Abstract
BackgroundCervical cancer is the second leading cause of death in women 20–39 years old. Because coverage for cervical cancer screening is low, and the vaccination rate of human papillomavirus (HPV) is poor in some countries, potential markers to detect the disease at early stages are needed. E2F transcription factors (E2Fs) are a family of transcription factors that function in cell proliferation, differentiation, apoptosis, and tumorigenesis. As abnormal activation and regulation of E2Fs are related to tumor development and poor prognosis, we performed bioinformatic analyses and in vitro assays to evaluate the role of E2Fs in cervical cancer.MethodsTranscriptional expression of E2Fs was initially evaluated in silico using ONCOMINE and Gene Expression Profiling Interactive Analysis (GEPIA), followed by evaluation of E2F1/2/7/8 protein levels using immunohistochemistry in 88 patient tissues. E2F2 and E2F7 mRNA levels were measured by RT-qPCR. LinkedOmics and Metascape were used to predict functions of E2Fs, and in vitro experiments were performed to assess the tumorigenic role of E2F2 and E2F7.ResultsIn silico analysis showed that E2F1/2/7/8 were significantly overexpressed in cervical cancer, findings which were confirmed at the protein level using immunohistochemistry. Further, upregulation of E2F1/2/7/8 was associated with different clinicopathological prognostic factors, including positivity for lymph vessel invasion and deep invasion of cervical stroma. Increased expression of E2F1/2/7/8 was also related to shorter overall survival (OS) and disease-free survival (DFS) in patients with cervical cancer. Using multivariate analysis, we confirmed E2F1/2/7/8 as independent prognostic factors for shorter OS of patients with cervical cancer. Finally, in vitro experiments showed that E2F2 and E2F7 are involved in cell proliferation and migration and cell cycle regulation in both HPV-positive and HPV-negative cervical cancer cells.ConclusionsE2F1/2/7/8 may be prognostic biomarkers for survival of patients with cervical cancer. E2F2 and E2F7 are involved in cell proliferation, migration, and cell cycle in both HPV-positive and HPV-negative cervical cancer cells.
Highlights
IntroductionBecause coverage for cervical cancer screening is low, and the vaccination rate of human papillomavirus (HPV) is poor in some coun‐ tries, potential markers to detect the disease at early stages are needed
Cervical cancer is the second leading cause of death in women 20–39 years old
Overexpression of E2F transcription factors (E2Fs) family members in cervical cancer To compare mRNA and protein levels of different E2F members in cervical cancer tissues with those found in normal tissues, we used the ONCOMINE database and Gene Expression Profiling Interactive Analysis (GEPIA) dataset in addition with IHC
Summary
Because coverage for cervical cancer screening is low, and the vaccination rate of human papillomavirus (HPV) is poor in some coun‐ tries, potential markers to detect the disease at early stages are needed. According to the American Cancer Society, it is estimated that 13,800 cases of invasive cervical cancer will be diagnosed and 4,290 deaths from cervical cancer will occur in the United States in 2020 [1]. It is the second leading cause of death in 20- to 39-year-old women, responsible for 10 premature deaths per week in this age group globally [2]. The identification of new therapeutic target is critically important for the treatment of cervical cancer
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