Loss of EIF4G2 Mediates Aggressiveness in Distinct Human Endometrial Cancer Subpopulations with Poorer Survival Outcome in Patients

Abstract

The non-canonical translation initiation factor EIF4G2 plays essential roles in embryonic development and differentiation, and contributes to the cellular stress response via translation of selective mRNA cohorts. Currently there is limited and conflicting information regarding the potential involvement of EIF4G2 in cancer development and progression. Endometrial cancer (EC) is the most pervasive gynecological cancer in the developed world, with increasing incidence every year. High grade ECs are largely refractory to conventional treatments, presenting poor survival rates and lacking suitable prognostic markers. Here we assayed a cohort of 280 EC patients across different types, grades, and stages, and found that low EIF4G2 expression highly correlated with poor overall and recurrence free survival in Grade 2 EC patients, monitored over a period of up to 12 years. To establish a causative connection between low EIF4G2 expression and cancer progression, we analyzed in parallel two independent human EC cell lines and demonstrated that stable EIF4G2 knock-down resulted in increased resistance to conventional therapies. Depletion of EIF4G2 also increased the prevalence of molecular markers for aggressive cell subsets, and altered their transcriptional and proteomic landscapes. Prominent among the proteins with decreased abundance were Kinesin-1 motor proteins KIF5B and KLC1, 2, 3. Multiplexed imaging of the tumors from this EC patient cohort showed a correlation between decreased protein expression of either KIF5B or KLC1, and poor survival in patients of certain grades and stages. The findings herein reveal potential novel biomarkers for Grade 2 EC with potential ramifications for patient stratification and therapeutic interventions. SignificanceDecreased EIF4G2 protein results in increased drug resistance of aggressive sub-populations of endometrial cancer cells, is associated with poor patient survival, and may serve as a novel prognosis marker for endometrial cancer.