TGF-β-induced PLEK2 promotes metastasis and chemoresistance in oesophageal squamous cell carcinoma by regulating LCN2

• Published in: Cell death & disease 2021-10, Vol.12 (10), p.901-12, Article 901
• Main Authors: Wang, Feng, Zhang, Chaoqi, Cheng, Hong, Liu, Chengming, Lu, Zhiliang, Zheng, Sufei, Wang, Sihui, Sun, Nan, He, Jie
• Format: Article
• Language: English
• Subjects: 13; 13/109; 13/51; 13/89; 14; 38; 38/77; 38/91; 42; 45; 45/15; 631/337; 631/67; 82; 96; 96/31; AKT protein; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell Cycle - drug effects; Cell Cycle - genetics; Cell Line, Tumor; Cell Movement - drug effects; Cell Movement - genetics; Cell proliferation; Cell Proliferation - drug effects; Cell Proliferation - genetics; Chemoresistance; Chemotherapy; Chromatin; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Esophageal cancer; Esophageal Neoplasms - genetics; Esophageal Neoplasms - pathology; Esophageal Squamous Cell Carcinoma - genetics; Esophageal Squamous Cell Carcinoma - pathology; Esophagus; Female; Gene Expression Regulation, Neoplastic - drug effects; Gene Knockdown Techniques; Humans; Immunology; Immunoprecipitation; Life Sciences; Lipocalin-2 - genetics; Lipocalin-2 - metabolism; Medical prognosis; Membrane Proteins - metabolism; Metastases; Metastasis; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Oncogenes; Phenotype; Prognosis; Smad2 protein; Squamous cell carcinoma; Therapeutic targets; Transforming Growth Factor beta - pharmacology; Transforming growth factor-b; Tumorigenicity; Wound Healing - drug effects
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-04155-z

Oesophageal squamous cell carcinoma (ESCC) has a relatively unfavourable prognosis due to metastasis and chemoresistance. Our previous research established a comprehensive ESCC database (GSE53625). After analysing data from TCGA database and GSE53625, we found that PLEK2 predicted poor prognosis in ESCC. Moreover, PLEK2 expression was also related to the overall survival of ESCC patients undergoing chemotherapy. Repression of PLEK2 decreased the proliferation, migration, invasion and chemoresistance of ESCC cells in vitro and decreased tumorigenicity and distant metastasis in vivo. Mechanistically, luciferase reporter assay and chromatin immunoprecipitation assay suggested that TGF-β stimulated the process that Smad2/3 binds to the promoter sequences of PLEK2 and induced its expression. RNA-seq suggested LCN2 might a key molecular regulated by PLEK2. LCN2 overexpression in PLEK2 knockdown ESCC cells reversed the effects of decreased migration and invasion. In addition, TGF-β induced the expression of LCN2, but the effect disappeared when PLEK2 was knockdown. Moreover, AKT was phosphorylated in all regulatory processes. This study detected the major role of PLEK2 in driving metastasis and chemoresistance in ESCC by regulating LCN2, which indicates the potential use of PLEK2 as a biomarker to predict prognosis and as a therapeutic target for ESCC.