Genes Regulated by HPV 16 E6 and High Expression of NFX1-123 in Cervical Cancers
Genes Regulated by HPV 16 E6 and High Expression of NFX1-123 in Cervical Cancers
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DOI：
10.2147/ott.s251926
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发表时间：
2020-01-01
影响因子：
4
通讯作者：
Katzenellenbogen, Rachel A.
中科院分区：
文献类型：
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作者：
Chintala, Sreenivasulu;Levan, Justine;Katzenellenbogen, Rachel A.
目的：高危型人乳头瘤病毒（HR HPV）可引起宫颈癌，其中以HPV 16型最为常见。HR病毒癌基因E6和E7与细胞蛋白质合作，以驱动癌症和调节免疫途径;以前，我们在角质形成细胞中证明，HPV 16 E6和内源性宿主蛋白质伴侣NFX 1 -123的高表达导致多个基因的表达增加，包括Notch 1，分泌性白细胞肽酶抑制剂（SLPI）和视黄酸早期转录本1G（RAET 1G）。本研究旨在确定NFX 1 -123是否在宫颈癌中高表达，以及NFX 1 -123和16 E6在角质形成细胞中的基因表达是否也在宫颈癌中增加。材料和方法：使用癌症基因组图谱（TCGA）数据库和人类蛋白质图谱数据库分别比较正常宫颈和宫颈癌中相对mRNA和蛋白质基因表达。采用免疫组化方法检测福尔马林固定石蜡包埋（FFPE）的正常宫颈和HPV 16阳性的宫颈癌组织中相关蛋白的表达。HPV阳性和阴性细胞系的蛋白质表达的一个子集进行了定量Western blot的HPV阳性和阴性cells lines.Results：HPV 16阳性宫颈不典型增生和癌的免疫组化染色显示高NFX 1 -123，Ki 67，和Notch 1的表达。在TCGA数据库中，与正常宫颈相比，宫颈癌中NFX 1和NFX 1 L1 mRNA水平升高。14个基因先前确定为上调角质形成细胞与16 E6和过度表达NFX 1 -123也有高mRNA表达和选定的基因有高蛋白表达在宫颈癌和细胞line.Conclusion：在宫颈癌，NFX 1 -123是高度表达，和16 E6和NFX 1 -123一起改变了广泛的一组基因的表达。这些基因在细胞增殖、分化、侵袭和转移中的参与提供了对HR HPV促进癌症起始和维持的潜在方式的进一步了解。
Purpose: High-risk human papillomaviruses (HR HPV) cause cervical cancer, and in these cancers, HPV type 16 is the most common HR type. The HR viral oncogenes E6 and E7 partner with cellular proteins to drive cancer and modulate immune pathways; previously, we demonstrated in keratinocytes that HPV 16 E6 and high expression of the endogenous host protein partner NFX1-123 led to the increased expression of multiple genes, including Notch1, secretory leukocyte peptidase inhibitor (SLPI), and retinoic acid early transcript 1G (RAET1G). The present study was conducted to determine if NFX1-123 was highly expressed in cervical cancer and if genes increased by NFX1-123 and 16E6 in keratinocytes were also increased in cervical cancers.Materials and Methods: The Cancer Genome Atlas (TCGA) database and The Human Protein Atlas database were used to compare relative mRNA and protein gene expression, respectively, in the normal cervix and cervical cancers. Formalin-fixed paraffin-embedded (FFPE) normal cervix and HPV 16 positive cervical cancer samples were analyzed for relative protein expression by immunohistochemical staining. Protein expression of a subset of regulated genes was quantified by Western blot of HPV positive and negative cell lines.Results: Immunohistochemical staining of HPV 16 positive cervical dysplasias and cancers revealed high NFX1-123, Ki67, and Notch1 expression. NFX1 and NFX1L1 mRNA levels were increased in cervical cancers compared to normal cervix in the TCGA database. Fourteen genes previously identified as upregulated in keratinocytes with 16E6 and over-expressed NFX1-123 also had high mRNA expression and selected genes had high protein expression in cervical cancers and cell lines.Conclusion: In cervical cancer, NFX1-123 is highly expressed, and 16E6 and NFX1-123 together alter the expression of a wide set of genes. The involvement of these genes in cell proliferation, differentiation, invasion, and metastasis provides further insight into potential ways that HR HPVs promote cancer initiation and maintenance.