EI24 Inhibits Cell Proliferation and Drug Resistance of Esophageal Squamous Cell Carcinoma

Abstract

Drug resistance, whether intrinsic or acquired, often leads to treatment failure in esophageal squamous cell carcinoma (ESCC). Clarifying the mechanism of drug resistance in ESCC has great significance for reversing drug resistance, as well as improving the prognosis of patients. Previously, we demonstrated that etoposideinduced 2.4-kb mRNA (EI24) is the target of miR-483-3p, which promoted the growth, migration, and drug resistance in ESCC, suggesting that EI24 participates in repressing the tumorigenesis and progression of ESCC. Here, we observed that EI24 was remarkably decreased in ESCC tissues. Moreover, its expression was directly linked to the prognosis of patients. We then confirmed that the forced overexpression of EI24 repressed cell growth and sensitized ESCC cells to chemotherapeutic agents, whereas EI24 silencing had the opposite effect. Furthermore, gene microarray and ingenuity pathway analysis (IPA) were performed to establish the potential mechanisms and indicated that EI24 exerts a tumor-suppressive role via suppressing the acute phase response signaling pathway or IL-1 signaling pathway in ESCC. Collectively, our data reveal that EI24 overexpression attenuates malignant phenotypes of ESCC and that it is a novel possible ESCC therapeutic target.

miR‑483 promotes the development of colorectal cancer by inhibiting the expression level of EI24

“…5B), and it was identified that EI24 expression in the overexpression group was notably lower compared with that in the NC group, suggesting that upregulation of miR-483 may inhibit the expression of EI24 protein. These results are consistent with our previous studies (24,28), suggesting a targeting relationship between miR-483 and EI24.…”

“…miR-483 expression is negatively associated with EI24 levels in CRC tissues. Our previous studies reported that the expression level of miR-483 was increased in esophageal squamous cell carcinoma, and that upregulation of miR-483 could promote the development of esophageal cancer (24,28). Furthermore, a reporter gene test confirmed that EI24 was the target molecule of miR-483 (21).…”

“…Both miR-483 and EI24 are involved in important biological processes, including tumor cell proliferation, invasion and migration, and they overlap in the process of tumor metastasis (28). Our previous study revealed that the expression level of miR-483 was increased in esophageal cancer (24).…”

Intersections of Ubiquitin-Proteosome System and Autophagy in Promoting Growth of Glioblastoma Multiforme: Challenges and Opportunities

“…EI24 is an important autophagy-associated protein and tumor suppressor that has been found to be under expressed in a variety of malignancies [ 90 , 91 , 92 , 93 ], although other studies have found no correlation or even positive correlation between EI24 expression and tumorigenesis in certain cancers, indicating that effects of EI24 depend on the cellular context of the cancers [ 94 , 95 ]. Additionally, EI24 regulates the UPS by targeting certain RING E3 ligases for autophagy mediated degradation; earlier studies have identified 161 RING E3 ligases as potential targets of EI24, the best characterized of which are TNFR-associated factor 2/5 (TRAF2/5), mouse double minute 2 homolog (MDM2), and tripartite motif containing 41 (TRIM41)—also called RING finger protein that interacts with C kinase 1 (RINCK1) [ 94 , 96 ].…”

MicroRNAs and Corresponding Targets in Esophageal Cancer as ShownIn VitroandIn Vivoin Preclinical Models

“…EI24 has been identified as a direct target of miR-483-3p (31). EI24, a p53-response protein, contains six transmembrane domains and suppresses cell growth through caspase 9 and mitochondrial pathways including in ESCC (32,33). Furthermore, EI24 has been shown to contribute to EMT (34).…”