miR-146a target gene CD147 regulates energy metabolism and promotes tumor growth, angiogenesis and invasion of ALK+ ALCL. undefined

We recently reported that miR-146a is differentially expressed in ALK+ and ALK- anaplastic large cell lymphoma (ALCL). In this study, the downstream targets of miR-146a in ALK+ ALCL were investigated. Transcriptome analysis identified ZNF275, SRPRB, PNPO and CD147 as miR-146a potential target genes. We have further confirmed that miR-146a directly targets CD147. Because CD147 is also differentially expressed in ALK+ ALCL versus ALK- ALCL and normal T cells, this gene emerged as a strong candidate for the pathogenesis of this tumor. Here we demonstrate that CD147 contributes to the survival and proliferation of ALK+ ALCL cells in vitro and to the engraftment and tumor growth in vivo in an ALK+ ALCL-xenotransplant mouse model. CD147 knockdown in ALK+ ALCL cells resulted in loss of monocarboxylate transporter 1 (MCT1) expression, a transmembrane transporter of lactate. The loss of CD147-MCT1 complexes in ALK+ ALCL tumors resulted in reduced glucose consumption and tumour growth retardation, as demonstrated by [18F]FDG-PET/MRI analysis. Targeted metabolomics supported these findings revealing a reduced energy metabolism illustrated by reduced of aerobic glycolysis and basal respiration in CD147 knockdown in vitro and in vivo. Additionally, the expression of metalloproteinsase 7 (MMP7), CD31 and VEGFR2a, downstream targets of CD147 was lost after CD147 knockdown, suggesting that CD147 stimulates invasion and angiogenesis of ALK+ ALCL tumors. In conclusion, our findings indicate that CD147 is of vital importance for ALK+ ALCL to maintain the high-energy demand of rapid cell proliferation, promoting lactate export, and tumour growth. Furthermore, CD147 has the potential to serve as a novel therapeutic target in ALK+ ALCL.