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Article

Neonatal Nav1.5 Protein Expression in Human Colorectal Cancer: Immunohistochemical Characterization and Clinical Evaluation

1
Department of Experimental and Clinical Medicine, University of Florence, viale GB Morgagni 50, 50134 Florence, Italy
2
Department of Life Sciences, South Kensington Campus, Imperial College London, London SW7 2AZ, UK
3
Department of Oncology, Division of Oncologic Surgery and Robotics, Azienda Ospedaliero-Universitaria Careggi, Largo Brambilla 3, 50134 Florence, Italy
4
Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Via P Maroncelli 40, 47014 Meldola, Italy
5
Institute of Pathology, ASST Spedali Civili di Brescia, Piazzale Spedali Civili 1, 25123 Brescia, Italy
6
Pathology Unit, Campus Bio-Medico University, via A del Portillo 200, 00128 Rome, Italy
7
Cyprus International University, Biotechnology Research Centre, Haspolat, Mersin 10, Cyprus
*
Author to whom correspondence should be addressed.
Present address: Biruni Laboratories, Istanbul, Turkey.
Academic Editor: John Souglakos
Cancers 2021, 13(15), 3832; https://doi.org/10.3390/cancers13153832
Received: 23 June 2021 / Revised: 22 July 2021 / Accepted: 23 July 2021 / Published: 30 July 2021
(This article belongs to the Special Issue Molecular Biomarkers in Colorectal Cancer)
The voltage-gated sodium channel is a type of protein normally expressed in the ‘excitable’ tissues (nerves and muscles) of the body. Epithelial tissues (gut, lungs etc.), which are normally devoid of such a channel, express it at high levels upon becoming cancerous. This occurs also in colorectal cancer cells where the channel subtype is the embryonic (‘neonatal’) variant, nNav1.5. In colorectal cancer cells, as in other solid cancer cells, channel activity promotes invasiveness. However, there is little information on the status of nNav1.5 in human colorectal tissues and how this might relate to patient outcome. Here, we show (i) that nNav1.5 expression is much higher in cancer tissues compared with normal; (ii) that nNav1.5 co-occurs with several other biomarkers of pathological importance; and (iii) that disease-free survival of colorectal patients is inversely correlated with channel expression. In conclusion, nNav1.5 has combined diagnostic and therapeutic potential in clinical management of colorectal cancer.
Voltage-gated Na+ channels (VGSCs) are expressed widely in human carcinomas and play a significant role in promoting cellular invasiveness and metastasis. However, human tissue-based studies and clinical characterization are lacking. In several carcinomas, including colorectal cancer (CRCa), the predominant VGSC is the neonatal splice variant of Nav1.5 (nNav1.5). The present study was designed to determine the expression patterns and clinical relevance of nNav1.5 protein in human CRCa tissues from patients with available clinicopathological history. The immunohistochemistry was made possible by the use of a polyclonal antibody (NESOpAb) specific for nNav1.5. The analysis showed that, compared with normal mucosa, nNav1.5 expression occurred in CRCa samples (i) at levels that were significantly higher and (ii) with a pattern that was more delineated (i.e., apical/basal or mixed). A surprisingly high level of nNav1.5 protein expression also occurred in adenomas, but this was mainly intracellular and diffuse. nNav1.5 showed a statistically significant association with TNM stage, highest expression being associated with TNM IV and metastatic status. Interestingly, nNav1.5 expression co-occurred with other biomarkers associated with metastasis, including hERG1, KCa3.1, VEGF-A, Glut1, and EGFR. Finally, univariate analysis showed that nNav1.5 expression had an impact on progression-free survival. We conclude (i) that nNav1.5 could represent a novel clinical biomarker (‘companion diagnostic’) useful to better stratify CRCa patients and (ii) that since nNav1.5 expression is functional, it could form the basis of anti-metastatic therapies including in combination with standard treatments. View Full-Text
Keywords: colorectal cancer; metastasis; voltage-gated sodium channel; neonatal Nav1.5; immunohistochemistry colorectal cancer; metastasis; voltage-gated sodium channel; neonatal Nav1.5; immunohistochemistry
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MDPI and ACS Style

Lastraioli, E.; Fraser, S.P.; Guzel, R.M.; Iorio, J.; Bencini, L.; Scarpi, E.; Messerini, L.; Villanacci, V.; Cerino, G.; Ghezzi, N.; Perrone, G.; Djamgoz, M.B.A.; Arcangeli, A. Neonatal Nav1.5 Protein Expression in Human Colorectal Cancer: Immunohistochemical Characterization and Clinical Evaluation. Cancers 2021, 13, 3832. https://doi.org/10.3390/cancers13153832

AMA Style

Lastraioli E, Fraser SP, Guzel RM, Iorio J, Bencini L, Scarpi E, Messerini L, Villanacci V, Cerino G, Ghezzi N, Perrone G, Djamgoz MBA, Arcangeli A. Neonatal Nav1.5 Protein Expression in Human Colorectal Cancer: Immunohistochemical Characterization and Clinical Evaluation. Cancers. 2021; 13(15):3832. https://doi.org/10.3390/cancers13153832

Chicago/Turabian Style

Lastraioli, Elena, Scott P. Fraser, R. M. Guzel, Jessica Iorio, Lapo Bencini, Emanuela Scarpi, Luca Messerini, Vincenzo Villanacci, Giulia Cerino, Niccolo’ Ghezzi, Giuseppe Perrone, Mustafa B.A. Djamgoz, and Annarosa Arcangeli. 2021. "Neonatal Nav1.5 Protein Expression in Human Colorectal Cancer: Immunohistochemical Characterization and Clinical Evaluation" Cancers 13, no. 15: 3832. https://doi.org/10.3390/cancers13153832

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