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Exosomal miR?663b exposed to TGF??1 promotes cervical cancer metastasis and epithelial?mesenchymal transition by targeting MGAT3.


ABSTRACT: Transforming growth factor (TGF)??1 is a key cytokine affecting the pathogenesis and progression of cervical cancer. Tumor?derived exosomes contain microRNAs (miRNAs/miRs) that interact with cancer and stromal cells, thereby contributing to tissue remodeling in the tumor microenvironment (TME). The present study was designed to clarify how TGF??1 affects tumor biological functions through exosomes released by cervical cancer cells. Deep RNA sequencing found that TGF??1 stimulated cervical cancer cells to secrete more miR?663b?containing exosomes, which could be transferred into new target cells to promote metastasis. Further studies have shown that miR?663b directly targets the 3'-untranslated regions (3'?UTR) of mannoside acetylglucosaminyltransferase 3 (MGAT3) and is involved in the epithelial?mesenchymal transition (EMT) process. Remarkably, the overexpression of MGAT3 suppressed cervical cancer cell metastasis promoted by exosomal miR?663b, causing increased expression of epithelial differentiation marker E?cadherin and decreased expression of mesenchymal markers N?cadherin and ??catenin. Throughout our study, online bioinformation tools and dual luciferase reporter assay were applied to identify MGAT3 as a novel direct target of miR?663b. Exosome PKH67?labeling experiment verified that exosomal miR?663b could be endocytosed by cervical cancer cells and subsequently influence its migration and invasion functions which were measured by wound healing and Transwell assays. The expression of miR?663b and MGAT3 and the regulation of the EMT pathway caused by MGAT3 were detected by quantitative real?time transcription?polymerase chain reaction (qPCR) and western blot analysis. These results, thus, provide evidence that cancer cell?derived exosomal miR?663b is endocytosed by cervical cancer cells adjacent or distant after TGF??1 exposure and inhibits the expression of MGAT3, thereby accelerating the EMT process and ultimately promoting local and distant metastasis.

SUBMITTER: You X 

PROVIDER: S-EPMC7877003 | BioStudies | 2021-01-01

REPOSITORIES: biostudies

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