DUSP4/MKP2 overexpression is associated with BRAFV600E mutation and aggressive behavior of papillary thyroid cancer

The study was performed to retrospectively analyze the correlation of dual specificity phosphatase 4 (DUSP4) expression with clinicopathological variables and BRAF(V600E) mutation to better characterize the potential role of DUSP4 as a biomarker in papillary thyroid cancer (PTC). Patients (n=120) who underwent surgery for PTC at Fudan University Shanghai Cancer Center (FUSCC) were enrolled in this study, and a validation cohort from The Cancer Genome Atlas (TCGA) database was identified to confirm the preliminary findings in our study. We investigated DUSP4 expression at the mRNA level in PTC tissues and adjacent normal tissues using real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR). BRAF(V600E) mutation analysis was also performed in PTC tissues using Sanger sequencing. Initially, we compared PTC tissues with paired normal tissues in DUSP4 expression using Student's t-test, and then analyzed the correlation of DUSP4 with clinicopathological variables and BRAF(V600E) mutation in PTC using Mann-Whitney U, Kruskal-Wallis, chi(2), and Fisher's exact tests. Human-derived thyroid cell lines were also used to verify our findings. DUSP4 was significantly overexpressed in PTC tissues compared with the adjacent normal tissues (P<0.001). High DUSP4 expression showed a significant association with lymph node metastasis and extrathyroidal extension in both FUSCC and TCGA cohorts, and DUSP4 overexpression was an independent risk factor for lymph node metastasis in multivariate analysis. Additionally, DUSP4 expression was associated with BRAF(V600E) mutation in both the cohorts (FUSCC: P=0.002, TCGA: P<0.001) and PTC cell lines (P=0.023). In conclusion, DUSP4 was identified as a potential biomarker for aggressive behavior in PTC, and its overexpression was BRAF(V600E) mutation-related.