Heterogenous Ribonucleoprotein A18 (hnRNP A18) Promotes Tumor Growth by Increasing Protein Translation of Selected Transcripts in Cancer Cells

Abstract

The heterogenous ribonucleoprotein A18 (hnRNP A18) promotes tumor growth by coordinating the translation of selected transcripts associated with proliferation and survival. hnRNP A18 binds to and stabilizes the transcripts of pro-survival genes harboring its RNA signature motif in their 3'UTRs. Under cellular stress, hnRNP A18 binds to ATR, RPA, TRX, HIF-1? and several protein translation factor mRNAs on polysomes and increases de novo protein translation. Most importantly, down-regulation of hnRNP A18 decreases proliferation, invasion, and migration, in addition to significantly reducing tumor growth in two mouse xenograft models, melanoma and breast cancer. Moreover, tissue microarrays performed on human melanoma, prostate, breast, and colon cancer show that hnRNP A18 is over-expressed in 40 to 60% of these malignant tissue as compared to normal adjacent tissues. Immunohistochemistry data reveal that hnRNP A18 is over-expressed in the stroma and hypoxic areas of human tumors. These data thus indicate that hnRNP A18 can promote tumor growth in in vivo models by coordinating the translation of pro-survival transcripts which support the demands of proliferating cells and ultimately increase survival under cellular stress. hnRNP A18 therefore represents a new target to selectively inhibit protein translation in tumor cells.