the role of RPL22 in solid tumors, specifically colorectal cancer (CRC), had not been explored. We report here that RPL22 is either deleted or mutated in 36% of CRC and provide new insights into its mechanism of action. Indeed, Rpl22 inactivation causes the induction of its highly homologous paralog, RPL22L1, which serves as a driver of cell proliferation and anchorage-independent growth in CRC cells. Moreover, RPL22L1 protein is highly expressed in patient CRC samples and correlates with poor survival. Interestingly, the association of high RPL22L1 expression with poor prognosis appears to be linked to resistance to 5-Fluorouracil, which is a core component of most CRC therapeutic regimens. Indeed, in an avatar trial, we found that human CRC samples that were unresponsive to 5-Fluorouracil in patient-derived xenografts exhibited elevated expression levels of RPL22L1. This link between RPL22L1 induction and 5-Fluorouracil resistance appears to be causal, because ectopic expression or knockdown of RPL22L1 in cell lines increases and decreases 5-Fluorouracil resistance, respectively, and this is associated with changes in expression of the DNA-repair genes, MGMT and MLH1. In summary, our data suggest that RPL22L1 might be a prognostic marker in CRC and predict 5-FU responsiveness.