Université de Reims Champagne Ardenne, SFR CAP-Santé (FED 4231), Laboratoire de Biochimie Médicale et Biologie Moléculaire, Reims, France.
CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire - MEDyC, Reims, France.
Br J Cancer. 2019 Feb;120(4):453-465. doi: 10.1038/s41416-019-0382-0. Epub 2019 Feb 11.
Carcinogenesis occurs in elastin-rich tissues and leads to local inflammation and elastolytic proteinase release. This contributes to bioactive matrix fragment (Matrikine) accumulation like elastin degradation products (EDP) stimulating tumour cell invasive and metastatic properties. We previously demonstrate that EDPs exert protumoural activities through Hsp90 secretion to stabilised extracellular proteinases.
EDP influence on cancer cell blebbing and extracellular vesicle shedding were examined with a videomicroscope coupled with confocal Yokogawa spinning disk, by transmission electron microscopy, scanning electron microscopy and confocal microscopy. The ribosomal protein SA (RPSA) elastin receptor was identified after affinity chromatography by western blotting and cell immunolocalisation. mRNA expression was studied using real-time PCR. SiRNA were used to confirm the essential role of RPSA.
We demonstrate that extracellular matrix degradation products like EDPs induce tumour amoeboid phenotype with cell membrane blebbing and shedding of extracellular vesicle containing Hsp90 and proteinases in the extracellular space. EDPs influence intracellular calcium influx and cytoskeleton reorganisation. Among matrikines, VGVAPG and AGVPGLGVG peptides reproduced EDP effects through RPSA binding.
Our data suggests that matrikines induce cancer cell blebbing and extracellular vesicle release through RPSA binding, favouring dissemination, cell-to-cell communication and growth of cancer cells in metastatic sites.
癌变发生在富含弹性蛋白的组织中，并导致局部炎症和弹性蛋白水解蛋白酶的释放。这有助于生物活性基质片段（Matrikine）的积累，如弹性蛋白降解产物（EDP），刺激肿瘤细胞的侵袭和转移特性。我们之前证明 EDP 通过 HSP90 分泌对细胞外蛋白酶的稳定作用发挥促肿瘤活性。
使用与共焦 Yokogawa 旋转盘耦合的视频显微镜检查 EDP 对癌细胞起泡和细胞外囊泡脱落的影响，通过透射电子显微镜、扫描电子显微镜和共聚焦显微镜进行检查。通过亲和层析，用 Western blot 和细胞免疫定位鉴定核糖体蛋白 SA（RPSA）弹性蛋白受体。使用实时 PCR 研究 mRNA 表达。使用 siRNA 来确认 RPSA 的重要作用。
我们证明细胞外基质降解产物（如 EDP）诱导肿瘤阿米巴样表型，导致细胞膜起泡和含有 HSP90 和细胞外空间中蛋白酶的细胞外囊泡脱落。EDP 影响细胞内钙离子内流和细胞骨架重组。在基质素中，VGVAPG 和 AGVPGLGVG 肽通过与 RPSA 结合再现了 EDP 的作用。
我们的数据表明，基质素通过与 RPSA 结合诱导癌细胞起泡和细胞外囊泡释放，促进癌症细胞在转移部位的扩散、细胞间通讯和生长。
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