Prognostic role of E2F1 gene expression in human cancer: a meta-analysis

E2F family, an important transcription factor family that regulates gene expression, consists of eight members, that can be organized into three subcategories based on function and expression patterns during the cell cycle: activators (E2F1-3), canonical repressors (E2F4-6), and atypical repressors (E2F7 and E2F8) [1]. The E2F family can regulate cell cycle gene expression, inducing cell proliferation [2] of both normal and cancer cell [3], also they have more molecular activities, such as cell differentiation [4], DNA repair, and cell death. E2F1, encoded by the human E2F1 gene that was the first mature transcription activator discovered in the E2F family, is a transcription activator that binds to DNA with dimerization partner (DP) proteins via the E2 recognition site, 5’-TTTC[CG]CGC-3’, found in the promoter region of various genes [5]. The E2F1 domain enables it to act as a transcriptional activator to drive gene expression, determine the orderly transition of cell cycle from G1 phase to S phase, and enhanced cellular proliferation [3], playing a key role in regulating cell proliferation, also it is significant for normal cell homeostasis, uniquely induces apoptosis [6]. E2F1 consisted with CDKs, cyclins, CDK inhibitors and the RB family of proteins forming a cyclin-dependent kinase (CDK)—retinoblastoma (Rb)-E2F1 regulatory axis [2] has been found in almost all cancers. E2F1 was directly implicated with poor prognosis in types of cancer, such as bladder cancer [7], breast cancer [8], ovarian cancer [9], prostate cancer [4], and has been demonstrated to be a key cancer biomarker [5]. Moreover, highly expressed E2F1 was observed in a variety of tumor tissues [9].

Many of the identified genes are well-known E2F family target genes, which are involved in the origin of DNA replication or mitosis [10], resulting in aneuploidy, which is associated with poor prognosis and drug resistance of tumors. The activity of E2F1 has been investigated in connection with RB-dependent control of G1/S progression of the cell cycle. And, components of the RB-E2F pathway have been implicated in promoting aneuploidy in types of cancers, such as breast, bladder, liver, lung and retinal tumors [11]. Therefore, E2F1 expression and/or elevated E2F1 target expression have been linked with poor prognosis [1]. Although there are many articles suggested that the elevate of E2F1 is related to the occurrence of cancer development and prognosis, a few of study for the dysregulation of E2F1 effect on the prognosis of cancer for more effective meta-analysis, which can provide more reliable results compared with a single study and serves as a powerful tool to explain controversial conclusions [12]. For this reason, we evaluated the prognosis value of E2F1 for human cancers in this article based on published data.

In this study, we evaluated the prognostic value of E2F1 in cancer patients according to published data. The results showed that higher E2F1 level was significantly correlated with unfavorable OS and DFS in cancer patients.

In fact, previous studies have found that E2F1 expression was elevated in tumor tissues and associated with the poor prognosis of cancer. The expression levels of E2Fs (E2F1-8) were all significantly up-regulated in LUAD tissues [14], Wang et al. investigated the expression, prognosis value, mutation, and potential relationship with immunological aspects of E2Fs in LUAD by bio-informatics analysis [14].E2F1 is expressed strongly in 59.8% of ESCC and that the over-expression was correlated with tumor progression, lymph node metastasis, and poor prognosis after surgery [16]. Over-expression of E2F1 was significantly associated to worsen OS in all NSCLC patients followed for 200 months, as well as in LUAD patients [26],which was duplicated in HCC patients [27].

The pooled results indicated that there was a significant association between elevated E2F1 and cancer patients’ poor survival (OS/DFS). However, there was significant heterogeneity among the enrolled studies. The two articles conducted by Kwon [19] and Gao [24] were the origin of heterogeneity for subgroup of the OS group, which was attributed to: (1) the types of patients included were different in that the patients included in Kwon's [19] paper were patients with surgically treated, while the rest of the literature included patients with untreated; (2) tumor size varies: most of the patients with tumor size > 4 were included in Kwon et al. [19] tumor size > 4 cm; (3) the difference of statistical methods: for example, statistical data reported by Kwon et al. [19] was analysis with Pearson’s v2 test, indicating that the clinical state of patient, pathology of tumor, and statistical analysis methods may affect the result.

The number of patients in the DFS group maybe the origin of heterogeneous which could be eliminated by removing one study coming from Kwon [19]. The possible reason is: (1) the age ratio of the included patients varied: patients older than 60 years in the article reported by Mans et al. [20], whereas, most of the patients included in the other articles [17‐19, 21] were younger than 60 years old; (2) different stages of tumor development occur: the included tumor samples were mostly infiltrated by Wang et al. [17] and had distant metastasis, while the tumor samples in other literature were mostly in the early or middle stages. Therefore, more attention should be paid on the age of the included patients and the status of the included sample.

E2F1 is a prognostic marker in a variety of cancers, because E2F1 is involved in multiple regulatory pathways, which also the reason for its elevated expression in the tumor micro-environment. A large number of essays have investigated the involvement of E2F1 in protein regulation and thus the impact of tumor development and prognosis. The distinct regulatory networks involving E2F1 in HCC with different backgrounds may contribute to the modulation of expression profiles due to different etiological factors [28]. E2F1 transactivates IQGAP3, and IQGAP3 competitively inhibits the interaction between PKCδ and PKCα, resulting in phosphorylation and activation of PKCα and promotion of cell proliferation in HCC cells [29]. The YY1/ miR-526b-3p/E2F1 axis as a pathway for abnormal E2F1 expression in CRC [30]. An over-activated NFYB-E2F1-CHK1 axis deteriorates the therapeutic effects of oxaliplatin, while the side-effect of chemotherapy persists, likely leading to a worse prognosis [31].

This analysis has several strengths. First, the analysis increases the strength of the current evidence by providing a large sample. Second, the included studies are widely representative, with data from five different countries. In addition, sensitivity analysis and publication bias suggest that the results of this study are robust. However, the study has some limitations. First of all, only summarized data rather than individual patient data were pooled in our study, which might preclude us from conducting a more in-depth analysis; most of the included studies were retrospective studies, and more prospective studies are still needed to validate our analysis. Second, some studies with negative results may not be published, which may lead to potential publication bias. Data from some studies did not specify the included patient information and tumor stage. Therefore, more detailed study designs and follow-up are still needed to explore the prognostic value of E2F1 in cancer patients.

In short, our study concluded that E2F1 can be used as a prognostic marker for cancers.