Abstract

Simple SummaryColorectal cancer (CRC) ranks third for incidence and second for number of deaths among cancer types worldwide. Poor patient survival due to inadequate response to currently available treatment regimens points to the urgent requirement for personalized therapy in CRC patients. Our aim was to provide mechanistic insights into the pro-tumorigenic role of the RNA-binding protein ESRP1, which is highly expressed in a subset of CRC patients. We show that, in CRC cells, ESRP1 binds to and has the same trend in expression as RAC1b, a well-known tumor promoter. Thus, RAC1b may be a potential therapeutic target in ESRP1-overexpressing CRC.RNA binding proteins are well recognized as critical regulators of tumorigenic processes through their capacity to modulate RNA biogenesis, including alternative splicing, RNA stability and mRNA translation. The RNA binding protein Epithelial Splicing Regulatory Protein 1 (ESRP1) can act as a tumor suppressor or promoter in a cell type- and disease context-dependent manner. We have previously shown that elevated expression of ESRP1 in colorectal cancer cells can drive tumor progression. To gain further insights into the pro-tumorigenic mechanism of action of ESRP1, we performed cDNA microarray analysis on two colorectal cells lines modulated for ESRP1 expression. Intriguingly, RAC1b was highly expressed, both at mRNA and protein levels, in ESRP1-overexpressing cells, while the opposite trend was observed in ESRP1-silenced CRC cells. Moreover, RAC1 and RAC1b mRNA co-immunoprecipitate with ESRP1 protein. Silencing of RAC1b expression significantly reduced the number of soft agar colonies formed by ESRP1-overexpressing cells, suggesting that ESRP1 acted, at least partially, through RAC1b in its tumor-promoting activities in CRC cells. Thus, our data provide molecular cues on targetable candidates in CRC cases with high ESRP1 expression.

Highlights

  • We previously demonstrated that Epithelial Splicing Regulatory Protein 1 (ESRP1) expression is absent in the highly metastatic cell line COLO320DM, while it is expressed at elevated levels in HCA24 cells [11]

  • We further investigated the underlying molecular mechanisms by which ESRP1 exerts its pro-tumorigenic function by performing large-scale gene expression profiling on two different Colorectal cancer (CRC) cell lines, in which ESRP1 expression was modulated

  • Genes (E-cadherin and Vimentin), as well as to modulate chemoresistance development (Figure S2) [55]. This is the first report of ESRP1 exerting its pro-tumorigenic function through RAC1b

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Summary

Introduction

Colorectal cancer (CRC) ranks third for prevalence and second for number of deaths among all cancers worldwide [1]. According to the worldwide cancer burden in 2020 and GLOBOCAN estimates of cancer incidence and mortality produced by the International. Agency for Research on Cancer, CRC was fifth among cancers with newly diagnosed cases, as well as deaths in 2020 [1]. Management of this malignant tumor is achieved by several strategies, including chemotherapy and targeted therapy using small molecules [2]. Poor patient survival, due to inadequate response to currently available treatment regimens and shortage of adequate risk-assessment biomarkers, points out to the urgent requirement for personalized therapy in CRC patients

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