Abstract
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.
Highlights
Emerging evidence suggests that some ribosomal proteins (RP) play critical, but poorly understood roles in disease [1, 2], including bone marrow failure syndromes featuring an increased predisposition to cancer
To determine how Rpl22 loss affected Rpl22L1 expression, we examined immortalized MEF cells with mono- (Rpl22+/-) or biallelic (Rpl22-/-) inactivation of Rpl22 and found that Rpl22 loss markedly increased the expression of RPL22L1 protein (Fig 1A) and RPL22L1 induction was not accompanied by a commensurate change in Rpl22l1 mRNA, suggesting post-transcriptional regulation of expression (S1B Fig)[20]
We report that RPL22 loss occurs in solid cancers, including colorectal cancer (CRC), where the RPL22 locus is deleted in ~36% or CRC patients
Summary
Emerging evidence suggests that some ribosomal proteins (RP) play critical, but poorly understood roles in disease [1, 2], including bone marrow failure syndromes featuring an increased predisposition to cancer. RPL22 is an RNA-binding RP that is a component of the 60S ribosomal subunit, but its physiological role in normal development and its contribution to disease. Role of RPL22L1 induction in colorectal cancer. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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