| 20 to 27 kDa Rab proteins are widespreadly existed in Eukaryotes and the switch regulators in vesicle transport processes, including exosome release. It has been reported that Rab27 A and Rab27 B are involved in the regulation of exosome secretion and can promote tumor progression. Rab3 D, as a small GTPase, is related to protein secretion in secretory tissues, but its functions in cancer are never reported.Here, we find abnormal high expression of Rab3 D in many cancer cells or tissues compared with normal ones, and its level is related to tumor malignancy. We further find that Rab3 D regulates tumor cell morphology and participates in tumor cells migration, invasion in vitro and metastasis in orthotopic xenograft model. Besides, Rab3 D can promote the epithelial to mesenchymal transition through AKT/GSK3β signaling activation, exosome release and heat shock protein 90α(Hsp90α) secretion, suggesting that Rab3 D is an important molecule in tumor metastasis and will become a potential target for tumor diagnosis and therapy.On the other hand, high levels of Rab3 D are also detected in the exosome or culture medium of tumor cells by immunoblotting, mass spectrometry and electron microscope assay. More importantly, there is a good correlation between secreted Rab3 D and tumor malignancy, indicating its possible roles as tumor biomarkers.Meanwhile, we also carried out the basic research about Hsp90α which is the molecular chaperone involved in many processes of tumor progression. Hsp90α can be secreted out of the cells and surface Hsp90α is involved in tumor invasion and metastasis, but the mechanism has not been elucidated. We find that the level and localization of Hsp90α on the cell protrusions can be regulated by epidermal growth factor. Signaling pathway PLCγ1-PKCγ, which is related to invadopodia formation, controls Hsp90α membrane translocation via exosomes. This molecular mechanism provides a new theoretical basis for Hsp90α-induced invadopodia formation and tumor metastasis. |
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