Garcia-Becerra Natalia, Aguila-Estrada Marco Ulises, Palafox-Mariscal Luis Arturo, Hernandez-Flores Georgina, Aguilar-Lemarroy Adriana, Jave-Suarez Luis Felipe
Programa de Doctorado en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico.
División de Inmunología, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara 44340, Mexico.
Cancers (Basel). 2023 Jan 5;15(2):347. doi: 10.3390/cancers15020347.
Cervical cancer (CC) is the fourth most common type of cancer among women; the main predisposing factor is persistent infection by high-risk human papillomavirus (hr-HPV), mainly the 16 or 18 genotypes. Both hr-HPVs are known to manipulate the cellular machinery and the immune system to favor cell transformation. FOXP3, a critical transcription factor involved in the biology of regulatory T cells, has been detected as highly expressed in the tumor cells of CC patients. However, its biological role in CC, particularly in the keratinocytes, remained unclarified. Therefore, this work aimed to uncover the effect of FOXP3 on the biology of the tumoral cells. First, public databases were analyzed to identify the expression levels and the transcribed isoforms in CC and normal tissue samples. The study's findings demonstrated an increased expression of FOXP3 in HPV16+ CC samples. Additionally, the variant was detected as the most frequent splicing isoform in tumoral cells, with a high differential expression level in metastatic samples. However, the analysis of expression in different CC cell lines, HPV+ and HPV-, suggests no relationship between the presence of HPV and expression. Since the variant was found highly expressed in the HPV16+ SiHa cell line, a model with constitutive expression of was established to evaluate its role in proliferation, migration, and cell division. Finally, RNAseq was performed to identify differentially expressed genes and enriched pathways modulated by . The exogenous expression of promotes cell division, proliferation, and migration. The transcriptomic analyses highlight the upregulation of multiple genes with protumor activities. Moreover, immunological and oncogenic pathways were detected as highly enriched. These data support the hypothesis that in epithelial cells induces cancer-related hallmarks and provides information about the molecular events triggered by this isoform, which could be important for developing CC.
宫颈癌（CC）是女性中第四大常见癌症类型；主要的诱发因素是高危型人乳头瘤病毒（hr - HPV）的持续感染，主要是16型或18型基因型。已知这两种hr - HPV均会操纵细胞机制和免疫系统以促进细胞转化。FOXP3是一种参与调节性T细胞生物学过程的关键转录因子，已在CC患者的肿瘤细胞中检测到其高表达。然而，其在CC中的生物学作用，尤其是在角质形成细胞中的作用仍不清楚。因此，本研究旨在揭示FOXP3对肿瘤细胞生物学的影响。首先，分析公共数据库以确定CC和正常组织样本中FOXP3的表达水平和转录异构体。研究结果表明，FOXP3在HPV16 +的CC样本中表达增加。此外，该变体被检测为肿瘤细胞中最常见的剪接异构体，在转移样本中的差异表达水平很高。然而，对不同CC细胞系（HPV +和HPV -）中FOXP3表达的分析表明，HPV的存在与FOXP3表达之间没有关系。由于发现该变体在HPV16 +的SiHa细胞系中高表达，因此建立了一个组成性表达该变体的模型来评估其在增殖、迁移和细胞分裂中的作用。最后，进行RNA测序以鉴定差异表达基因和由该变体调节的富集途径。该变体的外源表达促进细胞分裂、增殖和迁移。转录组分析突出了多个具有促肿瘤活性基因的上调。此外，还检测到免疫和致癌途径高度富集。这些数据支持这样的假设，即上皮细胞中的FOXP3诱导与癌症相关的特征，并提供有关该异构体触发的分子事件的信息，这对于CC的发展可能很重要。
