Cervical cancer (cervical squamous cell carcinoma and endocervical adenocarcinoma, CESC) is the fourth most common cancer in women, after breast, colorectal, and lung cancers (1). In the last 2 years, the incidence and the mortality of cervical cancer have been increasing globally, with more than 600,000 new cases and nearly 350,000 deaths in 2020 (2, 3). The age of onset of cervical cancer is “bimodal” and is concentrated in women in their 30s and 40s (4), and about 85% of cervical cancer deaths occur in less developed and developing countries due to medical conditions (5). Patients with early-stage (IB–IIA) cervical cancer overwhelmingly show a trend of good prognosis after receiving appropriate treatment (6), but the prognosis of patients with advanced and recurrent cervical cancer remains poor (7). In addition, cervical cancer is metastatic, with the most frequent site being the bone, and the median survival time after diagnosis is only 7–12 months (8).

Of the 22 million new cancer cases caused by an infection in 2018, up to 690,000 were affected by human papillomavirus (HPV) (9). HPV is a double-stranded DNA virus, and most types of HPV infections are cleared by autoimmunity. However, a few types of HPV viruses can transform infected cells into malignant tumor cells (10). HPV infection is transmitted through sexual contact (early-age sexual intercourse and multiple sexual partners are both high-risk factors for HPV infection), and persistent HPV infection is the most important factor in the development of cervical cancer (11). HPV testing is the primary modality for cervical cancer screening and can significantly reduce the risk of death from cervical cancer (12). In addition, broad-spectrum HPV vaccination is an effective way to prevent the development of cervical cancer (13, 14). To date, three HPV vaccines have been licensed for use: the bivalent HPV virus-like particle vaccine (2vHPV), the quadrivalent HPV virus-like particle vaccine (4vHPV), and the nonavalent HPV virus-like particle vaccine (9vHPV), which can prevent 70% of cervical cancers worldwide (15).

More than 40 HPV virus types colonize the genital tract, 15 of which are associated with cervical cancer, and HPV16 is one of the most virulent genotypes (16). High-risk HPV16 is associated with genital and oropharyngeal cancers (17) and approximately 50% of cases of squamous cell carcinoma (SCC), the most frequent type of cervical cancer (18). Women who have been persistently infected with HPV16 for 2 years have a high probability of developing precancerous lesions within the next 5 years (19), and persistent HPV16 infection is the most important factor leading to the recurrence of high-grade cervical intraepithelial neoplasia (CIN) after treatment in patients with HPV infection (20).

In this study, based on the analysis of The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database, we aimed to screen the pivotal genes through the screening of differentially expressed genes (DEGs) and the construction of a protein–protein interaction (PPI) network, identify the key gene by analyzing the relationship between the high and low expressions of the pivotal genes and the survival of cervical cancer patients, use this key gene to predict the survival of cervical cancer patients, and analyze the main functional pathways of the key gene using gene set enrichment analysis (GSEA) to determine the prognostic biomarkers for cervical cancer caused by HPV16 infection.

HPV infection is a major cause of cervical carcinogenesis, and repeated infections with the same species of HPV genotypes have a synergistic effect in inducing cervical carcinogenesis (22). HPV encodes two oncoproteins, E6 and E7, and their sustained expression promotes cervical carcinogenesis (23). In particular, HPV16 infection shows a high prevalence in cervical cancer cases, with most infections manifesting without symptoms (24). This study aimed to discover the genes associated with HPV16 cervical cancer and to provide biomarkers for the diagnosis, treatment, and prognosis of cervical cancer.

Ribosomal protein S27A (RPS27A), the only key gene screened in this study associated with prognostic survival in cervical cancer patients, belongs to the ribosomal protein S27AE family. It is a component of the ribosomal 40S subunit and is involved in the encoding of the ubiquitin carboxyl terminus (25). RPS27A is an RNA-binding protein that performs extra-ribosomal functions, including ribosome biosynthesis and post-translational modification processes (26). It has been documented that RPS27A is a direct transcriptional target of p53. It is overexpressed in DNA damage and in kidney, breast, and colon cancers (27) and has roles in promoting proliferation, regulating cell cycle progression, and inhibiting apoptosis (28). In addition, RPS27A is involved in the progression of several diseases or cancers: it may be a potential target for Epstein–Barr virus (EBV)-induced LMP1-positive cancer cells (29), its upregulated expression promotes colorectal cancer cell growth and inhibits apoptosis (30), it is involved in the pathogenesis of diabetic pancreatic ductal adenocarcinoma (PDAC) (25), and it is also one of the pathway links that promote the proliferation of HPV immortalized cervical epithelial cells (H8), which can promote cervical carcinogenesis (26). In the present study, a high expression of RPS27A could lead to poor prognosis in patients with advanced cervical cancer, serve as a prognostic survival predictor in patients with HPV16-positive cervical cancer, and act as an oncogene in the development of HPV16 cervical cancer.

GSEA showed that RPS27A is also associated with GO functions such as cytoplasmic translation, nuclear–transcriptional mRNA catabolic processes, and rRNA processing, all of which are associated with ribosomes. Ribosome biogenesis is a tightly regulated cellular process that begins in the nucleolus and is subsequently processed into rRNA (31). When disrupted during ribosome biogenesis, it can differentially promote cell cycle arrest, senescence, or apoptosis (32). In recent years, the role of ribosomes in carcinogenesis has been extensively validated, linking their involvement in cell cycle regulation and p53 activation to cancer progression (33). For example, RPS19, RPS21, and RPS24 can be used as biomarkers for prostate cancer (34), and ribosome dysfunction is associated with the pathogenesis of nasopharyngeal carcinoma (35) and can promote breast cancer metastasis (36).

In addition, CYP450 is also enriched for significant biological pathways. It is a large, intact membrane-conserved superfamily that includes 57 coding genes, mainly found in hepatocytes and enterocytes, involved in the metabolism of cholesterol, oestrogen, vitamin D, and arachidonic acid (37). Li et al. showed that HPV integrated genes strongly prefer the CP450 pathway (38), which is consistent with the results of the present study. Moreover, CP450 is one of the factors that predispose patients to cervical cancer. Studies by several scholars have shown that polymorphic variants in the CP450 family gene CYP1A1 can increase the risk of cervical cancer, especially in Asians (39, 40). In addition, CP450-related genes also play important roles in other cancers: CYP4Z1 is involved in regulating breast cancer progression (41), the CYP17 inhibitor prevents the growth of prostate cancer cells (42), CYP24A1, a proto-oncogene in human lung cancer, has anti-differentiation and anti-proliferative effects in human lung cancer cell lines (43), and CYP1B1 causes apoptosis in neural cancer cells by inducing melatonin (44). This shows that CP450 is important in cancer cell differentiation, proliferation, and apoptosis. The above analysis indicates that the functions between RPS27A and CP450 have overlapping parts, suggesting that RPS27A might have a synergistic effect with CP450.

Previously, comprehensive bioinformatics analysis methods, such as functional enrichment analysis, PPI network construction, and survival analysis, were used to screen DEGs using the GEO database or TCGA database to identify key genes for cancer progression. For example, Sun et al. (45) and Liu et al. (46) identified biomarkers associated with gastric cancer (GC) progression using this method. In this study, we identified the key gene for HPV16 cervical cancer as RPS27A, developed a survival prediction model to confirm its predictive ability, and performed a GSEA to investigate its functional pathway. In conclusion, this study identified RPS27A as a key gene for HPV type 16 cervical cancer using a comprehensive bioinformatics analysis approach and that it has an accurate predictive ability for patients’ prognostic survival. Although systematic bias may have arisen due to the large variation in sample size, our findings still provide therapeutic targets with clinical significance for HPV16-associated cervical cancer.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

This work was supported by Ningbo Medical and Health Care Brand Discipline (PPXK2018-06).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.