VAMP5 is a novel target for selective inhibition of gliomas with high NDRG4 expression via downregulating PLK1 and beyond

BackgroundSNAREs participate in cancers progression or stress resistance. But the current conclusions on their involvement in cancers are generally unsystematic and even contradictory on one SNAREs roles in different types of cancer. Its necessary to find universal mechanisms of SNAREs participation in cancers possessing generalizability within appropriate range for application of targeted therapy. MethodsOur study initiated with database analysis on clinical information and bulk RNA-seq data to locate potential effective target for certain cancer type. Then experiment validations/explorations were performed on clinical human sections, cell lines and xenograft models. Lentivirus (LV) were applied for gene KD, overexpression and microRNAs sponge; Bulk RNA-seq, microRNA-seq and DIA proteomics for identification, quantification, genesets/target analysis; WB, single-IF, TSA (Tyramide signal amplification) multi-IF, IHC for proteins detection using antibodies; QPCR for artificial microRNA-sponge sequences test; Other reagents/instruments applied for corresponding purposes. ResultsVAMP5 is a therapeutic target for gliomas with expression selectivity. Gliomas could be divided into 2 types according to effects after VAMP5 KD. In VAMP5-KD sensitive type, PLK1, a classical gene vital for tumor growth/survival, is universally protein-level down-regulated that mediated partly via decrease of several up-reg microRNAs like mir-1301-3p and mir-12135, causing growth inhibition. While among insensitive type that VAMP5-KD is invalid for growth inhibition, PLK1 is not altered consistently, which serves as an evaluation marker for inhibition effectiveness. NDRG4 is a prediction marker for VAMP5-KD sensitivity that sensitive gliomas express higher NDRG4 than insensitive type on RNA level. Moreover, NDRG4 overexpression converts VAMP5-KD insensitive gliomas into sensitive type and additionally cause protein-level downregulation of VCAM1 and especially TNKS which also benefit the growth inhibition and PLK1 reduction partly. Except for results above, LGALS1 correlated and colocalized with VAMP5 possessing broader consistency than other membrane proteins so indicates the immune-enhancing potential of down-reg LGALS1 via KD VAMP5. ConclusionsThese discoveries elucidated the mechanism of VAMP5 KD on gliomas inhibition preliminarily. New sights for glioma therapies including selective therapeutic target, prediction marker, evaluation marker, enhancing strategy and correlated immuno-checkpoint markers were concluded with further development potentials.