Open Access

ARTICLE

The SMAD2/miR-4256/HDAC5/p16^INK4a signaling axis contributes to gastric cancer progression

MIN WANG^1,#, HAILIANG ZHAO^1,2,#, WEIWEI CHEN^3,#, CAIQUN BIE^4,#, JINYING YANG¹, WENRUI CAI¹, CHUTIAN WU¹, YANFANG CHEN¹, SHUFEN FENG¹, YING SHI¹, YUTING LI¹, HUIJUN TANG⁴, LIXIAN ZHONG¹, LILIANGZI GUO¹, SISI CHEN¹, LINJING LONG⁵, SHAOHUI TANG^1,*

1 Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, 510632, China
2 Department of Gastroenterology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, 533000, China
3 Department of Gastroenterology, The First People’s Hospital of Zunyi, The Third Affiliated Hospital of Zunyi Medical University, Zunyi, 563099, China
4 Department of Gastroenterology, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, 518104, China
5 Department of Gastroenterology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510799, China

* Corresponding Author: SHAOHUI TANG. Email:
# These authors contributed equally to this work

Oncology Research 2023, 31(4), 515-541. https://doi.org/10.32604/or.2023.029101

Received 06 February 2023; Accepted 11 April 2023; Issue published 25 June 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^INK4a 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^INK4a 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^INK4a through the epigenetic modulation of HDAC5 at the p16^INK4a 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^INK4a axis, which participates in GC progression and provides novel therapeutic and prognostic biomarkers for GC.

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