ETV4 promotes the growth, metastasis, glycolysis, and oxaliplatin resistance of colorectal cancer by transcription activation-mediated SLC38A5 upregulation

Background: Colorectal Cancer (CRC) is one of the most common malignancies worldwide with a poor prognosis. Previous studies have indicated that solute carrier family 38 member 5 (SLC38A5), an Amino acid Transporter, plays an important role in some solid tumors. However, the role and mechanism of SLC38A5 in the progression of CRC are poorly defined.

Methods: In this research, TIMER, UALCAN, and GEPIA databases were applied to analyze the expression of SLC38A5 in CRC. SLC38A5 and E26 transformation-specific variant 4 (ETV4) mRNA levels were determined using real-time quantitative polymerase chain reaction (RT-qPCR) assay. SLC38A5, ETV4, HK-2, and LDHA protein levels were measured using western blot. Cell proliferation, migration, invasion, and Oxaliplatin (L-OHP) resistance were examined using Cell Counting Kit-8 (CCK-8) assay and Transwell assay. Glucose consumption, lactate production, and ATP levels were assessed using relevant kits. Binding between ETV4 and SLC38A5 promoter was predicted by JASPAR and validated using Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays. The biological role of ETV4 on CRC tumor growth was examined by the xenograft tumor model in vivo.

Results: ETV4 and SLC38A5 were highly expressed in CRC tissues and cells. Moreover, SLC38A5 deficiency could hinder CRC cell proliferation, migration, invasion, glycolysis, and improved L-OHP sensitivity in vitro. Mechanistically, ETV4 was a transcription factor of SLC38A5 and activated the transcriptional activity of SLC38A5 via binding to its promoter region. ETV4 silencing knockdown repressed tumor growth in vivo.

Conclusion: SLC38A5 transcriptionally mediated by ETV4 expedites CRC cell growth, metastasis, glycolysis, L-OHP resistance, which provides a promising therapeutic target for CRC treatment.

Colorectal cancer; ETV4; Oxaliplatin sensitivity; Proliferation; SLC38A5.