2. Academic Validation
  3. Integrative genomics characterizes HCC eRNAs for prognosis and targeted therapy

Integrative genomics characterizes HCC eRNAs for prognosis and targeted therapy

  • Sci Rep. 2025 Nov 25;15(1):41913. doi: 10.1038/s41598-025-25853-0.
Zhengxin Chen # 1,  Limei Wang # 1,  Jiaqi Chen # 1,  Lingxu Li 1,  Ruijie Zhang 1,  Yuxi Zhu 2,  Dehua Feng 1,  Huirui Han 1,  Tianyi Li 1,  Xinying Liu 1,  Xuefeng Wang 1,  Zhenzhen Wang 1,  Hongjiu Wang 1,  Xia Li 1,  Jingwen Hao 3,  Zhi Zeng 4,  Jin Li 5
Affiliations

Affiliations

  • 1 School of Intelligent Medicine and Technology, Big Data Research Center, Kidney Disease Research Institute at the Second Affiliated Hospital, Hainan Engineering Research Center for Health Big Data, Hainan Medical University, Haikou, 571199, Hainan, China.
  • 2 Division of Biostatistics, College of Public Health, The Ohio State University, Columbus, OH, 43202, US.
  • 3 Key Laboratory of Tropical Translational Medicine of Ministry of Education & Department of Anatomy, College of Basic Medical Sciences, Hainan Medical University, Haikou, 571199, Hainan, China. [email protected].
  • 4 Department of Pathology, Renmin Hospital, Wuhan University People's Hospital, Wuhan, 430060, China. [email protected].
  • 5 School of Intelligent Medicine and Technology, Big Data Research Center, Kidney Disease Research Institute at the Second Affiliated Hospital, Hainan Engineering Research Center for Health Big Data, Hainan Medical University, Haikou, 571199, Hainan, China. [email protected].
  • # Contributed equally.
PMID: 41290912 DOI: 10.1038/s41598-025-25853-0
Abstract

Hepatocellular carcinoma (HCC), a leading cause of cancer-related mortality globally, exhibits limited diagnostic and therapeutic biomarkers despite its clinical significance. Emerging evidence has positioned enhancer RNAs (eRNAs) as pivotal regulators in tumorigenesis, prompting this study to systematically identify HCC-specific eRNA signatures and elucidate their functional relevance. Through integrative analysis of three independent cohorts (n = 115 tumor-normal pairs), we identified three eRNA biomarkers-CAP2e, COLEC10e, and MARCOe-exhibiting significant differential expression between HCC and adjacent tissues, with validation in The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) dataset. Notably, these eRNAs demonstrated strong positive correlation with their host genes (r > 0.83, p < 0.05), suggesting co-regulatory mechanisms. Functional enrichment revealed their involvement in oncogenic pathways including MAPK signaling, with MARCOe emerging as a candidate therapeutic target due to its association with immune evasion pathways. Multi-omics characterization including survival analysis, immune infiltration profiling, and pan-cancer comparison further validated these eRNAs' diagnostic specificity and prognostic value. Critical experimental validation of MARCO was performed via immunohistochemistry (IHC) in 60 HCC tumor-normal paired samples, demonstrating significantly reduced MARCO protein expression in tumors (tumor vs. normal: 15% vs. 65% positivity, p < 0.001). MARCO overexpression experiments in HCC cells revealed significant alterations in MAPK pathway-related genes, suggesting potential therapeutic implications through pathway modulation. This investigation provides the first comprehensive identification of clinically relevant eRNA biomarkers for HCC, establishing their dual roles in disease progression and therapeutic targeting.

Keywords

Biomarker; Enhancer RNA; Functional analysis; Hepatocellular carcinoma; Therapeutic target.

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