Loss of EIF4G2 mediates aggressiveness in distinct human endometrial cancer subpopulations with poor survival outcome in patients

Sara Meril, Maya Muhlbauer Avni, Chen Lior, Marcela Bahlsen, Tsviya Olender, Alon Savidor, Judit Krausz, Hila Belhanes Peled, Hila Birisi, Nofar David, Shani Bialik, Ruth Scherz-Shouval, Yehuda Ben David, Adi Kimchi

Research output: Contribution to journalArticlepeer-review

Abstract

The non-canonical translation initiation factor EIF4G2 plays essential roles in cellular stress responses via translation of selective mRNA cohorts. Currently there is limited and conflicting information regarding its involvement in cancer development and progression. Here we assessed its role in endometrial cancer (EC), in 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 stably knocked-down EIF4G2 in two human EC cell lines in parallel. EIF4G2 depletion resulted in increased resistance to conventional therapies and increased the prevalence of molecular markers for aggressive cell subsets, altering 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 EC patient tumor cohort showed a correlation between decreased expression of the kinesin proteins, and poor survival in patients with tumors of certain grades and stages. These findings reveal potential novel biomarkers for Grade 2 EC with ramifications for patient stratification and therapeutic interventions.

Original languageEnglish
Pages (from-to)1098-1112
Number of pages15
JournalOncogene
Volume43
Issue number15
Early online date22 Feb 2024
DOIs
StatePublished - 5 Apr 2024
Externally publishedYes

Bibliographical note

Publisher Copyright:
© The Author(s) 2024.

Funding

We would like to thank Dr. Anastasia Lev and Prof. Rivka Dikstein from the Weizmann Institute for the polysomal profile analysis. We also thank Doron Bril for his assistance with conducting experiments necessary for revisions. This research was supported by grants from the Women’s Health Research Center at the Weizmann and the Pasteur-Weizmann Council for AK, and by a scholarship from Emek Medical Center for MMA.

FundersFunder number
Emek Medical Center for MMA
Pasteur-Weizmann Council
Women’s Health Research Center

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