E74-like factor 3 suppresses microRNA-485-5p transcription to trigger growth and metastasis of ovarian cancer cells with the involvement of CLDN4/Wnt/β-catenin axis

Abstract

Ovarian cancer (OC) is one of the most prevailing gynecological malignancies with high mortality rate, while E74 like ETS transcription factor 3 (ELF3) is reported to be associated with tumorigenesis. This work aims to analyze the role of ELF3 on the suppression of miR-485-5p transcription in OC. Expression of ELF3 in OC and its correlation with overall survival were predicted on a bioinformation system GEPIA. Then, the level of ELF3 in OC tissues and cells and in normal ones was evaluated. Binding relationships between ELF3 and microRNA (miR)-485-5p, and between miR-485-5p and claudin-4 (CLND4) were predicted through Bioinformatics tools. Altered expression of ELF3, miR-485-5p and CLND4 was introduced alone or jointly to probe their influences on OC cell growth. ELF3 was suggested to be highly expressed in OC, which was linked to poor prognosis in patients. Abundant expression of ELF3 was identified in OC tissues and cell lines as relative to the normal ones. ELF3 inhibition suppressed growth and metastasis of OC cells. ELF3 transcriptionally suppressed miR-485-5p expression to further enhance CLDN4 expression. Overexpression of miR-485-5p led to similar trends as ELF3 inhibition did. Importantly, upregulation of CLDN4 was found to block the roles of ELF3 inhibition in OC cells. In addition, the Wnt/signaling pathway suppressed by miR-485-5p mimic was reactivated following CLDN4 overexpression. This study evidenced that ELF3 suppresses miR-485-5p transcription to enhance CLDN4 expression, leading to Wnt/β-catenin activation and promoting OC cell growth and metastasis. This work may provide new ideas for gene-based therapies for OC.

Overview of the signaling pathways involved in metastasis: An intriguing story-tale of the metastatic journey of ovarian cancer cells

“…Claudin-4 (CLND4) is directly targeted by miR-485-5p. Accordingly, miR-485-5p targeted CLDN4 for the inactivation of Wnt/β-catenin cascade in ovarian cancer cells (34). Overall, these findings suggested that ELF3 transcriptionally reduced miR-485-5p to potentiate CLDN4 expression.…”

Single‐cell transcriptomics reveal metastatic CLDN4+ cancer cells underlying the recurrence of malignant pleural effusion in patients with advanced non‐small‐cell lung cancer

“…62 Kuang et al pointed out that ELF3 promoted tumour growth and metastasis by inhibiting microRNA-485-5p. 63 Horie et al also suggested that elevated ELF3 expression level was linked to the tumour promotion traits in cancers. 64 Overall, our study provided the initial data regarding the potential mechanisms of CLDN4 contributing to the recurrence of MPE in advanced NSCLC, while further in-depth experiments were required to perform to validate its specific mechanisms.…”

“…Kuang et al. pointed out that ELF3 promoted tumour growth and metastasis by inhibiting microRNA‐485‐5p 63 . Horie et al.…”

“…pointed out that ELF3 promoted tumour growth and metastasis by inhibiting microRNA‐485‐5p. 63 Horie et al. also suggested that elevated ELF3 expression level was linked to the tumour promotion traits in cancers.…”

Hypoxia‐induced ELF3 promotes tumor angiogenesis through IGF1/IGF1R

“…ELF3 overexpression is reported to promote the pathogenesis of OC through the mTOR signaling pathway and induce cisplatin resistance in OCs (Liu et al , 2021 ). Furthermore, ELF3 is also known to promote OC cell growth and metastasis by inhibiting miR‐485‐5p transcription, which interferes with the CLDN4/Wnt/β‐catenin axis (Kuang & Li, 2021 ). A number of researchers continue to investigate the relationship between OC and ELF3.…”