Decoding Hepatocellular Carcinoma Metastasis: Molecular Mechanisms, Targeted Therapies, and Potential Biomarkers

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with metastasis representing a pivotal factor in poor prognosis and high fatality rates. This review offers a comprehensive examination of the key molecular events and regulatory mechanisms driving HCC metastasis, with a particular focus on genetic mutations, epigenetic alterations, and dysregulated signaling pathways. Special emphasis is placed on the role of three-dimensional genome structural remodeling in HCC initiation and metastatic progression. Additionally, the latest advances in targeted therapies for advanced HCC are summarized, including both first-line and second-line treatments, highlighting their impact on controlling metastatic disease. The review also examines a variety of potential biomarkers linked to HCC metastasis, including circulating tumor cells, circulating tumor DNA, and exosomal contents, all of which demonstrate significant promise for the early detection, diagnosis, and therapeutic monitoring of HCC metastasis. By bridging molecular insights with clinical applications, this review provides valuable perspectives to guide future research in the diagnosis and treatment of HCC metastasis.

Keywords: biomarkers; hepatocellular carcinoma; metastasis; molecular mechanism; signaling pathways; targeted therapy.

Figure 2

Exploring and investigating potential biomarkers of HCC metastasis offers a promising pathway to enhance early detection and enable more precise, targeted therapeutic strategies. This figure underscores the critical importance of identifying and exploring potential biomarkers associated with HCC metastasis. On the left, it illustrates the major challenges posed by HCC metastasis, including difficulties in early detection, poor prognosis, drug inefficacy, resistance, high recurrence rates, and spatiotemporal heterogeneity. On the right, it highlights promising opportunities to address these challenges through the discovery of metastasis-related biomarkers driven by genetic mutations, epigenetic alterations, and aberrant activation of signaling pathways. Key biomarkers—such as CTCs, ctDNA, exosomes, and ncRNA—can be detected through liquid biopsy and analyzed using multi-omics technologies to enable metastasis prediction, facilitate early diagnosis, refine prognostic assessments, evaluate therapeutic responses, and identify targeted treatment strategies. Created using BioGDP.com (accessed on 3 April 2025) [193].

Figure 1

Key pathways involved in hepatocellular carcinoma metastasis. (a) Wnt/β-catenin pathway: Upon activation of the canonical Wnt/β-catenin pathway, Wnt proteins bind to receptors, forming a complex that recruits degradation complexes to the cell membrane. This results in the accumulation of β-catenin in the cytoplasm and its subsequent translocation to the nucleus. (b) TGF-β/Smad Pathway: The binding of the TGF-β ligand to TGFβRI leads to the phosphorylation of TGFβRI, after which SMAD2 and SMAD3 form a transcriptional complex with SMAD4. This complex then translocates to the nucleus, where it binds to DNA and regulates the expression of target genes in collaboration with various cofactors. SMAD6 and SMAD7 act as negative regulators in the TGF-β/Smad signaling pathway. (c) EGFR/PI3K/AKT/mTOR pathway: EGFR binds to ligands such as EGF, causing receptor dimerization and phosphorylation. Phosphorylated EGFR recruits PIK3, which, once activated, phosphorylates membrane lipid PIP2. PIP2 subsequently binds and activates Akt. PTEN dephosphorylates PI3K lipid products, negatively regulating the PI3K/AKT/mTOR pathway. (d) JAK/STAT pathway: Various cytokines and growth factors activate the JAK/STAT pathway. Activated JAKs phosphorylate each other and subsequently phosphorylate STAT3 molecules. Phosphorylated STAT3 forms dimers that translocate to the nucleus, acting as transcription factors to regulate gene expression. (e) Hippo-YAP/TAZ pathway: MST1/2 kinases bind SAV1 to form a complex that phosphorylates LATs1/2. Phosphorylated LATs1/2 inhibit the transcriptional coactivators YAP/TAZ, confining them to the cytoplasm or promoting their degradation. When the Hippo-YAP/TAZ pathway is inhibited, YAP/TAZ translocates to the nucleus, where they interact with transcription factors such as TEAD to initiate gene expression. (f) Hedgehog (Hh) pathway: Hh ligands bind to the transmembrane receptor Ptch, releasing the inhibition on SMO. Activated SMO initiates a signaling cascade in the cytoplasm, ultimately activating the Gli transcription factors. (g) Notch pathway: Jagged or Delta-like ligands bind to the Notch receptor, inducing structural changes. γ-secretase mediates receptor cleavage, releasing the Notch intracellular domain (NICD). NICD translocates to the nucleus and binds transcription factor complexes, activating downstream gene transcription. Raf family, initiating a signal transduction cascade. “P” stands for phosphorylation.