Down-Regulation of CIDEA Promoted Tumor Growth and Contributed to Cisplatin Resistance by Regulating the JNK-p21/Bad Signaling Pathways in Esophageal Squamous Cell Carcinoma

Front Oncol. 2021 Feb 3;10:627845. doi: 10.3389/fonc.2020.627845. eCollection 2020.

Abstract

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies with poor prognosis and lack of effective targeted therapies. In this study, we investigated the tumor suppressive role of the cell death inducing DFF like effector A (CIDEA) in ESCC. Firstly, public datasets and ESCC tissue microarray analysis showed that CIDEA was frequently down-regulated at both the mRNA and protein level. This was significantly associated with low differentiation and TNM stage in ESCC, and indicated poor prognosis for ESCC patients. Bisulfite genomic sequencing (BGS) and methylation-specific PCR (MSP) analysis revealed that the down-regulation of CIDEA was associated with hypermethylation of its promoter, which was also correlated with the poor prognosis in ESCC patients. In vitro and in vivo functional studies demonstrated that CIDEA decreased cell growth, foci formation, DNA replication, and tumorigenesis in nude mice. Further study revealed that, during starvation or cisplatin induced DNA damage, CIDEA facilitated the G1-phase arrest or caspase-dependent mitochondrial apoptosis through the JNK-p21/Bad pathway. Therefore, CIDEA is a novel tumor suppressor gene that plays an important role in the development and progression of ESCC, and may provide a potential therapeutic target for patients with ESCC.

Keywords: apoptosis; cell death inducing DFF like effector A; cisplatin; esophageal squamous cell carcinoma; methylation.