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 by transcriptome analysis, identifying CD147 as potential target gene. Because CD147 is 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 is a direct target of miR-146 and 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, reduced glucose consumption and tumor growth retardation, as demonstrated by [¹⁸F]FDG-PET/MRI analysis. Investigation of metabolism in vitro and in vivo supported these findings, revealing reduced aerobic glycolysis and increased basal respiration in CD147 knockdown. 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 tumor growth. Furthermore, CD147 has the potential to serve as a novel therapeutic target in ALK+ ALCL, and warrants further investigation.

我们最近报道了 miR-146a 在 ALK+ 和 ALK- 间变性大细胞淋巴瘤 (ALCL) 中差异表达。在本研究中，通过转录组分析研究了 ALK+ ALCL 中 miR-146a 的下游靶标，鉴定了CD147作为潜在的靶基因。由于 CD147 在 ALK+ ALCL 与 ALK-ALCL 和正常 T 细胞中的表达不同，因此该基因成为该肿瘤发病机制的有力候选者。在这里，我们证明 CD147 是 miR-146 的直接靶标，并有助于 ALK+ ALCL 细胞在体外的存活和增殖以及在 ALK+ ALCL-异种移植小鼠模型中的体内植入和肿瘤生长。ALK+ ALCL 细胞中的 CD147 敲低导致单羧酸转运蛋白 1 (MCT1) 表达丧失、葡萄糖消耗减少和肿瘤生长迟缓，如 [ ¹⁸F]FDG-PET/MRI 分析。体外和体内代谢研究支持了这些发现，揭示了 CD147 敲低时有氧糖酵解减少和基础呼吸增加。总之，我们的研究结果表明，CD147 对于 ALK+ ALCL 维持快速细胞增殖、促进乳酸输出和肿瘤生长的高能量需求至关重要。此外，CD147 有可能成为 ALK+ ALCL 的新治疗靶点，值得进一步研究。