Department of Analytical Biochemistry, Graduate School of health sciences, Kumamoto University, Kumamoto, Japan, 862-0976.
Department of Glyco-Oncology and Medical Biochemistry, Osaka International Cancer Institute, Osaka, Japan, 541-8567.
J Biochem. 2022 May 11;171(5):543-554. doi: 10.1093/jb/mvac008.
Protein glycosylation plays a pivotal role in tumour development by modulating molecular interactions and cellular signals. Sialyl-Tn (sTn) antigen is a tumour-associating carbohydrate epitope whose expression correlates with metastasis and poor prognosis of various cancers; however, its pathophysiological function is poorly understood. Extracellular vesicles (EVs) derived from cancer cells act as a signal mediator amongst tumour microenvironments by transferring cargo molecules. sTn antigen has been found in the glycans of EVs, thereby the functional relevance of sTn antigen to the regulation of tumour microenvironments could be expected. In the present study, we showed that sTn antigen induced TP53 and tumour suppressor-activated pathway 6 (TSAP6) and consequently enhanced EV production. Besides, the genetic attenuation of TSAP6 resulted in the reduction of the EV production in the sTn antigen expressing cells. The enhanced EV production in the sTn antigen-expressing cells consequently augmented the delivery of EVs to recipient cells. The produced EVs selectively and abundantly encased focal adhesion kinase and transferred it to EV-recipient cells, and thus, their cellular motility was enhanced. These findings would contribute to facilitate the elucidation of the pathophysiological significance of the sTn antigen in the tumour microenvironments and tumour development.
蛋白质糖基化通过调节分子相互作用和细胞信号在肿瘤发展中起着关键作用。唾液酸化 Tn（sTn）抗原是一种与肿瘤相关的碳水化合物表位，其表达与多种癌症的转移和预后不良相关；然而，其病理生理功能尚不清楚。癌细胞来源的细胞外囊泡（EVs）通过转移货物分子在肿瘤微环境中充当信号介质。sTn 抗原已在 EVs 的聚糖中发现，因此可以预期 sTn 抗原对肿瘤微环境调节的功能相关性。在本研究中，我们表明 sTn 抗原诱导 TP53 和肿瘤抑制激活途径 6（TSAP6），从而增强 EV 的产生。此外，TSAP6 的遗传衰减导致 sTn 抗原表达细胞中 EV 的产生减少。sTn 抗原表达细胞中 EV 的产生增加，从而增加了 EV 向受体细胞的传递。产生的 EV 选择性且丰富地包裹粘着斑激酶并将其转移到 EV 受体细胞中，从而增强了它们的细胞迁移能力。这些发现将有助于阐明 sTn 抗原在肿瘤微环境和肿瘤发展中的病理生理意义。
