Epigenetically upregulated GEFT-derived invasion and metastasis of rhabdomyosarcoma via epithelial mesenchymal transition promoted by the Rac1/Cdc42-PAK signalling pathway

Chunxia Liu; Liang Zhang; Wenwen Cui; Juan Du; Zhenzhen Li; Yuwen Pang; Qianqian Liu; Hao Shang; Lian Meng; Wanyu Li; Lingxie Song; Ping Wang; Yuwen Xie; Yuanyuan Wang; Yang Liu; Jianming Hu; Wenjie Zhang; Feng Li

EBioMedicine (Dec 2019)

Epigenetically upregulated GEFT-derived invasion and metastasis of rhabdomyosarcoma via epithelial mesenchymal transition promoted by the Rac1/Cdc42-PAK signalling pathway

Chunxia Liu,
Liang Zhang,
Wenwen Cui,
Juan Du,
Zhenzhen Li,
Yuwen Pang,
Qianqian Liu,
Hao Shang,
Lian Meng,
Wanyu Li,
Lingxie Song,
Ping Wang,
Yuwen Xie,
Yuanyuan Wang,
Yang Liu,
Jianming Hu,
Wenjie Zhang,
Feng Li

Affiliations

Chunxia Liu: Department of Pathology, Shihezi University School of Medicine and The Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Chinese Ministry of Education, Shihezi 832002, Xinjiang, PR China; Corresponding author.
Liang Zhang: Department of Pathology, Shihezi University School of Medicine and The Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Chinese Ministry of Education, Shihezi 832002, Xinjiang, PR China
Wenwen Cui: Department of Pathology, Shihezi University School of Medicine and The Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Chinese Ministry of Education, Shihezi 832002, Xinjiang, PR China
Juan Du: Department of Pathology, Shihezi University School of Medicine and The Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Chinese Ministry of Education, Shihezi 832002, Xinjiang, PR China
Zhenzhen Li: Department of Pathology, Shihezi University School of Medicine and The Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Chinese Ministry of Education, Shihezi 832002, Xinjiang, PR China
Yuwen Pang: Department of Pathology, Shihezi University School of Medicine and The Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Chinese Ministry of Education, Shihezi 832002, Xinjiang, PR China
Qianqian Liu: Department of Pathology, Shihezi University School of Medicine and The Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Chinese Ministry of Education, Shihezi 832002, Xinjiang, PR China
Hao Shang: Department of Pathology, Shihezi University School of Medicine and The Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Chinese Ministry of Education, Shihezi 832002, Xinjiang, PR China
Lian Meng: Department of Pathology, Shihezi University School of Medicine and The Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Chinese Ministry of Education, Shihezi 832002, Xinjiang, PR China
Wanyu Li: Department of Pathology, Shihezi University School of Medicine and The Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Chinese Ministry of Education, Shihezi 832002, Xinjiang, PR China
Lingxie Song: Department of Pathology, Shihezi University School of Medicine and The Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Chinese Ministry of Education, Shihezi 832002, Xinjiang, PR China
Ping Wang: Department of Pathology, Shihezi University School of Medicine and The Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Chinese Ministry of Education, Shihezi 832002, Xinjiang, PR China
Yuwen Xie: Department of Pathology, Shihezi University School of Medicine and The Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Chinese Ministry of Education, Shihezi 832002, Xinjiang, PR China
Yuanyuan Wang: Department of Pathology, Shihezi University School of Medicine and The Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Chinese Ministry of Education, Shihezi 832002, Xinjiang, PR China
Yang Liu: Department of Pathology, Shihezi University School of Medicine and The Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Chinese Ministry of Education, Shihezi 832002, Xinjiang, PR China
Jianming Hu: Department of Pathology, Shihezi University School of Medicine and The Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Chinese Ministry of Education, Shihezi 832002, Xinjiang, PR China
Wenjie Zhang: Department of Pathology, Shihezi University School of Medicine and The Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Chinese Ministry of Education, Shihezi 832002, Xinjiang, PR China
Feng Li: Department of Pathology, Shihezi University School of Medicine and The Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Chinese Ministry of Education, Shihezi 832002, Xinjiang, PR China; Department of Pathology and Medical Research Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, PR China; Corresponding author.

Journal volume & issue: Vol. 50
pp. 122 – 134

Abstract

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Background: Metastasis of rhabdomyosarcoma (RMS) is the primary cause of tumour-related deaths. Previous studies have shown that overexpression of the guanine nucleotide exchange factor T (GEFT) is correlated with a poorer RMS prognosis, but the mechanism remains largely unexplored. Methods: We focused on determining the influence of the GEFT-Rho-GTPase signalling pathway and the epithelial–mesenchymal transition (EMT) or mesenchymal–epithelial transition (MET) on RMS progression and metastasis by using RMS cell lines, BALB/c nude mice and cells and molecular biology techniques. Findings: GEFT promotes RMS cell viability, migration, and invasion; GEFT also inhibits the apoptosis of RMS cells and accelerates the growth and lung metastasis of RMS by activating the Rac1/Cdc42 pathways. Interestingly, GEFT upregulates the expression levels of N-cadherin, Snail, Slug, Twist, Zeb1, and Zeb2 and reduces expression level of E-cadherin. Thus, GEFT influences the expression of markers for EMT and MET in RMS cells via the Rac1/Cdc42-PAK1 pathways. We also found that the level of GEFT gene promoter methylation in RMS is lower than that in normal striated muscle tissue. Significant differences were observed in the level of GEFT gene methylation in different histological subtypes of RMS. Interpretation: These findings suggest that GEFT accelerates the tumourigenicity and metastasis of RMS by activating Rac1/Cdc42-PAK signalling pathway-induced EMT; thus, it may serve as a novel therapeutic target. Fund: This work was supported by grants from the National Natural Science Foundation of China (81660441, 81460404, and 81160322) and Shihezi University Initiative Research Projects for Senior Fellows (RCZX201447). Funders had no role in the design of the study, data collection, data analysis, interpretation, or the writing of this report. Keywords: Rhabdomyosarcoma, GEFT, Rac1/Cdc42-PAK1 pathways, EMT, Methylation

Published in EBioMedicine

ISSN: 2352-3964 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General)
Website: http://www.journals.elsevier.com/ebiomedicine/

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