MicroRNA-7 as a potential therapeutic target for aberrant NF-?B-driven distant metastasis of gastric cancer.

ABSTRACT: BACKGROUND:Dysregulated miR-7 and aberrant NF-?B activation were reported in various human cancers. However, the expression profile, clinical relevance and dysregulated mechanism of miR-7 and NF-?B RelA/p65 in human gastric cancers (GC) metastasis remain largely unknown. This study is to investigate the expression profile, clinical relevance and dysregulated mechanism of miR-7 and NF-?B RelA/p65 in GC and to explore the potential therapeutic effect of miR-7 to GC distant metastasis. METHODS:TCGA STAD and NCBI GEO database were used to investigate the expression profile of miR-7 and NF-?B RelA/p65 and clinical relevance. Lentivirus-mediated gene delivery was applied to explore the therapeutic effect of miR-7 in GC. Real-time PCR, FACS, IHC, IF, reporter gene assay, IP, pre-miRNA-7 processing and binding assays were performed. RESULTS:Low miR-7 correlated with high RelA/p65 in GC with a clinical relevance that low miR-7 and high RelA/p65 as prognostic indicators of poor survival outcome of GC patients. Moreover, an impaired pre-miR-7 processing caused by dysregulated Dicer1 expression is associated with downregulated miR-7 in GC cells. Functionally, delivery of miR-7 displays therapeutic effects to GC lung and liver metastasis by alleviating hemangiogenesis, lymphangiogenesis as well as inflammation cells infiltration. Mechanistically, miR-7 suppresses NF-?B transcriptional activity and its downstream metastasis-related molecules Vimentin, ICAM-1, VCAM-1, MMP-2, MMP-9 and VEGF by reducing p65 and p-p65-ser536 expression. Pharmacologic prevention of NF-?B activator LPS obviously restored miR-7-suppressed NF-?B transcriptional activation and significantly reverted miR-7-inhibited cell migration and invasion. CONCLUSIONS:Our data suggest loss of miR-7 in GC promotes p65-mediated aberrant NF-?B activation, facilitating GC metastasis and ultimately resulting in the worse clinical outcome. Thus, miR-7 may act as novel prognostic biomarker and potential therapeutic target for aberrant NF-?B-driven GC distant metastasis.

SUBMITTER: Ye T 

PROVIDER: S-EPMC6364399 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature