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Accepted Articles of Congress

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  • miR-21 Promoter Hypermethylation, PI3K/AKT Pathway Activation, and Prognosis in Hepatocellular Carcinoma: A Systematic Review

  • Kimia Heydariyar,1,* Hori Ghaneialvar,2 Omid Raiesi,3 Alireza Vasiee,4
    1. Student Research Committee, Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran
    2. Biotechnology and Medicinal Plants Research Center, Ilam University of Medical Sciences, Ilam, Iran
    3. Omid Raiesi
    4. Department of Nursing, Faculty of Nursing and Midwifery, Ilam University of Medical Sciences, Ilam, Iran


  • Introduction: Aberrant DNA methylation of microRNA promoters can dysregulate oncogenic signaling in hepatocellular carcinoma (HCC). Hypermethylation of the miR-21 promoter may enhance PI3K/AKT pathway activation, promoting tumor progression and affecting patient survival. We systematically evaluated the prevalence of miR-21 promoter hypermethylation in HCC, its quantitative association with PI3K/AKT activation markers, and its impact on clinical outcomes.
  • Methods: We searched PubMed, EMBASE, Web of Science, and Scopus uo to June 2025 for studies reporting miR-21 promoter methylation status, PI3K/AKT activation (e.g., p-AKT expression), and survival data in adult HCC patients. Search terms combined (“miR-21” AND “methylation”) AND (“PI3K” OR “AKT”) AND (“hepatocellular carcinoma” OR “HCC”). Two reviewers independently screened 1,047 titles/abstracts, extracted data on methylation prevalence, standardized mean differences (SMD) for p-AKT levels, odds ratios (OR) for clinicopathologic features, and hazard ratios (HR) for overall (OS) and disease-free survival (DFS). Study quality was assessed using the Newcastle–Ottawa Scale; disagreements were resolved by consensus.
  • Results: Ten studies encompassing 1,312 HCC patients (median follow-up 32 months) met inclusion criteria. The pooled prevalence of miR-21 promoter hypermethylation was 38.7% (95% CI 34.2–43.3). Hypermethylated tumors exhibited higher PI3K/AKT activation with a pooled SMD of 0.85 (95% CI 0.68–1.02; p < 0.05) for p-AKT expression compared to unmethylated tumors. Promoter hypermethylation correlated with advanced tumor stage (OR 2.15; 95% CI 1.68–2.76; p < 0.001). Patients with miR-21 hypermethylation had significantly poorer OS (HR 1.75; 95% CI 1.50–2.04; p < 0.02) and DFS (HR 1.62; 95% CI 1.37–1.92; p < 0.01).
  • Conclusion: miR-21 promoter hypermethylation occurs in nearly 40% of HCC cases and is robustly associated with enhanced PI3K/AKT activation, advanced tumor stage, and a 60–75% increased risk of recurrence and death. These aggregated findings support incorporating miR-21 methylation status into risk stratification and exploring demethylating strategies to modulate oncogenic signaling in HCC.
  • Keywords: miR-21; promoter hypermethylation; PI3K/AKT pathway; hepatocellular carcinoma

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