Promising predictive molecular biomarkers for cervical cancer (Review)

Abstract

Cervical cancer (CC) constitutes a serious public health problem. Vaccination and screening programs have notably reduced the incidence of CC worldwide by >80%; however, the mortality rate in low‑income countries remains high. The staging of CC is a determining factor in therapeutic strategies: The clinical management of early stages of CC includes surgery and/or radiotherapy, whereas radiotherapy and/or concurrent chemotherapy are the recommended therapeutic strategies for locally advanced CC. The histopathological characteristics of tumors can effectively serve as prognostic markers of radiotherapy response; however, the efficacy rate of radiotherapy may significantly differ among cancer patients. Failure of radiotherapy is commonly associated with a higher risk of recurrence, persistence and metastasis; therefore, radioresistance remains the most important and unresolved clinical problem. This condition highlights the importance of precision medicine in searching for possible predictive biomarkers to timely identify patients at risk of treatment response failure and provide tailored therapeutic strategies according to genetic and epigenetic characteristics. The present review aimed to summarize the evidence that supports the role of several proteins, methylation markers and non‑coding RNAs as potential predictive biomarkers for CC.

Keywords: DNA methylation; cervical cancer; non‑coding RNAs; predictive biomarkers; treatment.

Figure 1

Categories of biomarkers. (A) Types of biomarkers depending on their characteristics and the methods used for their detection. (B) Type of biomarkers based on their clinical relevance. Biomarkers can provide information about the stage of cancer, the clinical outcome and the response to therapy; a panel of biomarkers can be simultaneously evaluated, including both proteins and nucleic acids. EGF, Epidermal growth factor; VEGF, Vascular endothelial growth factor; Cf DNA cell-free DNA; ncRNA, non-coding RNA; miRNA, microRNA; IncRNA, long non-coding RNA; circRNA, circular RNA; BRCA1, breast cancer gene 1 protein; BRCA2, breast cancer gene 2 protein; CA-125, cancer antigen 125; PSA, prostate-specific antigen; BRC-ABL, Philadelphia chromosome; HER-2/neu, human epidermal growth factor receptor 2; SHR, Steroid hormone receptors.

Figure 2

Promising predictive molecular biomarkers for cervical cancer. (A) Candidate protein biomarkers. The predictive value of protein biomarkers is mainly based on their abnormal expression levels and aberrant glycosylation; this is the case of VEGF, HIF-1, hemoglobin and SCC-Ag, which have shown that alterations in their levels are related to the clinical response. (B) Possible methylation-based biomarkers. Modifications in DNA methylation patterns, are present in cervical cancer, mainly hypermethylation in several genes including PAX-1, ZNF582, ESR1, MYOD1, BRCA1, RASSF1A and hTERT, favoring decreased gene expression. Some of these genes have been evaluated to identify new predictive biomarkers. (C) Potential role of non-coding RNAs as predictive biomarkers. miRNAs are implicated in post-transcriptional regulation of gene expression. Profiles of aberrantly expressed miR, such as miR-9, miR-200a, miR-145, miR-342, miR-492, miR-100-5p, miR-411, miR-326, miR-378c and miR-155, have been associated with treatment response in cervical cancer; also long non-coding RNAs and circular RNAs have been associated with clinical response; however, the involved molecular mechanisms have not yet been elucidated and are subject of further investigation. VEGF, vascular endothelial growth factor; HIF-1, hypoxia-inducible factor; SCC-Ag, squamous cell carcinoma antigen; PAX-1, paired-box transcription factor 1; ZNF582, zinc finger protein 582; ESR1, estrogen receptor 1; MYOD1, myogenic differentiation 1; BRCA1, breast cancer gene 1; RASSF1A, Ras association domain family member 1A; hTERT, human telomerase reverse transcriptase; miRNA/miR, microRNA.