Signaling pathways in liver cancer: pathogenesis and targeted therapy

Abstract

Liver cancer remains one of the most prevalent malignancies worldwide with high incidence and mortality rates. Due to its subtle onset, liver cancer is commonly diagnosed at a late stage when surgical interventions are no longer feasible. This situation highlights the critical role of systemic treatments, including targeted therapies, in bettering patient outcomes. Despite numerous studies on the mechanisms underlying liver cancer, tyrosine kinase inhibitors (TKIs) are the only widely used clinical inhibitors, represented by sorafenib, whose clinical application is greatly limited by the phenomenon of drug resistance. Here we show an in-depth discussion of the signaling pathways frequently implicated in liver cancer pathogenesis and the inhibitors targeting these pathways under investigation or already in use in the management of advanced liver cancer. We elucidate the oncogenic roles of these pathways in liver cancer especially hepatocellular carcinoma (HCC), as well as the current state of research on inhibitors respectively. Given that TKIs represent the sole class of targeted therapeutics for liver cancer employed in clinical practice, we have particularly focused on TKIs and the mechanisms of the commonly encountered phenomena of its resistance during HCC treatment. This necessitates the imperative development of innovative targeted strategies and the urgency of overcoming the existing limitations. This review endeavors to shed light on the utilization of targeted therapy in advanced liver cancer, with a vision to improve the unsatisfactory prognostic outlook for those patients.

Keywords: Hepatocellular carcinoma (HCC); Liver cancer; Signaling pathways; Sorafenib; Targeted therapy.

Fig. 1

An overview of signaling pathways in the pathogenesis of liver cancer. Here we present a diagram of the pathways and their key components related to the occurrence of liver cancer, including growth factor receptor-related signaling pathway, Wnt-β-catenin, JAK/STAT, Hedgehog, Hippo, Notch and NF-κB signaling pathway

Fig. 2

Growth factor receptor-related signaling pathways. Various growth factors act as external signals that trigger the activation of tyrosine kinase receptors such as VEGFR, FGFR, c-MET, PDGFR, EGFR, IGFR, and TGFβR. Excluding the unique case of TGFβR, the transmission of signals to the cell nucleus mainly involves two pathways: the Ras/Raf/MEK/ERK and the PI3K/AKT/mTOR cascades, which ultimately influence the transcription of specific genes. TGF-β signaling can be categorized into SMAD pathway and non-SMAD pathway. The latter falls under the previously mentioned pathways. In the case of SMAD-dependent signaling, TGFβR phosphorylates SMAD2/3, which then associates with SMAD4. This complex moves to the nucleus to modulate gene transcription. By figdraw

Fig. 3

Wnt-β-catenin signaling pathway. When Wnt signaling is inactive (Wnt OFF), β-catenin within the cytoplasm undergoes phosphorylation by a degradation complex, which subsequently leads to its breakdown via the proteasome. Conversely, in the presence of Wnt ligands (Wnt ON), the interaction between the FZD and LRP5/6 receptors is initiated, followed by the phosphorylation of LRP6. This event attracts GSK-3β, CK1γ, and DVL, disrupting the Axin-led phosphorylation of β-catenin. Consequently, β-catenin accumulates in the cytoplasm and then relocates to the nucleus, where it regulates the transcription of specific genes. By figdraw

Fig. 4

JAK/STAT signaling pathway. Ligand-receptor interaction triggers the phosphorylation of the receptor's cytoplasmic domain via JAK activation, establishing docking points for STAT attachment and its subsequent phosphorylation by JAK. These phosphorylated STAT molecules then dimerize within the cytoplasm and migrate to the nucleus, where they direct the transcription of specific genes. By figdraw

Fig. 5

Canonical Hedgehog signaling pathway. In the absence of extracellular Hedgehog ligands (HH OFF), SMO is suppressed by PTCH1, leading to Gli2/3 phosphorylation by Sufu. This phosphorylation facilitates the proteasome-mediated partial degradation of Gli2/3. Subsequently, the repressor forms of Gli3 and Gli2 (Gli3/2R) are transported into the nucleus to repress the transcription of specific genes. When Hedgehog ligands are present (HH ON), their binding to PTCH1 lifts PTCH1's inhibition on SMO, enabling the activation of Gli proteins (GliA). GliA then enters the nucleus to promote the transcription of target genes. By figdraw

Fig. 6

Hippo signaling pathway. Following the binding of specific ligands to their receptors, there is a sequential phosphorylation of MST1/2 and LATS1/2. Additionally, the presence of SAV1 and MOB1A/B enhances their activities. Notably, the phosphorylation of LATS1/2 leads to the phosphorylation and inactivation of YAP/TAZ, resulting in their retention in the cytoplasm or their degradation via the proteasome. Conversely, YAP/TAZ migrate to the nucleus to influence the transcription of target genes only when Hippo signaling is diminished. By figdraw

Fig. 7

Canonical Notch signaling pathway. Cell-to-cell contact facilitates the interaction between receptors and ligands, leading to the endocytosis of Notch. The initial cleavage at site 2 (S2) by the ADAM generates the NEXT fragment, which is a substrate for further cleavage by the γ-secretase complex from site 3 (S3) to site 4 (S4). This process ultimately releases the Notch Intracellular Domain (NICD) fragment, which then travels to the nucleus to modulate the transcription of specific target genes. By figdraw

Fig. 8

NF-κB signaling pathway. In the NEMO dependent pathway, ligand presence triggers the phosphorylation of IKKα and IKKβ within the IKK complex, leading to the activation and nuclear translocation of p50-p65 dimers to govern the transcription of target genes. Conversely, in the NEMO independent pathway, NIK is activated, which then phosphorylates IKKα-IKKα homodimers. This phosphorylation prompts the formation of p100-RelB dimers, subsequently replaced by p52-RelB dimers that migrate into the nucleus to regulate gene transcription. By figdraw

Fig. 9

Mechanisms of sorafenib resistance in HCC. Complex mechanisms lie in the resistance to sorafenib in HCC. Not only do they include aspects of epigenetics such as circRNA-SORE, lncRNA SNHG3, and METTL3-mediated processes, but transporters like ABC and exosomes are also involved in resistance. Additionally, from regulated cell death, represented by ferroptosis and autophagy, to tumor metabolic reprogramming, and factors like TAK1 and PCSK9 have also been found to participate in HCC's resistance to sorafenib. By figdraw