The lysyl oxidase (LOX) family members are secreted copper-dependent amine oxidases, comprised of five paralogues: LOX and LOX-like l-4 (LOXL1-4), which are characterized by catalytic activity contributing to the remodeling of the cross-linking of the structural extracellular matrix (ECM). ECM remodeling plays a key role in the angiogenesis surrounding tumors, whereby a corrupt tumor microenvironment (TME) takes shape. Primary liver cancer includes hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), ranked as the seventh most common cancer globally, with limited therapeutic options for advanced stages. In recent years, a growing body of evidence has revealed the key roles of LOX family members in the pathogenesis of liver cancer and the shaping of TME, indicating their notable potential as therapeutic targets.
The lysyl oxidase (LOX) family members are secreted copper-dependent amine oxidases, comprised of five paralogues: LOX and LOX-like l-4 (LOXL1-4) . As shown in Figure 1, LOX family members encoded by the human LOX/LOXLs genes are located at various chromosome sites, including 5q23.1, 15q24.1, 8p21.3, 2p13.1, and 10q24.2 . These members structurally consist of a variable N-terminal domain and a highly conserved C-terminal domain (Figure 1). The conserved C- terminal consists of copper binding domain amino acid residues forming lysine tryosylquinone (LTQ), and a cytokine receptor-like (CRL) domain . In the N-terminal domain, LOX and LOXL1 possess a propeptide sequence, whereas LOXL2–4 present four scavenger-receptor cysteine-rich (SRCR) domains in this region . The matured active forms of LOX and LOXL1 are formed by a cleavage process executed by bone morphogenetic protein 1 (BMP-1), which is not a required program for LOXL2, LOXL3, or LOXL4  (Figure 1). LOX family members are characterized by their catalytic activity contributing to structural integrity and increased tensile strength, acting to remodel the cross-linking of the structural extracellular matrix (ECM) of fibrotic organs such as the liver , as well as that of the cancer microenvironments . A growing body of evidence indicates that the expression of LOX family members increases in invasive and metastatic cancers, and their elevated expression correlates with poor survival . Their crucial role in tumor proliferation, epithelial–mesenchymal transition (EMT), migration, invasion, formation of pre-metastatic niches, and immunomodulation have been well documented . Consistent with these reports, we note that a genomic big data-centric pathway activity analysis reveals their role in the activation of the EMT pathway in cancer (Figure 2).
Figure 1. The structure of lysyl oxidase (LOX) family members. LOX family members encoded by the human LOX/LOXLs genes are located at various chromosome sites, including 5q23.1, 15q24.1, 8p21.3, 2p13.1, and 10q24.2. These members consist of a variable N-terminal domain and a highly conserved C-terminal domain. Sig, signal peptide (Sig); copper binding domain (Cu); lysyl-tyrosyl-quinone (LTQ) co-factor; scavenger receptor cysteine-rich (SRCR) domain; cytokine receptor-like (CRL) domain.
Figure 2. The epithelial–mesenchymal transition (EMT) pathway is activated by LOX, LOXL1, LOXL2, LOXL3, and LOXL4 in genomic big data-centric pathway analysis. Heatmap data demonstrated that LOX, LOXL1, LOXL2, LOXL3, and LOXL4 have activating/inhibiting (red/blue) functions on each cancer-related pathway. Note that LOX, LOXL1, LOXL2, LOXL3, and LOXL4 account for 54%, 47%, 44%, 44%, and 25% of cancers in the EMT-activating pathway, respectively. The pathway activity module was assessed with the GSCALite web server. High-throughput antibody-based technique reverse phase protein array (RPPA) was conduct to determine the expression of The Cancer Genome Atlas (TCGA) samples of at least 5 cancer types. Known cancer-related pathways are included: TSC/mTOR, RTK, RAS/MAPK, PI3K/AKT, hormone ER, hormone AR, EMT, DNA damage response, cell cycle, apoptosis.
Primary liver cancer is ranked as the seventh most common cancer globally, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) . HCC accounts for approximately 90%, while CCA and the combination of HCC and CCA account for 10% of liver cancers . HCC features hepatocellular characteristics at the morphological and molecular levels, whereas CCA exhibits biliary epithelial cell properties. Of note, limited therapeutic options are currently available for the advanced stages of liver cancers. Furthermore, as estimated by the World Health Organization (WHO), more than one million patients are projected to die from liver cancer in the next decade . Growing evidence supports the role of the tumor microenvironment (TME) in the development and progression of HCC. The TME is composed of cellular and non-cellular components. Cellular components include angiogenic endothelial cells, immune system cells, tumor-associated fibroblasts (TAF), and tumor-associated macrophage (TAM); while non-cellular components involve ECM, exosomes, soluble cytokines, and signaling molecules .
Mounting evidence in recent years has revealed the key roles of LOX family members in the pathogenesis of liver cancer. Their ECM-remodeling and secretable nature permits the shaping of TME in both the primary organ and distal metastatic sites. More importantly, their potential as therapeutic targets is notably emerging. This expeditious progress prompted us to summarize the prognostic significance of such research, and to review the novel biological roles of LOX family members in tumor cells and the TME of liver cancer. Furthermore, we highlight recent insights into their mechanisms and potential for target therapy approaches.