Investigating the role of eukaryotic initiation factor 5B (eIF5B) in oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) is a common malignancy of the mucosal epithelium affecting ~600,000 patients a year. Patient prognosis remains poor despite improvements in the therapeutic regime. Therefore, new therapeutic targets must be identified that improve the current standard of care. Regulation of mRNA translation plays a critical role in oncogenesis and cancer progression. Particularly, the IRES-mediated non-canonical translation of distinct mRNAs has been implicated in tumorigenesis. Eukaryotic initiation factor 5B (eIF5B) is a key factor that drives IRES-mediated translation of distinct anti-apoptotic proteins and is implicated in the pathophysiology of several malignancies. Single-cell RNAseq data analysis demonstrated that EIF5B is predominantly expressed in cancer cells compared to other cells in the tumor microenvironment. Further bioinformatic analyses revealed that higher EIF5B mRNA is correlated with poor patient prognosis for OSCC patients. Therefore, we aimed to establish the pre-clinical rationale for eIF5B as a therapeutic target for OSCC. Cell viability data suggested that RNAi-mediated eIF5B depletion significantly increased OSCC cell death under TRAIL treatment. eIF5B depletion also resulted in decreased levels of multiple antiapoptotic proteins. Bromodeoxyuridine (BrdU) incorporation, invasion, and wound healing assays suggested eIF5B depletion hinders proliferation, invasion and migration phenotypes, respectively. Western blot analysis revealed that proteins involved in ERK and NF-κΒ signalling, VEGF and HIF-1α, decreased upon eIF5B depletion. eIF5B depletion also resulted in the decrease of angiogenic biomarkers and endothelial tube formation, suggesting a role of eIF5B depletion in decreasing the angiogenic capability of OSCC cells. Stable eIF5B depletion was achieved with the use of shRNA. Under these conditions, eIF5B depletion increased cell death in the presence of cisplatin. Decreased invasion phenotypes were also observed using shRNA-mediated knockdown, setting up the pipeline to transition experiments into preclinical mouse models. Thus, my work has a strong potential to establish eIF5B as a therapeutic target for OSCC treatment.

Authors

• Patel, Jinay
• University of Lethbridge. Faculty of Arts and Science

• Oral squamous cell carcinoma
• Squamous cell cancer
• Eukaryotic

Identifier

hdl:10133/6845

OAI identifier oai:identifier

oai:opus.uleth.ca:10133/6845