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The SMAD2/miR-4256/HDAC5/p16INK4a signaling axis contributes to gastric cancer progression.
- Source :
- Oncology Research; 2023, Vol. 31 Issue 4, p515-541, 27p
- Publication Year :
- 2023
-
Abstract
- The dysregulation of exosomal microRNAs (miRNAs) plays a crucial role in the development and progression of cancer. This study investigated the role of a newly identified serum exosomal miRNA miR-4256 in gastric cancer (GC) and the underlying mechanisms. The differentially expressed miRNAs were firstly identified in serum exosomes of GC patients and healthy individuals using next-generation sequencing and bioinformatics. Next, the expression of serum exosomal miR-4256 was analyzed in GC cells and GC tissues, and the role of miR-4256 in GC was investigated by in vitro and in vivo experiments. Then, the effect of miR-4256 on its downstream target genes HDAC5/p16<superscript>INK4a</superscript> was studied in GC cells, and the underlying mechanisms were evaluated using dual luciferase reporter assay and Chromatin Immunoprecipitation (ChIP). Additionally, the role of the miR-4256/HDAC5/p16<superscript>INK4a</superscript> axis in GC was studied using in vitro and in vivo experiments. Finally, the upstream regulators SMAD2/p300 that regulate miR-4256 expression and their role in GC were explored using in vitro experiments. miR-4256 was the most significantly upregulated miRNA and was overexpressed in GC cell lines and GC tissues; in vitro and in vivo results showed that miR-4256 promoted GC growth and progression. Mechanistically, miR-4256 enhanced HDAC5 expression by targeting the promoter of the HDAC5 gene in GC cells, and then restrained the expression of p16<superscript>INK4a</superscript> through the epigenetic modulation of HDAC5 at the p16<superscript>INK4a</superscript> promoter. Furthermore, miR-4256 overexpression was positively regulated by the SMAD2/p300 complex in GC cells. Our data indicate that miR-4256 functions as an oncogene in GC via the SMAD2/miR-4256/HDAC5/p16<superscript>INK4a</superscript> axis, which participates in GC progression and provides novel therapeutic and prognostic biomarkers for GC. [ABSTRACT FROM AUTHOR]
- Subjects :
- STOMACH cancer
GENE expression
CANCER invasiveness
PROGNOSIS
NUCLEOTIDE sequencing
Subjects
Details
- Language :
- English
- ISSN :
- 09650407
- Volume :
- 31
- Issue :
- 4
- Database :
- Complementary Index
- Journal :
- Oncology Research
- Publication Type :
- Academic Journal
- Accession number :
- 164691162
- Full Text :
- https://doi.org/10.32604/or.2023.029101