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

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

Maider Beitia et al. Cancers (Basel).

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.

Keywords: (pro)renin receptor; Wnt; adenoma; angiotensin; biomarkers; colorectal cancer; vATPase.

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Immunohistochemical PRR staining along the adenomatous polyp-cancer sequence of CRC. (a) Representative fractions of uninvolved colonic mucosa, polyp and cancer tissue of 42 CRC patients were immunohistochemically stained with an antibody against PRR. Granular cytoplasmic staining was observed in neoplastic cells (black arrowhead). Stromal cellularity (lymphocytes and fibroblasts) did not express PRR (red asterisk). (b) PRR staining intensity was scored as negative, moderate or strong. The scores were quantified in each tissue type and statistical significance of the PRR intensity pattern among the different tissues was determined by Chi-Square test. H&E: Hematoxylin and Eosin staining. PRR: (pro)renin receptor staining.
Figure 2
Figure 2
Immunohistochemical PRR staining along the conversion of the primary tumour into metastasis. (a) Representative fractions of the centre of the primary tumour (n = 228), infiltrating front of the primary tumour (n = 222), local lymph node metastasis (n = 176) and distant metastasis (n = 94) were immunohistochemically stained with an antibody against PRR. Granular cytoplasmic staining was observed in neoplastic cells (black arrowhead). Stromal cellularity (lymphocytes and fibroblasts) did not express PRR (red asterisk). (b) PRR staining intensity was scored as negative, moderate or strong. The scores were quantified in each tissue type and statistical significance of the PRR intensity pattern among the different tissues was determined by Chi-Square test. H&E: Hematoxylin and Eosin staining. PRR: (pro)renin receptor staining.
Figure 3
Figure 3
PRR protein expression according to the metastatic relapse time of CRC patients. PRR staining intensity was scored as negative, moderate or strong. The scores were quantified in each tissue group and statistical significance of the PRR intensity pattern among the different tissues was determined by Chi-Square test. (*) p < 0.05.
Figure 4
Figure 4
Overall survival of CRC patients according to PRR staining. Tissues scored as negative were not included in the study for conforming groups with insufficient number of cases. Survival Kaplan–Meier curves were generated along 5 years (60-months) follow-up, comparing moderate and strong PRR staining in CRC tissues belonging to the centre, infiltrating front, local metastasis and distant metastasis.
Figure 5
Figure 5
Soluble PRR concentration in plasma samples. (a) SPRR plasma concentrations (ng/mL) comparing healthy controls and CRC cases. (b) 5-year overall survival in patients expressing high and low sPRR levels (cut-off point at 20.7 ng/mL) (Log-rank test p = 0.271).

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