The RNA-binding protein ESRP1 promotes human colorectal cancer progression.

Sharmila Fagoonee,Silvio Aime,Pier Paolo Pandolfi,Enzo Medico,Lorenzo Silengo,Roberto Piva,Arrigo Arrigoni,Paola Cassoni,Gabriele Picco,Dario L Longo,Irene Scarfò,Daniela Taverna,Fiorella Altruda,Emanuela Tolosano,Francesca Orso,Adele Cassenti,Marco Forni,Mara Brancaccio

doi:10.18632/oncotarget.14318

Abstract

Epithelial splicing regulatory protein 1 (ESRP1) is an epithelial cell-specific RNA binding protein that controls several key cellular processes, like alternative splicing and translation. Previous studies have demonstrated a tumor suppressor role for this protein. Recently, however, a pro-metastatic function of ESRP1 has been reported. We thus aimed at clarifying the role of ESRP1 in Colorectal Cancer (CRC) by performing loss- and gain-of-function studies, and evaluating tumorigenesis and malignancy with in vitro and in vivo approaches. We found that ESRP1 plays a role in anchorage-independent growth of CRC cells. ESRP1-overexpressing cells grown in suspension showed enhanced fibroblast growth factor receptor (FGFR1/2) signalling, Akt activation, and Snail upregulation. Moreover, ESRP1 promoted the ability of CRC cells to generate macrometastases in mice livers. High ESRP1 expression may thus stimulate growth of cancer epithelial cells and promote colorectal cancer progression. Our findings provide mechanistic insights into a previously unreported, pro-oncogenic role for ESRP1 in CRC, and suggest that fine-tuning the level of this RNA-binding protein could be relevant in modulating tumor growth in a subset of CRC patients.

Highlights

Colorectal cancer (CRC) is the third most common cancer worldwide [1]
As the receptor tyrosine kinase (RTK) Fibroblast Growth Factor Receptor (FGFR) 2 is a known splicing target of Epithelial splicing regulatory protein 1 (ESRP1) and is highly expressed in some Colorectal Cancer (CRC) cell lines, we investigated whether the FGFR pathway www.impactjournals.com/oncotarget www.impactjournals.com/oncotarget was involved in the activation of Akt in the ESRP1overexpressing cells [23,26]
As an RNA-binding proteins (RBPs), ESRP1 is involved in several cellular processes like alternative splicing, regulation of translation and mRNA stability [30,31]

Summary

Introduction

Colorectal cancer (CRC) is the third most common cancer worldwide [1]. Colorectal carcinogenesis is a complex process in which the activation of oncogenes and inactivation of tumor suppressor genes affect several critical cancer-related pathways [2, 3]. Recent advances in the field of CRC have highlighted several new key regulators of tumour initiation and progression, including short and long regulatory non-coding RNAs [4, 5]. Dysregulation in these molecules may alter many gene regulatory networks at the transcriptional, posttranscriptional or epigenetic level leading to cancer cell transformation. Alterations in RBPs expression or mutation in the binding sites of target RNAs may lead to the formation of aberrant ribonucleoprotein complexes, changing their function and contributing to cancer initiation [9]. The finding that RBPs can act both as oncogene or tumor suppressor, like Hu Antigen R, further complicates this issue [11]

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