Lastraioli Elena, Fraser Scott P, Guzel R Mine, Iorio Jessica, Bencini Lapo, Scarpi Emanuela, Messerini Luca, Villanacci Vincenzo, Cerino Giulia, Ghezzi Niccolo', Perrone Giuseppe, Djamgoz Mustafa B A, Arcangeli Annarosa
Department of Experimental and Clinical Medicine, University of Florence, viale GB Morgagni 50, 50134 Florence, Italy.
Department of Life Sciences, South Kensington Campus, Imperial College London, London SW7 2AZ, UK.
Cancers (Basel). 2021 Jul 30;13(15):3832. doi: 10.3390/cancers13153832.
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.
电压门控钠通道（VGSCs）在人类癌症中广泛表达，在促进细胞侵袭和转移方面发挥着重要作用。然而，缺乏基于人体组织的研究和临床特征描述。在包括结直肠癌（CRCa）在内的几种癌症中，主要的VGSC是Nav1.5的新生儿剪接变体（nNav1.5）。本研究旨在确定nNav1.5蛋白在有可用临床病理病史的CRC患者的人体CRCa组织中的表达模式及其临床相关性。通过使用对nNav1.5特异的多克隆抗体（NESOpAb）进行免疫组织化学检测。分析表明，与正常黏膜相比，nNav1.5在CRCa样本中的表达情况如下：（i）水平显著更高；（ii）模式更清晰（即顶端/基底或混合模式）。腺瘤中也出现了令人惊讶的高nNav1.5蛋白表达水平，但这主要是细胞内的且呈弥漫性。nNav1.5与TNM分期具有统计学意义的关联，最高表达与TNM IV期和转移状态相关。有趣的是，nNav1.5表达与其他与转移相关的生物标志物共同出现，包括hERG1、KCa3.1、VEGF - A、Glut1和EGFR。最后，单因素分析表明nNav1.5表达对无进展生存期有影响。我们得出以下结论：（i）nNav1.5可能代表一种新型临床生物标志物（“伴随诊断”），有助于更好地对CRCa患者进行分层；（ii）由于nNav1.5表达具有功能，它可以成为包括与标准治疗联合使用的抗转移治疗的基础。
