Identification of Pivotal Cellular Factors Involved in HPV‐Induced Dysplastic and Neoplastic Cervical Pathologies

Abstract

Cervical carcinoma represents the paradigm of virus-induced cancers, where virtually all cervical cancers come from previous "high-risk" HPV infection. The persistent expression of the HPV viral oncoproteins E6 and E7 is responsible for the reprogramming of fundamental cellular functions in the host cell, thus generating a noticeable, yet only partially explored, imbalance in protein molecular networks and cell signaling pathways. Eighty-eight cellular factors, identified as HPV direct or surrogate targets, were chosen and monitored in a retrospective analysis for their mRNA expression in HPV-induced cervical lesions, from dysplasia to cancer. Real-time quantitative PCR (qPCR) was performed by using formalin-fixed, paraffin embedded archival samples. Gene expression analysis identified 40 genes significantly modulated in LSIL, HSIL, and squamous cervical carcinoma. Interestingly, among these, the expression level of a panel of four genes, TOP2A, CTNNB1, PFKM, and GSN, was able to distinguish between normal tissues and cervical carcinomas. Immunohistochemistry was also done to assess protein expression of two genes among those up-regulated during the transition between dysplasia and carcinoma, namely E2F1 and CDC25A, and their correlation with clinical parameters. Besides the possibility of significantly enhancing the use of some of these factors in diagnostic or prognostic procedures, these data clearly outline specific pathways, and thus key biological processes, altered in cervical dysplasia and carcinoma. Deeper insight on how these molecular mechanisms work may help widen the spectrum of novel innovative approaches to these virus-induced cell pathologies.

The lysine acetyltransferase GCN5 contributes to human papillomavirus oncoprotein E7‐induced cell proliferation via up‐regulating E2F1

“…E2F1 also binds to the promoter of Cyclin A and regulated its expression, resulting in induction of S‐phase entry . E2F1 has been found to be deregulated in many types of cancers, including cervical cancer . E2F1 overexpression has been reported to promote cervical carcinogenesis .…”

“…47 E2F1 has been found to be deregulated in many types of cancers, including cervical cancer. 62 E2F1 overexpression has been reported to promote cervical carcinogenesis. 63 HPV E7 can bind and promote the degradation of retinoblastoma protein (pRb), resulting in the release of E2F1 from the pRb-E2F complex and thereby promote malignant transformation of cervical epithelium.…”

Human Papillomavirus Induced Transformation in Cervical and Head and Neck Cancers

“…Analyses in 2013 utilized a retrospective approach to identify novel genes involved in dysplastic and neoplastic cervical lesions, based on targets previously published in the literature [ 155 ]. The authors confirmed earlier results where FOXM1 , TOP2A , and E2F1 were not only overexpressed, but where their respective expression levels gradually increased as cervical lesions progressed from low-grade to high-grade lesions and eventually to carcinomas.…”

“…Other de-regulated genes included CDC25A , TP73 , and CCNE2 . Conversely, genes that demonstrated reduced expression in the progression from dysplastic tissue to carcinoma included PTGS2 , BCL2 , and FOS [ 155 ].…”

Identification and validation of a six-gene signature associated with glycolysis to predict the prognosis of patients with cervical cancer

“…In addition, previous studies have found that ANGPTL4 is significantly associated with the susceptibility of CC, is a potential risk factor [ 30 ]. Muscular phosphofructokinase (PFKM), a member of the phosphofructokinase (PFK) family, can promote the growth of muscle-infiltrating bladder cancer [ 31 ] and can be used as a new breast cancer gene [ 32 ], and its expression level can distinguish normal tissues from CC tissues [ 33 ]. 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4), is a key kinase in Warburg pathway [ 34 ], has been found to be associated with a variety of cancers, including breast cancer [ 35 ], prostate cancer [ 36 ] and glioblastoma [ 37 ], promoting the progression and metastasis of cancer, and may become an effective molecular target of anti-tumor drugs.…”