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Simple Summary  Liver cancer, mainly represented by hepatocellular carcinoma (HCC), constitutes the current third leading cause of tumor-associated death worldwide. Therefore, finding new molecules that improve early HCC diagnosis, prognosis and patient outcomes is crucial. Forkhead box O3 (FOXO3), a central factor expressed by hepatocytes, has been related to cancer progression. This novel systematic review, with meta-analysis, aimed to unravel the diagnostic and prognostic value of FOXO3 expression in HCC. We systematically searched Cochrane, Embase, PubMed, Scopus and Web of Science for articles evaluating FOXO3 levels in HCC samples and its association with HCC development, survival or clinicopathological features. After study selection, overall effect and heterogeneity assessment, and subgroup and publication bias analysis were carried out. Based on five studies involving 1059 cases, we found that high FOXO3 expression correlates with tumor development, poor survival and invasion in HCC. Thus, FOXO3 emerges as a novel diagnostic and prognostic biomarker for HCC monitoring.    Abstract  Forkhead box O3 (FOXO3), an essential transcription factor related to liver disease, has been linked to cancer progression. The most frequent primary liver tumor, hepatocellular carcinoma (HCC), has an elevated mortality rate and patient outcomes remain very poor. Here, we examined the diagnostic, prognostic and clinicopathological significance of FOXO3 expression in HCC. We systematically searched Cochrane, Embase, PubMed, Scopus and Web of Science. Articles analyzing FOXO3 levels in HCC patient samples and its relationship with tumor development, survival or clinicopathological factors were selected. Hazard ratios, odds ratios and 95% confidence intervals were extracted, estimated by Parmar method or calculated and pooled across studies. Heterogeneity was evaluated by chi-square-based Q and I 2  tests, while publication bias by funnel plots and Egger’s test. Subgroup analysis was performed when heterogeneity was evident. The study protocol was registered in PROSPERO (CRD42021237321), and data were meta-analyzed employing STATA 16. Five studies involving 1059 HCC cases were finally included in this meta-analysis, finding that high FOXO3 levels significantly correlate with HCC development and shorter overall survival. Moreover, subgroup analysis revealed a significant association between positive FOXO3 expression and the risk of invasion. Thus, FOXO3 could function as a novel biomarker with diagnostic and prognostic value in HCC.

cancers

Association of FOXO3 Expression with Tumor Pathogenesis, Prognosis and Clinicopathological Features in Hepatocellular Carcinoma: A Systematic Review with Meta-Analysis