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The SMAD2/miR-4256/HDAC5/p16INK4a signaling axis contributes to gastric cancer progression

MIN WANG1,#, HAILIANG ZHAO1,2,#, WEIWEI CHEN3,#, CAIQUN BIE4,#, 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 TANG1,*

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: email
# These authors contributed equally to this work

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

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/p16INK4a 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/p16INK4a 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 p16INK4a through the epigenetic modulation of HDAC5 at the p16INK4a 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/p16INK4a axis, which participates in GC progression and provides novel therapeutic and prognostic biomarkers for GC.

Graphical Abstract

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

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APA Style
WANG, M., ZHAO, H., CHEN, W., BIE, C., YANG, J. et al. (2023). The smad2/mir-4256/hdac5/p16ink4a signaling axis contributes to gastric cancer progression. Oncology Research, 31(4), 515-541. https://doi.org/10.32604/or.2023.029101
Vancouver Style
WANG M, ZHAO H, CHEN W, BIE C, YANG J, CAI W, et al. The smad2/mir-4256/hdac5/p16ink4a signaling axis contributes to gastric cancer progression. Oncol Res. 2023;31(4):515-541 https://doi.org/10.32604/or.2023.029101
IEEE Style
M. WANG et al., "The SMAD2/miR-4256/HDAC5/p16INK4a signaling axis contributes to gastric cancer progression," Oncol. Res., vol. 31, no. 4, pp. 515-541. 2023. https://doi.org/10.32604/or.2023.029101



cc This work is licensed under a Creative Commons Attribution 4.0 International License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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