Bona Amanda Braga, Calcagno Danielle Queiroz, Ribeiro Helem Ferreira, Muniz José Augusto Pereira Carneiro, Pinto Giovanny Rebouças, Rocha Carlos Alberto Machado, Lacreta Junior Antonio Carlos Cunha, de Assumpção Paulo Pimentel, Herranz Juan Antonio Rey, Burbano Rommel Rodriguez
Oncology Research Laboratory, Ophir Loyola Hospital, Governador Magalhães Barata Avenue, 992 Belém, PA, 66063-240, Brazil Biological Sciences Institute, Federal University of Pará, Belém, Brazil.
Oncology Research Nucleus, University Hospital João de Barros Barreto, Federal University of Pará, Belém, Brazil.
Therap Adv Gastroenterol. 2020 Jan 11;13:1756284819895435. doi: 10.1177/1756284819895435. eCollection 2020.
Gastric cancer is one of the most incident types of cancer worldwide and presents high mortality rates and poor prognosis. oncogene overexpression is a key event in gastric carcinogenesis and it is known that its protein positively regulates CDC25B expression which, in turn, plays an essential role in the cell division cycle progression. Menadione is a synthetic form of vitamin K that acts as a specific inhibitor of the CDC25 family of phosphatases.
To better understand the menadione mechanism of action in gastric cancer, we evaluated its molecular and cellular effects in cell lines and in , nonhuman primates from the new world which had gastric carcinogenesis induced by N-Methyl-N-nitrosourea. We tested CDC25B expression by western blot and RT-qPCR. assays include proliferation, migration, invasion and flow cytometry to analyze cell cycle arrest. In experiments, in addition to the expression analyses, we followed the preneoplastic lesions and the tumor progression by ultrasonography, endoscopy, biopsies, histopathology and immunohistochemistry.
Our tests demonstrated menadione reducing CDC25B expression and . It was able to reduce migration, invasion and proliferation rates, and induce cell cycle arrest in gastric cancer cell lines. Moreover, our experiments demonstrated menadione inhibiting tumor development and progression.
We suggest this compound may be an important ally of chemotherapeutics in the treatment of gastric cancer. In addition, CDC25B has proven to be an effective target for investigation and development of new therapeutic strategies for this malignancy.
胃癌是全球发病率最高的癌症类型之一，死亡率高且预后不良。癌基因过表达是胃癌发生的关键事件，已知其蛋白可正向调节细胞分裂周期蛋白25B（CDC25B）的表达，而CDC25B在细胞分裂周期进程中起重要作用。甲萘醌是维生素K的一种合成形式，可作为CDC25磷酸酶家族的特异性抑制剂。
为了更好地了解甲萘醌在胃癌中的作用机制，我们评估了其对细胞系以及由N-甲基-N-亚硝基脲诱导胃癌发生的新大陆非人灵长类动物的分子和细胞效应。我们通过蛋白质免疫印迹法和逆转录定量聚合酶链反应检测CDC25B的表达。检测方法包括增殖、迁移、侵袭和流式细胞术分析细胞周期阻滞。在动物实验中，除了表达分析外，我们还通过超声、内镜检查、活检、组织病理学和免疫组织化学观察癌前病变和肿瘤进展情况。
我们的检测表明甲萘醌可降低CDC25B的表达，并能够降低胃癌细胞系的迁移、侵袭和增殖率，并诱导细胞周期阻滞。此外，我们的动物实验表明甲萘醌可抑制肿瘤的发生和进展。
我们认为这种化合物可能是治疗胃癌的化疗药物的重要辅助药物。此外，已证明CDC25B是研究和开发针对这种恶性肿瘤的新治疗策略的有效靶点。
