(Pro)renin Receptor Expression Increases throughout the Colorectal Adenoma-Adenocarcinoma Sequence and It Is Associated with Worse Colorectal Cancer Prognosis.

Maider Beitia,Alberto Loizate,Jon Danel Solano-Iturri,Peio Errarte,Mari Carmen Etxezarraga,Begoña Sanz,Gorka Larrinaga,Julio Calvete-Candenas

doi:10.3390/cancers11060881

Abstract

(Pro)renin receptor (PRR) is a protein that takes part in several signaling pathways such as Renin Angiotensin System and Wnt signalling. Its biological role has recently been related to cancer progression and in this study, we investigated its relevance in colorectal cancer (CRC). To that end, we analysed the immunohistochemical expression of PRR in adenomatous polyps and CRCs from the same patients (n = 42), and in primary tumours and nodal and liver metastases from advanced CRC patients (n = 294). In addition, the soluble fraction of PRR was measured by ELISA in plasma samples from 161 CRC patients. The results showed that PRR expression was gradually augmented along the uninvolved mucosa–adenoma–adenocarcinoma sequence. Besides, the stronger expression of PRR in primary tumours was markedly associated with local tumour extent and the onset of metastases. Moreover, PRR expression in both primary and distant metastases was associated with worse 5- and 10-year survival of CRC patients. Plasmatic PRR levels did not change with respect to controls and were not associated with CRC aggressiveness. These results suggest a key role of PRR in the development and progression of CRC and a potential use of this protein as a new prognostic biomarker and/or therapeutic target for this disease.

Highlights

Colorectal cancer (CRC) is one of the most common cancers worldwide, considerably increased in Western countries for its association with sedentary lifestyles and bad diet habits [1]
The collection included a tissue fraction of four different anatomic locations that represent the progression of colorectal cancer (CRC): the centre and the infiltrating front of the primary tumour, which were obtained in all the cases; tissues from local lymph node metastases, which were obtained in 232 cases; and liver metastases, obtained in 123 cases
The analyses showed a gradual increase in PRR staining intensity along the sequence, which was mainly negative in the uninvolved mucosa, mostly moderate in adenomatous polyps and predominantly strong in CRC

Summary

Introduction

Colorectal cancer (CRC) is one of the most common cancers worldwide, considerably increased in Western countries for its association with sedentary lifestyles and bad diet habits [1]. (Pro)renin receptor (PRR) was discovered in 2002 by Nguyen et al [3]. Renin Angiotensin System (RAS), an endocrine peptide system classically related to the regulation of blood pressure and hydro-electrolytic balance [4]. Beyond its classically known functions, RAS has been proved to be a complex system expressed in several tissues whose bioactive peptides and receptors locally regulate processes such as cell growth and proliferation too. In the last two decades, there has been an exponential increase in epidemiologic, basic and translational research demonstrating that imbalances in RAS are associated with cancer development and progression [7,14,15]

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