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

Flavia Fondevila,José L Mauriz,Paula Fernández-Palanca,Tania Payo-Serafín,Elisa Lozano,Jose J G Marin,Javier González-Gallego,Carolina Méndez-Blanco

doi:10.3390/cancers13215349

Abstract

Simple SummaryLiver 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.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 I2 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.

Highlights

Liver cancer constitutes a major health problem worldwide, ranking as the sixth most frequently diagnosed cancer and the third leading cause of cancer-associated death [1]
The full-text of 117 articles was checked for eligibility, finding 69 articles without patients, one without English full-text, 10 without hepatocellular carcinoma (HCC) patients and 32 without Forkhead box O3 (FOXO3)-related tumor pathogenesis, survival or clinicopathological features evaluation
All these studies reached the quality threshold according to Newcastle– Ottawa scale (NOS) score (Table 2) and were included for quantitative meta-analysis (Figure 1)

Summary

Introduction

Liver cancer constitutes a major health problem worldwide, ranking as the sixth most frequently diagnosed cancer and the third leading cause of cancer-associated death [1]. Since the majority of HCC cases are detected at advanced stages [3,4], only a slight percentage of patients are eligible for curative therapeutical approaches and, postoperative relapse is frequent [2,3]. Despite the latest advances in diagnostic and therapeutic strategies, the prognosis of HCC remains very poor, with an overall 5-year survival rate lower than 18% [6]. FOXO3 has shown to play physiological and pathological roles by controlling the transcription of target genes involved in oxidative defense, metabolic state [9,10], proliferation, cell cycle, autophagy [10] and apoptosis [10,11]. There are opposing reports about the role of FOXO3 expression in cancer, finding that FOXO3 upregulation can act either as a tumor-suppressive or an oncogenic mechanism, depending on the tumor type or specific circumstances [7,10]

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