Department of Nursing I, School of Nursing, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain.
Department of Physiology, Faculty of Medicine and Dentistry, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain.
Int J Med Sci. 2019 Jun 2;16(6):813-821. doi: 10.7150/ijms.32599. eCollection 2019.
: Colorectal cancer (CRC) is a major health problem in developed countries. Adenomatous lesions in the large bowel are the main precursors of CRC and the adenoma-adenocarcinoma sequence still provides a solid model for research on carcinogenesis. The finding of local renin-angiotensin systems (RAS) has been crucial to understand the role of this peptidergic system in cancer and has opened new perspectives in the study of colorectal carcinogenetic processes. : In this study we analyzed the immunohistochemical expression of three main RAS receptors (AT1, AT2 and MAS) in a large series of CRC samples (n=161), including uninvolved intestinal mucosa-adenoma-adenocarcinoma sequences from the same patients (n=50). : 1) AT1 and AT2 showed a biphasic expression pattern along the sequence. The expression significantly decreased in adenomas with respect to uninvolved mucosa but increased in CRCs. 2) AT2 expression was lower in advanced CRCs with high local invasion (pT4), high stage (IV), high nodal (N2) and vascular invasion. 3) MAS receptor was moderately expressed in the uninvolved mucosa and in adenomas. This expression increased very significantly in CRC tissues. : These results suggest that: 1) RAS receptors are differentially regulated as the genetic and epigenetic alterations accumulate throughout the uninvolved mucosa-adenoma-CRC sequence. 2) Loss of AT2 expression could contribute to the aggressive behavior of advanced CRC cells.
结直肠癌（CRC）是发达国家的一个主要健康问题。大肠的腺瘤性病变是 CRC 的主要前体，腺瘤-腺癌序列仍然为致癌发生的研究提供了坚实的模型。局部肾素-血管紧张素系统（RAS）的发现对于理解该肽能系统在癌症中的作用至关重要，并为结直肠致癌发生过程的研究开辟了新的视角。在这项研究中，我们分析了大量 CRC 样本（n=161）中三种主要 RAS 受体（AT1、AT2 和 MAS）的免疫组织化学表达，包括来自同一患者的未受累肠黏膜-腺瘤-腺癌序列（n=50）。1）AT1 和 AT2 沿序列呈双相表达模式。与未受累黏膜相比，腺瘤中的表达显著降低，但在 CRC 中增加。2）在具有高局部侵袭（pT4）、高分期（IV）、高淋巴结（N2）和血管侵袭的晚期 CRC 中，AT2 表达较低。3）MAS 受体在未受累黏膜和腺瘤中中度表达。在 CRC 组织中，这种表达显著增加。这些结果表明：1）随着未受累黏膜-腺瘤-CRC 序列中遗传和表观遗传改变的积累，RAS 受体受到差异调节。2）AT2 表达的丧失可能导致晚期 CRC 细胞的侵袭行为。
