MTHFD1L confers a poor prognosis and malignant phenotype in esophageal squamous cell carcinoma by activating the ERK5 signaling pathway

• Published in: Experimental cell research 2023-06, Vol.427 (1), p.113584-113584, Article 113584
• Main Authors: Zhou, Jianfeng, Yang, Yushang, Cheng, Jiahan, Luan, Siyuan, Xiao, Xin, Li, Xiaokun, Fang, Pinhao, Gu, Yimin, Shang, Qixin, Zhang, Hanlu, Chen, Longqi, Zeng, Xiaoxi, Yuan, Yong
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Cell Movement - genetics; Cell Proliferation - genetics; ERK5 pathway5; Esophageal Neoplasms - pathology; Esophageal Squamous Cell Carcinoma - pathology; Esophageal squamous cell carcinoma1; Gene Expression Regulation, Neoplastic; Malignant phenotype4; Mice; MTHFD1L2; Phenotype; Prognosis3; Signal Transduction
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2023.113584

MTHFD1L, a key enzyme of folate metabolism, is seldom reported in cancer. In this study, we investigate the role of MTHFD1L in the tumorigenicity of esophageal squamous cell carcinoma (ESCC). ESCC tissue microarrays (TMAs) containing 177 samples from 109 patients were utilized to evaluate whether MTHFD1L expression, determined using immunohistochemical analysis, is a prognostic indicator for ESCC patients. The function of MTHFD1L in the migration and invasion of ESCC cells was studied with wound healing, Transwell, and three-dimensional spheroid invasion assays in vitro and a lung metastasis mouse model in vivo. The mRNA microarrays and Ingenuity pathway analysis (IPA) were used to explore the downstream of MTHFD1L. Elevated expression of MTHFD1L in ESCC tissues was significantly associated with poor differentiation and prognosis. These phenotypic assays revealed that MTHFD1L significantly promote the viability and metastasis of ESCC cell in vivo and in vitro. Further detailed analyses of the molecular mechanism demonstrated that the ESCC progression driven by MTHFD1L was through up-regulation ERK5 signaling pathways. These findings reveal that MTHFD1L is positively associated with the aggressive phenotype of ESCC by activating ERK5 signaling pathways, suggesting that MTHFD1L is a new biomarker and a potential molecular therapeutic target for ESCC. [Display omitted] •This is the first study assessing the mechanism of MTHFD1L, a key enzyme of folate metabolism, in the progression of ESCC