Disease progression role as well as the diagnostic and prognostic value of microRNA-21 in patients with cervical cancer: A systematic review and meta-analysis

Abstract

Introduction: Cervical cancer is the fourth commonest and the fourth leading cause of cancer death in females globally. The upregulated expression of microRNA-21 in cervical cancer has been investigated in numerous studies, yet given the inconsistency on some of the findings, a systematic review and meta-analysis is needed. Therefore, the aim of this systematic review and meta-analysis is to investigate the role in disease progression as well as the diagnostic and prognostic value of microRNA-21 in patients with cervical cancer.

Methods: Literature search was carried out through visiting several electronic databases including PubMed/MEDLINE/ PubMed Central, Web of Science, Embase, WorldCat, DOAJ, ScienceDirect, and Google Scholar. After extraction, data analysis was carried out using Rev-Man 5.3, STATA 15.0 and Meta-disk 1.4. I2 and meta-bias statistics assessed heterogeneity and publication bias of the included studies, respectively. The area under summary receiver operating characteristic curve and other diagnostic indexes were used to estimate diagnostic accuracy.

Result: A total of 53 studies were included for this systematic review and meta-analysis. This study summarized that microRNA-21 targets the expression of numerous genes that regulate their subsequent downstream signaling pathways which promote cervical carcinogenesis. The targets addressed in this study included TNF-α, CCL20, PTEN RasA1, TIMP3, PDCD-4, TPM-1, FASL, BTG-2, GAS-5, and VHL. In addition, the meta-analysis of reports from 6 eligible studies has demonstrated that the overall area under the curve (AUC) of summary receiver operating characteristic (SROC) of microRNA-21 as a diagnostic accuracy index for cervical cancer was 0.80 (95% CI: 0.75, 0.86). In addition, evidence from studies revealed that upregulated microRNA-21 led to worsening progression and poor prognosis in cervical cancer patients.

Conclusion: microRNA-21 is an oncogenic microRNA molecule playing a key role in the development and progression of cervical malignancy. It has good diagnostic accuracy in the diagnosis of cervical cancer. In addition, the upregulation of microRNA-21 could predict a worse outcome in terms of prognosis in cervical cancer patients.

Fig 1. PRISMA 2020 flow diagram summarising the selection process of studies in the systematic review and meta-analysis.

Fig 2. The quality assessment results of included studies in the meta-analysis, carried out using RevMan 5.3 software based on the QUADAS-2 evaluation tool.

(A) Risk of bias and applicability concerns summary. Review author judgements about each domain for each study included. (B) Risk of bias and applicability concerns graph. Review author judgements about each domain are presented as percentages across the included studies.

Fig 3. The role of microRNA-21 in the cancer progression via different signaling pathways.

TNF-α: tumor necrosis factor α; TNFR: tumor necrosis factor receptor; CCL20: chemokine ligand 20; TRAF-2: TNF receptor-associated factor 2; NF-ΚB: nuclear factor κB; JNK: c-Jun N-terminal kinase; PTEN: phosphatase and tensin homolog; PI3K: phosphoinositide 3-kinase; AKT/PKB: Akt/protein kinase B; mTOR: mammalian target of rapamycin; RASA-1: Ras P21 Protein Activator 1; RAS: Ras protein; RAF: Raf proto-oncogene; MEK: mitogen-activated protein kinase kinase; ERK: extracellular signal-regulated kinase; PDCD-4: programmed cell death 4; eIF4A: eukaryotic initiation factor 4A, TPM-1: tropomyocin-1; FASL: Fas ligand; FASR: fas ligand receptor; FADD: Fas-associated via death domain; BTG-2: B-cell translocation gene 2; VHL: von Hippel‑Lindau tumor suppressor; TIMP-3: Tissue inhibitor of metalloproteinases 3; MMPs: matrix metalloproteinases, GAS5: growth arrest-specific 5.

Fig 4. A forest plot depicting the area under the curve (AUC) of summary receiver operating characteristics (SROC) of microRNA-21 assay diagnostic value in cervical cancer.

Fig 5. Forest plots depicting the pooled sensitivity, specificity, PLR, NLR, and DOR of microRNA-21 assay diagnostic value in cervical cancer (LR: Likelihood ratio; OR: odds ratio; CI: confidence interval).

Fig 6. A funnel plot showing the publication bias.

Fig 7. A forest plot showing subgroup analysis based on the sample source of microRNA-21 assay diagnostic value in cervical cancer.