Cervical Cancer Development: Implications of HPV16 E6E7-NFX1-123 Regulated Genes.
Cervical Cancer Development: Implications of HPV16 E6E7-NFX1-123 Regulated Genes.
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DOI：
10.3390/cancers13246182
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发表时间：
2021-12-08
期刊：
影响因子：
5.2
通讯作者：
Katzenellenbogen RA
中科院分区：
文献类型：
--
作者：
Quist KM;Solorzano I;Wendel SO;Chintala S;Wu C;Wallace NA;Katzenellenbogen RA
高危型人乳头瘤病毒（HPV）导致4.5%的癌症和几乎所有的宫颈癌。HPV的致癌潜力取决于HPV的癌蛋白E6和E7对细胞蛋白的挪用。高危型HPV 16（HPV 16）E6直接与细胞蛋白NFX 1 -123结合，并使增殖，分化和免疫基因失调。尚未研究HPV 16 E7与HPV 16 E6-NFX 1 -123介导的失调的关系。由于HPV表达两种癌基因，并且HPV致癌需要E6和E7，因此研究在这种情况下发生的失调是有价值的。了解它们的临床和预后后果也很重要。这项研究的目标是确定HPV 16 E6，E7和NFX 1 -123在宫颈癌前病变和癌症中调控的基因表达谱，鉴定与疾病进展相关的基因，评估患者生存率，并验证细胞模型中的发现。发现生存和疾病进展的相关性有助于生物标志物的鉴定，并关注未来的研究。高危型人乳头瘤病毒（HR HPV）导致几乎所有的宫颈癌，其中一半是由于HPV 16型（HPV 16）。HPV 16癌蛋白E6（16 E6）与NFX 1 -123结合，并使基因表达失调，但其临床意义尚不清楚。此外，HPV 16 E7的作用尚未与NFX 1 -123和16 E6一起研究。HR HPV表达两种癌基因，并且转化需要它们的表达，因此我们试图研究E7对基因表达的影响。这项研究的目标是定义宫颈癌前病变和癌症阶段的基因表达谱，识别与疾病进展相关的基因，评估患者生存率，并验证细胞模型中的发现。我们分析了包含与宫颈癌分期相关的转录组数据的NCBI GEO数据集，并利用LASSO分析来识别癌症驱动基因。检测表达16 E6和16 E7（16 E6 E7）和外源性NFX 1 -123的角质形成细胞的LASSO鉴定的基因表达。19个基因中有10个与疾病进展相关，包括CEBPD，NOTCH 1和KRT 16，并影响生存。角质形成细胞中的16 E6 E7增加CEBPD、KRT 16和SLPI，并降低NOTCH 1。16 E6 E7角质形成细胞中的外源性NFX 1 -123导致CEBPD和NOTCH 1显著增加，SLPI降低。这项工作证明了CEBPD，NOTCH 1，KRT 16和SLPI的临床相关性，并显示了16 E6 E7和NFX 1 -123的调节作用。
High-risk human papillomavirus (HPV) causes 4.5% of cancers and nearly all cervical cancers. HPV’s carcinogenic potential depends on its misappropriation of cellular proteins by HPV’s oncoproteins E6 and E7. High-risk HPV type 16 (HPV16) E6 binds directly to the cellular protein NFX1-123 and dysregulates proliferation, differentiation, and immunity genes. The effect of HPV16 E7 has not been studied in relation to HPV16 E6-NFX1-123-mediated dysregulation. As HPV expresses both oncogenes, and HPV carcinogenesis requires E6 and E7, it is valuable to investigate what dysregulations occur in this context. It is also important to understand their clinical and prognostic ramifications. This study’s goal was to define the gene expression profile regulated by HPV16 E6, E7, and NFX1-123 across cervical precancers and cancers, identify genes correlating with disease progression, assess patient survival, and validate findings in cell models. Finding correlates of survival and disease progression aids in biomarker identification and focuses future studies. High-risk human papillomavirus (HR HPV) causes nearly all cervical cancers, half of which are due to HPV type 16 (HPV16). HPV16 oncoprotein E6 (16E6) binds to NFX1-123, and dysregulates gene expression, but their clinical implications are unknown. Additionally, HPV16 E7’s role has not been studied in concert with NFX1-123 and 16E6. HR HPVs express both oncogenes, and transformation requires their expression, so we sought to investigate the effect of E7 on gene expression. This study’s goal was to define gene expression profiles across cervical precancer and cancer stages, identify genes correlating with disease progression, assess patient survival, and validate findings in cell models. We analyzed NCBI GEO datasets containing transcriptomic data linked with cervical cancer stage and utilized LASSO analysis to identify cancer-driving genes. Keratinocytes expressing 16E6 and 16E7 (16E6E7) and exogenous NFX1-123 were tested for LASSO-identified gene expression. Ten out of nineteen genes correlated with disease progression, including CEBPD, NOTCH1, and KRT16, and affected survival. 16E6E7 in keratinocytes increased CEBPD, KRT16, and SLPI, and decreased NOTCH1. Exogenous NFX1-123 in 16E6E7 keratinocytes resulted in significantly increased CEBPD and NOTCH1, and reduced SLPI. This work demonstrates the clinical relevance of CEBPD, NOTCH1, KRT16, and SLPI, and shows the regulatory effects of 16E6E7 and NFX1-123.
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