Identification of the Pro-Tumorigenic Role of the ELK4-METTL3-CEMIP Axis in Colorectal Carcinoma: Promotion of Cancer Cell Stemness and Malignant Phenotypes.

Background: Colorectal carcinoma (CRC) is the third most prevalent and deadly malignancy worldwide. CEMIP has emerged as a significant player in colorectal tumorigenesis and CRC metastasis. Here, we explored the specific role of CEMIP in the malignant phenotypes and stemness of CRC cells.

Methods: The expression analysis was performed by quantitative PCR, immunohistochemistry, or immunoblot methods. The effect on CRC cell malignant phenotypes was determined by detecting cell colony formation, invasion, and migration. The influence on CRC cell stemness was evaluated by analyzing cell spheroid formation potential and related protein expression. The METTL3-CEMIP relationship was confirmed by RIP, luciferase, and mRNA stability assays. The ELK4-METTL3 relationship was verified by ChIP and luciferase assays.

Results: High levels of CEMIP in CRC were associated with poor patient outcomes. CEMIP downregulation inhibited CRC cell growth, migration, invasion, and stemness while promoting apoptosis. Moreover, METTL3 stabilized CEMIP mRNA to upregulate its expression. CEMIP restoration reversed METTL3 knockdown-driven alterations in cell phenotypes and stemness. The transcription factor (TF) ELK4 transcriptionally upregulated METTL3, thereby influencing the stemness and malignant behaviors of CRC cells. Furthermore, ELK4 increased CEMIP expression through METTL3 in CRC cells. Additionally, ELK4 depletion hindered the in vivo tumorigenesis of SW620 CRC cells.

Conclusion: Our findings demonstrate that the ELK4-METTL3-CEMIP axis enhances the development of CRC. Targeting the axis may lead to the development of novel strategies against CRC.