TGF‐β1 induces amoeboid‐to‐mesenchymal transition of CD44high oral squamous cell carcinoma cells via miR‐422a downregulation through ERK activation and Cofilin‐1 phosphorylation

Background The objective of this study was to clarify the molecular mechanism of amoeboid‐to‐mesenchymal transition (AMT) of CD44high oral squamous cell carcinoma (OSCC) cells. Methods Morphology and expression of mesenchymal genes were investigated in CD44high OSCC cells (CD44high OM‐1 cells) cultu...

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Published in:Journal of oral pathology & medicine 2021-02, Vol.50 (2), p.155-164
Main Authors: Yokoyama, Sho, Shigeishi, Hideo, Murodumi, Hiroshi, Sakuma, Miyuki, Kato, Hiroki, Higashikawa, Koichiro, Ohta, Kouji, Sugiyama, Masaru, Takechi, Masaaki
Format: Article
Language:English
Subjects:
amoeboid‐to‐mesenchymal transition
Cadherins
CD44
Cell morphology
Cofilin
Cytology
Cytoplasm
Extracellular signal-regulated kinase
Gene expression
Invasiveness
Laminin
Mesenchyme
MicroRNAs
miRNA
miR‐422a
Morphology
Oral cancer
Oral squamous cell carcinoma
Phosphorylation
Silicones
Squamous cell carcinoma
TGF‐β1
Transforming growth factor-b1
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Summary:Background The objective of this study was to clarify the molecular mechanism of amoeboid‐to‐mesenchymal transition (AMT) of CD44high oral squamous cell carcinoma (OSCC) cells. Methods Morphology and expression of mesenchymal genes were investigated in CD44high OSCC cells (CD44high OM‐1 cells) cultured on laminin‐coated soft silicone gel. Additionally, microarray analysis was performed to investigate microRNA (miRNA) expression inhibited by transforming growth factor‐β1 (TGF‐β1) in CD44high OM‐1 cells. Results When CD44high OM‐1 cells were cultured on 2.0‐kPa laminin‐coated silicone gel, the cells exhibited an amoeboid‐like round morphology. Cofilin‐1 expression was found in the nucleus and cytoplasm of amoeboid‐like CD44high OM‐1 cells. The invasive capacity was significantly reduced after Cofilin‐1 knockdown. Additionally, Cofilin‐1 knockdown cells had an irregularly extended shape. Phosphorylated Cofilin‐1 was significantly upregulated by TGF‐β1. Additionally, TGF‐β1 enhanced N‐cadherin and Snail mRNA expression and induced a spindle‐shaped morphology. ERK1/2 phosphorylation was induced by TGF‐β1. Microarray analysis revealed that miR‐422a exhibited the greatest downregulation (fold change: 0.22) in the presence of TGF‐β1. Importantly, TGF‐β1‐inhibited miR‐422a expression was recovered by the ERK inhibitor or ERK1/2 knockdown. Additionally, miR‐422a inhibitor‐transfected CD44high OM‐1 cells exhibited high N‐cadherin and Snail mRNA expression. Furthermore, Cofilin‐1 knockdown and miR‐422a inhibition induced a spindle cell morphology. Conclusion Cofilin‐1 is involved in the invasive ability of CD44high OSCC cells. TGF‐β1 contributes to AMT by downregulation of miR‐422a via ERK activation and Cofilin‐1 phosphorylation. Our findings suggest that miR‐422a and Cofilin‐1 play major roles in the maintenance of amoeboid‐like CD44high cells.
ISSN:0904-2512
1600-0714
DOI:10.1111/jop.13113