Larrauri-Rodríguez Karen Andrea, Leon-Chavez Bertha Alicia, Vallejo-Ruiz Verónica, Peña Lourdes Millán-Perez, Maycotte Paola
Centro de Investigación Biomédica de Oriente (CIBIOR), Instituto Mexicano del Seguro Social (IMSS), OOAD Puebla, Puebla, Mexico.
Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla (BUAP), Ciudad Universitaria, Puebla, Mexico.
Front Cell Dev Biol. 2024 Nov 19;12:1465729. doi: 10.3389/fcell.2024.1465729. eCollection 2024.
Among the types of cancer affecting women, cervical cancer (CC) is a public health problem with high global incidence and mortality rates. It is currently classified into three main histological types: squamous cell carcinoma (SCC), adenocarcinoma (AC), and adenosquamous (ASC) carcinoma. All of them lack a targeted therapy. The primary risk factor for CC is Human Papilloma Virus (HPV) infection, which is known to increase reactive oxygen species (ROS), contributing to malignant transformation and tumor progression. At basal levels, ROS can function as second messengers in signaling pathways, and elevated concentrations have been linked to their overactivation. One of these, the ERK pathway, is implicated in both cell proliferation and differentiation and is often dysregulated in cancer, promoting malignant transformation. Several studies have proposed antioxidant supplementation or ERK inhibitors as potential therapies.
In vitro studies were performed using CC cell lines. ROS levels were evaluated by flow cytometry; cellular proliferation, death and migration were evaluated using real-time microscopy; cell viability was evaluated with crystal violet staining, and phosphorylated ERK levels were evaluated by Western Blot. A bioinformatic analysis was done in a cervical cancer database.
We elucidate part of the complex interplay between ROS and ERK pathway in CC pro-tumorigenic characteristics. Through bioinformatic analysis, we found distinct ROS and ERK activation patterns across CC tumor samples from different histological types. However, , ROS regulated migration and viability in CC, with no discernible variance based on histological classification. ERK activation, however, differed according to the histological type with SCC displaying increased ERK activation compared to AC and regulating cellular migration in SCC cells.
Our study identifies a potential synergistic interaction between ROS and ERK inhibitors, highlighting the therapeutic promise of combinatorial targeting for CC treatment. These findings underscore the importance of personalized approaches aimed at improving the outcomes of CC patients.
在影响女性的癌症类型中，宫颈癌（CC）是一个具有全球高发病率和死亡率的公共卫生问题。目前它主要分为三种组织学类型：鳞状细胞癌（SCC）、腺癌（AC）和腺鳞癌（ASC）。所有这些类型都缺乏靶向治疗。CC的主要危险因素是人类乳头瘤病毒（HPV）感染，已知这种感染会增加活性氧（ROS），促进恶性转化和肿瘤进展。在基础水平上，ROS可作为信号通路中的第二信使，其浓度升高与过度激活有关。其中之一的ERK通路与细胞增殖和分化都有关，并且在癌症中常常失调，促进恶性转化。一些研究提出补充抗氧化剂或使用ERK抑制剂作为潜在疗法。
使用CC细胞系进行体外研究。通过流式细胞术评估ROS水平；使用实时显微镜评估细胞增殖、死亡和迁移；用结晶紫染色评估细胞活力，通过蛋白质免疫印迹法评估磷酸化ERK水平。在一个宫颈癌数据库中进行了生物信息学分析。
我们阐明了CC促肿瘤发生特征中ROS与ERK通路之间复杂相互作用的部分情况。通过生物信息学分析，我们在来自不同组织学类型的CC肿瘤样本中发现了不同的ROS和ERK激活模式。然而，ROS调节CC中的迁移和活力，基于组织学分类没有明显差异。然而，ERK激活根据组织学类型而有所不同，与AC相比，SCC显示出更高的ERK激活，并调节SCC细胞中的细胞迁移。
我们的研究确定了ROS与ERK抑制剂之间潜在的协同相互作用，突出了联合靶向治疗CC的治疗前景。这些发现强调了旨在改善CC患者治疗结果的个性化方法的重要性。
