Mapping Heterogeneity of Hepatocellular Carcinoma by Investigating Hepatocyte-Specific Genes/TFs/Pathways Across Cellular and Tumor Landscapes

Abstract

Background: Hepatocellular carcinoma (HCC) presents challenges due to tumor heterogeneity and therapeutic resistance. Understanding the molecular mechanisms driving heterogeneity is crucial. Key transcription factors (HNF4A, HNF1A, FOXA1/2, etc.) and signaling pathways (Wnt/β-catenin, FGF, HGF, etc.) are dysregulated in HCC. Dysregulation disrupts hepatocyte genetic programming, leading to heterogeneous cell populations. Investigating these mechanisms offers insights for targeted therapies and improving patient outcomes in HCC. Methods: Databases, including PubMed, MEDLINE, Google Scholar, and open access/ subscription-based journals were searched for published articles without any date restrictions, to trace the emergence of HCC heterogeneity by investigating the hepatocyte-specific genes/TFs/signaling pathways across cellular and tumor landscapes. Based on the criteria mentioned in the methods section, studies were systematically reviewed to investigate HCC Heterogeneity. This study adheres to relevant PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). Results: This study into hepatocellular carcinoma (HCC) revealed dysregulation of key transcription factors (TFs) and signaling pathways. Transcription factors HNF4A, HNF1A, FOXA1/2, CEBPA, GATA4/6, PROX1, SOX9, HNF6/Onecut1, and ONECUT2/HNF6β showed altered expression patterns, disrupting hepatocyte genetic programming and promoting heterogeneous cell populations in HCC. Dysregulated Wnt/β-catenin, FGF, HGF, TGF-β, and Hippo signaling pathways influenced cellular fate decisions and interactions with the tumor microenvironment, further contributing to HCC heterogeneity. Dysregulated NOTCH signaling and TBX3/18 transcription factors highlighted the complexity of HCC heterogeneity. This study points to the critical role of dysregulated TFs and signaling pathways in driving HCC heterogeneity and transdifferentiation, providing insights for targeted therapeutic interventions to improve patient outcomes. Conclusion: The decline in the gene expression of hepatocyte cell type-specific genes dysregulates the genetic programing of hepatocytes involved in cell type-specific homeostasis. The multiple roles of every gene/TF begin to manifest themselves causing the emergence of heterogeneity. The dysregulation of hepatocyte-specific genes and signaling pathways in hepatocellular carcinoma (HCC) disrupts cellular homeostasis, leading to the emergence of heterogeneity and transdifferentiation. Key transcription factors like HNF4A, HNF1A, and FOXA1/2, along with pathways such as Wnt/β-catenin and Hippo signaling, play crucial roles. This disruption sets the stage for diverse cellular phenotypes within the tumor microenvironment. Understanding these molecular mechanisms is vital for developing targeted therapeutic strategies to address HCC heterogeneity and improve patient outcomes.