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

被引：7

作者：

Yokoyama, Sho ^{[1
]}

Shigeishi, Hideo ^{[2
]}

Murodumi, Hiroshi ^{[1
]}

Sakuma, Miyuki ^{[1
]}

Kato, Hiroki ^{[1
]}

Higashikawa, Koichiro ^{[1
]}

Ohta, Kouji ^{[2
]}

Sugiyama, Masaru ^{[2
]}

Takechi, Masaaki ^{[1
]}

机构：

[1] Hiroshima Univ, Grad Sch Biomed & Hlth Sci, Dept Oral & Maxillofacial Surg, Program Dent, Hiroshima, Japan

[2] Hiroshima Univ, Grad Sch Biomed & Hlth Sci, Dept Publ Oral Hlth, Program Oral Hlth Sci, Hiroshima, Japan

来源：

JOURNAL OF ORAL PATHOLOGY & MEDICINE | 2021年 / 50卷 / 02期

关键词：

amoeboid‐ to‐ mesenchymal transition; CD44; miR‐ 422a; oral squamous cell carcinoma; TGF‐ β 1; CANCER STEM-CELLS; HEAD; INVASION;

D O I：

10.1111/jop.13113

中图分类号：

R78 [口腔科学];

学科分类号：

1003 ;

摘要：

Background The objective of this study was to clarify the molecular mechanism of amoeboid-to-mesenchymal transition (AMT) of CD44(high) oral squamous cell carcinoma (OSCC) cells. Methods Morphology and expression of mesenchymal genes were investigated in CD44(high) OSCC cells (CD44(high) 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-beta 1 (TGF-beta 1) in CD44(high) OM-1 cells. Results When CD44(high) 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 CD44(high) 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-beta 1. Additionally, TGF-beta 1 enhanced N-cadherin and Snail mRNA expression and induced a spindle-shaped morphology. ERK1/2 phosphorylation was induced by TGF-beta 1. Microarray analysis revealed that miR-422a exhibited the greatest downregulation (fold change: 0.22) in the presence of TGF-beta 1. Importantly, TGF-beta 1-inhibited miR-422a expression was recovered by the ERK inhibitor or ERK1/2 knockdown. Additionally, miR-422a inhibitor-transfected CD44(high) 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 CD44(high) OSCC cells. TGF-beta 1 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 CD44(high) cells.

引用

页码：155 / 164

页数：10

共 29 条

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