Epithelial-to-mesenchymal transition (EMT) plays essential roles in non-small cell lung cancer (NSCLC) progression and was related to TWIST1 reactivation. Among regulators of EMT, microRNAs are extensively studied. This work aimed at identifying microRNAs that might be important regulators of TWIST1 and EMT in NSCLC.
We performed miRSeq in a series of EGFR-mutated lung adenocarcinomas (n = 24, series A) and identified a set of miRNAs (n = 12) associated to TWIST1 reactivation. These miRNAs and additional EMT-related miRNAs selected from the literature and from TCGA public data were reanalysed by Fluidigm® technology on the same series. Two miRNAs were significantly associated with TWIST1 reactivation. We then quantified these two miRNAs in a series of 176 consecutive operated NSCLC (series B), in addition to E-cadherin, Jup, N-cadherin, Zeb1, Snai1, Twist1, Vimentin, TCF3 and CD44 using qPCR. Results were validated using TCGA public data.
MiR-200a-3p and miR-429 were significantly associated with TWIST1 reactivation (p = 0.018) in series A, not confirmed by the 16 EGFR-mutated lung adenocarcinomas of series B, but by TCGA analysis (p = 0.03). In series B, miR-200a-3p and miR-429 expression levels were highly correlated (p < 0.001) together and associated to Twist1 up-regulation (p = 0.02 and p = 0.07, respectively), EMT (p = 0.003) and stem cell features (p < 0.05). Low miR-200a-3p and miR-429 expression levels were significantly associated with overall survival in multivariate analyses (Cox; p = 0.008 and p = 0.01, respectively), thus identified as independent prognostic factors. TCGA overall survival multivariate analyses confirmed this finding (p < 0.02).
This study provides new insights on the clinical impact of miR-200 family members down-regulation in localized NSCLC. EMT targeting should be considered as a therapeutic option for a subset of NSCLC patients.
Clinical trial identification
trial protocol number under request
Legal entity responsible for the study
Assistance Publique des Hôpitaux de Paris.
Site de la Recherche Intégrée sur le Cancer (SIRIC) Cancer Research for Personalized Medicine (Carpem).
The author has declared no conflicts of interest.