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首页> 外文期刊>Neoplasia: an international journal for oncology research >Human Renal Normal, Tumoral, and Cancer Stem Cells Express Membrane-Bound Interleukin-15 Isoforms Displaying Different Functions
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Human Renal Normal, Tumoral, and Cancer Stem Cells Express Membrane-Bound Interleukin-15 Isoforms Displaying Different Functions

机译：人肾正常，肿瘤和癌症干细胞表达膜结合的白细胞介素-15同种型显示不同功能

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Intrarenal interleukin-15 (IL-15) participates to renal pathophysiology, but the role of its different membrane-bound isoforms remains to be elucidated. In this study, we reassess the biology of membrane-bound IL-15 (mb-IL-15) isoforms by comparing primary cultures of human renal proximal tubular epithelial cells (RPTEC) to peritumoral (ptumTEC), tumoral (RCC), and cancer stem cells (CSC/CD105+). RPTEC express a 14 to 16 kDa mb-IL-15, whose existence has been assumed but never formally demonstrated and likely represents the isoform anchored at the cell membrane through the IL-15 receptor α (IL-15Rα) chain, because it is sensitive to acidic treatment and is not competent to deliver a reverse signal. By contrast, ptumTEC, RCC, and CSC express a novel N-hyperglycosylated, short-lived transmembrane mb-IL-15 (tmb-IL-15) isoform around 27 kDa, resistant to acidic shock, delivering a reverse signal in response to its soluble receptor (sIL-15Rα). This reverse signal triggers the down-regulation of the tumor suppressor gene E-cadherin in ptumTEC and RCC but not in CSC/CD105+, where it promotes survival. Indeed, through the AKT pathway, tmb-IL-15 protects CSC/CD105+ from non-programmed cell death induced by serum starvation. Finally, both mb-IL-15 and tmb-IL-15 are sensitive to metalloproteases, and the cleaved tmb-IL-15 (25 kDa) displays a powerful anti-apoptotic effect on human hematopoietic cells. Overall, our data indicate that both mb-IL-15 and tmb-IL-15 isoforms play a complex role in renal pathophysiology downregulating E-cadherin and favoring cell survival. Moreover, “apparently normal” ptumTEC cells, sharing different properties with RCC, could contribute to organize an enlarged peritumoral “preneoplastic” environment committed to favor tumor progression.
机译：Intrarenal白细胞介素-15（IL-15）参与肾病理生理学，但其不同膜结合同种型的作用仍有待阐明。在这项研究中，我们通过将人肾近端管状上皮细胞（RPTEC）的原发性培养物与Peritumoral（Ptumtec），肿瘤（RCC）和癌症进行比较来重新评估膜结合的IL-15（MB-IL-15）同种型的生物学。干细胞（CSC / CD105 +）。 RPTEC表达14至16 kda MB-IL-15，其存在已经假定但从未经常证明并且可能代表通过IL-15受体α（IL-15Rα）链在细胞膜处锚定的同种型，因为它很敏感酸性处理并不称职，以提供反向信号。相比之下，Ptumtec，RCC和CSC表达了一种新型的N高血糖化的短寿命的短型跨膜MB-IL-15（TMB-IL-15）同种型约27kDa，耐酸性冲击，响应其响应而提供反向信号可溶受体（SIL-15Rα）。该反向信号触发Ptumtec和RCC中肿瘤抑制基因E-钙粘蛋白的下调，但不在CSC / CD105 +中，其中促进存活。实际上，通过AKT途径，TMB-IL-15保护CSC / CD105 +从血清饥饿诱导的非程序化细胞死亡中保护CSC / CD105 +。最后，Mb-IL-15和TMB-IL-15对金属蛋白酶敏感，并且切割的TMB-IL-15（25kDA）对人造血细胞显示出强烈的抗凋亡作用。总的来说，我们的数据表明，MB-IL-15和TMB-IL-15同种型在肾病理生理学中起复杂作用下调E-Cadherin并有利于细胞存活。此外，“显然正常”的Ptumtec细胞，与RCC分享不同的性质，可以有助于组织致力于有利于肿瘤进展的扩大的蠕动“营养性”环境。

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