EIF3a Regulates Colorectal Cancer Metastasis via Translational Activation of RhoA and Cdc42

Chao Mei,Wei Zhang,Wen-Ting Dai,Ying Gao,Zhao-Qian Liu,Xi Li,Chong Liu

doi:10.3389/fcell.2022.794329

Abstract

Tumor metastasis is the major cause of tumor relapse and cancer-associated mortality in colorectal cancer, leading to poor therapeutic responses and reduced survival. eIF3a was previously described as an oncogene. However, its role in colorectal cancer progression and metastasis has not yet been fully investigated. In this study, the expression specificity and predictive value of eIF3a were investigated in clinical samples. The effects of eIF3a on cell proliferation and migration were verified in vivo and in vitro, respectively. The underlying molecular mechanism was revealed by western blotting, immunofluorescence, RNA-binding protein immunoprecipitation, and dual-luciferase reporter gene assays. The results showed that eIF3a was significantly overexpressed in tumor tissues compared with adjacent normal tissues. High eIF3a expression was correlated with tumor metastasis and overall survival. Downregulation of eIF3a obviously inhibited the proliferation and motility of malignant cells in vitro and in vivo. Mechanistically, eIF3a regulates Cdc42 and RhoA expression at the translation level, which further affects pseudopodia formation and actin cytoskeleton remodeling. Taken together, eIF3a accelerates the acquisition of the migratory phenotype of cancer cells by activating Cdc42 and RhoA expression at the translational level. Our study identified eIF3a as a promising target for inhibiting colorectal cancer metastasis.

Highlights

Colorectal cancer is the third most common cancer type with increasing incidence and mortality (Dekker et al, 2019; Keum and Giovannucci, 2019)
We found that Eukaryotic translation initiation factor 3a (eIF3a) expression in the metastasis sites is higher than primary tumors (Figures 1F,G)
Given the proto-oncogenic role of eIF3a in several other types of tumors, we investigated the specific features of eIF3a in colorectal cancer

Summary

Introduction

Colorectal cancer is the third most common cancer type with increasing incidence and mortality (Dekker et al, 2019; Keum and Giovannucci, 2019). EIF3a Promotes Colorectal Cancer Metastasis degradation (Tang et al, 2018; Kai et al, 2019; Lauko et al, 2020; Li and Wang, 2020) Such cytoskeletal dynamics and intracellular signaling are mainly regulated by the Rho family of small guanosine triphosphatases (GTPases) (Lawson and Ridley, 2018; Svensmark and Brakebusch, 2019). One of the most characterized enzymes, cell division cycle 42 (Cdc42), plays an irreplaceable role in cell polarization, filopodia formation, cytoskeletal reorganization, cell proliferation, and migration (Stengel and Zheng, 2011). Another member of the Rho family, ras homologue family member A (RhoA), is hyperactivated in several types of human cancer (Jansen et al, 2018; Nam et al, 2019). RhoA switches to an activated GTP-bound form and transmits the signal to downstream effectors, including the Rhoassociated serine-threonine kinase (Rock), promoting actin cytoskeleton reorganization and a variety of cellular functions (Narumiya et al, 2009; Wei et al, 2016)

Methods

Results

Conclusion