MicroRNA-124-3p suppresses PD-L1 expression and inhibits tumorigenesis of colorectal cancer cells via modulating STAT3 signaling.
Apoptosis
B7-H1 Antigen
/ genetics
Cell Movement
Cell Proliferation
Coculture Techniques
Colorectal Neoplasms
/ genetics
Cytokines
/ genetics
G1 Phase Cell Cycle Checkpoints
Gene Expression Regulation, Neoplastic
HCT116 Cells
HT29 Cells
Humans
Hyaluronan Receptors
/ genetics
Lymphocytes, Tumor-Infiltrating
/ immunology
Matrix Metalloproteinase 9
/ genetics
MicroRNAs
/ genetics
Neoplasm Invasiveness
STAT3 Transcription Factor
/ genetics
Signal Transduction
T-Lymphocytes, Regulatory
/ enzymology
Colorectal cancer
PD-L1
STAT3
miRNA-124
Journal
Journal of cellular physiology
ISSN: 1097-4652
Titre abrégé: J Cell Physiol
Pays: United States
ID NLM: 0050222
Informations de publication
Date de publication:
10 2021
10 2021
Historique:
revised:
12
03
2021
received:
19
07
2020
accepted:
15
03
2021
pubmed:
7
4
2021
medline:
30
11
2021
entrez:
6
4
2021
Statut:
ppublish
Résumé
Programmed death ligand 1 (PD-L1) plays a significant role in colorectal tumorigenesis through induction of regulatory T cells (Tregs) and suppression of antitumor immunity. Furthermore, microRNAs (miRNAs) as the posttranscriptional regulators of gene expression show considerable promise as a therapeutic target for colorectal cancer (CRC) treatment. Considering this, in vitro effects of miRNA-124 (miR-124-3p) on CRC cell tumorigenesis and Tregs differentiation via targeting PD-L1 were investigated in the current study. Functional analysis showed that miR-124 is significantly downregulated in CRC tissues as compared with marginal normal samples (p < .0001), and its downregulation was negatively correlated with PD-L1 expression. Moreover, a specific region in PD-L1 3'-untranslated region was predicted as the miR-124 target and validated using the luciferase assay. Further investigation showed that transfection of HT29 and SW480 cells with miR-124 mimics significantly reduced PD-L1 mRNA, protein, and cell surface expression, and inhibited Tregs in coculture models via modulating interleukin [IL]-10, IL-2, tumor necrosis factor α, transforming growth factor beta, and interferon gamma expression levels. Besides, miR-124 overexpression decreased CRC cell proliferation and arrested cell cycle at the G1 phase through downregulation of c-Myc and induced apoptosis in CRC cells via upregulation of both intrinsic and extrinsic pathways. Also, miR-124 exogenous overexpression could reduce colony and spheroid formation ability of CRC cells via downregulating CD44 mRNA expression. miR-124 also diminished MMP-9 expression and subsequently suppressed cell migration and invasion. We also illustrated that STAT3 signaling was repressed by miR-124 in CRC cells. Taken together, our findings imply that considering the involvement of miR-124 in the regulation of PD-L1 through colorectal tumorigenesis and its remarkable antitumor effects, this miRNA could be regarded as the promising target for the development of therapeutic approaches for colorectal cancer.
Substances chimiques
B7-H1 Antigen
0
CD274 protein, human
0
CD44 protein, human
0
Cytokines
0
Hyaluronan Receptors
0
MIRN124 microRNA, human
0
MicroRNAs
0
STAT3 Transcription Factor
0
STAT3 protein, human
0
MMP9 protein, human
EC 3.4.24.35
Matrix Metalloproteinase 9
EC 3.4.24.35
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7071-7087Informations de copyright
© 2021 Wiley Periodicals LLC.
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