Annexin A2 overexpression associates with colorectal cancer invasiveness and TGF-\xdf induced epithelial mesenchymal transition via Src/ANXA2/STAT3

Murilo R Rocha,Mariana Boroni,Annie Cristhine M Sousa-Squiavinato,Pedro Barcellos-De-Souza,Priscila V Fernandes,Jose A Morgado-Diaz,Ivanir M De Oliveira

doi:10.1038/s41598-018-29703-0

Abstract

Annexin A2 (ANXA2) is upregulated in several malignancies, including colorectal cancer (CRC). However, there is little knowledge on the molecular mechanisms involved to its upregulation. The aim of this study was to identify the mechanism through which ANXA2 overexpression leads to CRC progression and evaluate its potential prognostic value. We used human CRC samples to analyse the correlation between ANXA2 levels and tumour staging. ANXA2 expression was increased in CRC tissues compared to normal colon tissues. In addition, we observe increased ANXA2 levels in stage IV tumours and metastasis, when compared to stage I-III. Whereas E-cadherin, an epithelial marker, decreased in stage II-IV and increased in metastasis. We’ve also shown that TGF-β, a classic EMT inductor, caused upregulation of ANXA2, and internalization of both E-cadherin and ANXA2 in CRC cells. ANXA2 silencing hindered TGF-β-induced invasiveness, and inhibitors of the Src/ANXA2/STAT3 pathway reversed the EMT. In silico analysis confirmed overexpression of ANXA2 and association to the consensus moleculars subtypes (CMS) with the worst prognosis. Therefore, ANXA2 overexpression play a pivotal role in CRC invasiveness through Src/ANXA2/STAT3 pathway activation. The association of ANXA2 to distinct CMSs suggests the possible use of ANXA2 as a prognostic marker or directed target therapy.

Highlights

colorectal cancer (CRC) is the third most commonly diagnosed cancer and, in 2012, it was responsible for over 690 thousand deaths and accounted for 1.4 million new cases
We sought to confirm if Annexin A2 (ANXA2) is overexpressed in CRC human samples by analysing its expression in different stages of the disease, evaluate its prognostic value potential and explore the pathways through which ANXA2 overexpression leads to cancer progression
As E-cadherin downregulation is a hallmark of EMT; we evaluate EMT role in CRC progression by investigating E-cadherin levels in the same samples

Summary

Introduction

CRC is the third most commonly diagnosed cancer and, in 2012, it was responsible for over 690 thousand deaths and accounted for 1.4 million new cases. CRC’s heterogeneity has eluded researchers in the attempt to clearly characterize and define treatment strategies and markers that work for most of the patients To tackle this problem, a consortium has analysed over 4,150 patients with this cancer and identified four consensus molecular subtypes (CMS) for CRC. The EMT is a metastable cellular process, during which cells lose their apical-basal polarity, disassemble their cell-cell junctions and gain mesenchymal characteristics, and enhanced migratory and invasive capabilities[7]. These features make EMT-related proteins interesting in the attempt to prevent metastasis. The association of ANXA2 levels to distinct CMSs suggests the possible use of ANXA2 as a prognostic marker or directed target therapy

Objectives

Methods

Results

Conclusion