Insights into the molecular mechanisms underlying the function of lysyl oxidase like 1 in cancers

Introduction

Cancer is the second leading cause of death among human diseases and the largest cause of death for people under 85 years old (Siegel, Giaquinto & Jemal, 2024). At present, most cancers are difficult to cure and are in great need of effective treatment methods. Over the past few centuries, many rationally designed cancer treatments have been developed. Many cancer therapies introduced long ago are still available and are still used in oncology treatment (Sonkin, Thomas & Teicher, 2024). From 1970 to 2023, the main treatment modalities for cancer included surgery, radiation therapy, chemotherapy, allogeneic hematopoietic stem cell transplantation, pharmacological hormone therapy, treatments targeting genes with oncogenic alterations and related signaling pathways, photodynamic therapy, antibody-drug conjugates, immune checkpoint inhibitors, bispecific T-cell engagers, oncolytic virus therapy, and chimeric antigen receptor T cell therapy. In the future, these treatment approaches will continue to be utilized (Sonkin, Thomas & Teicher, 2024).

The lysyl oxidase (LOX) family is a group of secreted copper-dependent amine oxidases consisting of five members, namely, LOX and lysyl oxidase like 1-4 (LOXL1-4) (Chen et al., 2020; Laczko & Csiszar, 2020) (Fig. 1A). Members of the LOX protein family share a common conserved C-terminal domain and a variable N-terminal front region. The C-terminal domain includes copper ion binding sites, lysyl tyrosyl quinone, and cytokine receptor-like domains, which are essential for their catalytic activity in cross-linking collagen and elastin (Ye et al., 2020). The N-terminal sequences of LOX family members are diverse, with LOX and LOXL1 containing a pro-domain. LOXL2 to LOXL4 form a subgroup of this family that participates in cell adhesion and protein-protein interactions. In the LOX protein family, the N-terminus typically starts from the first amino acid and extends approximately 20 amino acid residues, constituting a signal peptide sequence crucial for the secretion of LOX proteins. Both LOX and LOXL1 possess leader sequences, resulting in their secretion as inactive proenzymes. Zymogens directly interact with the extracellular matrix (ECM), depositing the enzyme into elastic tissues (Rodríguez & Martínez-González, 2019). The catalytic domains of LOX family members are highly similar, indicating that they may function in a comparable manner (Chitty, Setargew & Cox, 2019). LOX family proteins are involved in the cross-linking of collagen and elastin, and play a key role in the remodeling of the extracellular matrix during development, injury, fibrosis, and the progression of cancer (Vallet & Ricard-Blum, 2019). LOX and LOXL1 both participate in the crosslinking of collagen and elastin proteins. Abnormal expression of LOXL1 underlies many pathological processes associated with imbalanced synthesis or degradation of the ECM. In addition, the LOX family also plays an important role in cancer drug treatment. For example, research has demonstrated that intraductal xenografts show lobular carcinoma cells rely on their own extracellular matrix and LOXL1 (Sflomos et al., 2021). Another study showed that a new ECM-targeting nanotherapy was developed by attaching an inhibitor of the ECM-related enzyme lysyl oxidase (LOX) to a lipid-based nanoparticle. When these conjugated nanoparticles were loaded with the chemotherapy drug epirubicin, they demonstrated significantly better inhibition of triple-negative breast cancer (TNBC) cell growth in both in vitro and in vivo settings. Additionally, the in vivo results indicated extended survival, reduced cytotoxicity, and improved biocompatibility when compared to both free epirubicin and epirubicin-loaded nanoparticles (De Vita et al., 2021).

Cancer research has increasingly leveraged transcriptomic data thanks to advancements in high-throughput technologies. Transcriptomics offers detailed insights into gene expression and regulation, enhancing our understanding of cancer biology (Liu et al., 2025). There are currently many open transcriptomic datasets available for cancer research, with The Cancer Genome Atlas (TCGA) being one of the most commonly used data mining databases. The TCGA project is an important research initiative that has provided the scientific community with a large amount of genomic and transcriptomic data. TCGA is a groundbreaking cancer genomics initiative that has molecularly analyzed more than 20,000 primary cancer samples and corresponding normal samples across 33 cancer types. This project was collaboratively initiated by the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI) (Liu et al., 2025). The insights provided should assist the scientific community in navigating the complexities of transcriptomic data and improving the translation of research findings into clinical applications, ultimately contributing to better cancer diagnosis, treatment, and prognosis.

Given the broad range of biological functions of the LOX family, disruptions in LOXL1 expression are implicated in the development of various pathological processes associated with imbalances in ECM synthesis and degradation. This article primarily examines the structure, function, and role of LOXL1 in cancer initiation and progression. Additionally, it explores the potential applications of LOXL1 in cancer research, offering theoretical insights and references that may support clinical diagnosis and treatment strategies for cancer.

The structure and function of the LOXL1 protein

Cellular signalling regulation of the LOXL1 protein

Several intracellular signaling pathways promote the secretion of LOXL1. The activity of LOXL1 mRNA is primarily induced by TGF-β1 and TGF-β2 through three distinct pathways. The TGF-β ligands bind to cell surface receptors, leading to the phosphorylation of the Smad2/Smad3 complex, which, with the help of Smad4, translocates to the nucleus (Sethi, Wordinger & Clark, 2013; Sethi et al., 2011). This complex can then bind directly to the LOXL1 promoter or interact with activator protein 1 (AP-1) to regulate transcription (Sethi et al., 2011). Additionally, TGF-β receptor activation can stimulate LOXL1 via the MAPK/JNK1/2 pathway, which phosphorylates the c-Jun component of AP-1 (Sethi, Wordinger & Clark, 2013; Sethi et al., 2011). Lastly, TGF-β may also enhance LOXL1 expression through the PI3K/Akt pathway (Gao et al., 2018) (Fig. 2). Furthermore, the BMP antagonist gremlin has been shown to indirectly increase LOXL1 expression by inhibiting BMP4 and BMP7, which usually suppress TGF-β2-induced LOXL1 expression (Sethi, Wordinger & Clark, 2013).

The role of LOXL1 protein in the occurrence and progression of cancer

Studies have shown that LOXL1 protein expression varies across different cancer tissues and cell lines. When compared to adjacent or normal tissues, LOXL1 expression is notably reduced in renal cell carcinoma (RCC) and bladder cancer (BLCA) but significantly elevated in salivary adenoid cystic carcinoma (SACC), non-small cell lung cancer (NSCLC), malignant pleural mesothelioma (MPM), brain glioma, prostate cancer (PRAD), gastric cancer (GC), breast cancer (BC), thyroid carcinoma (THCA), pancreatic adenocarcinoma (PAAD), and osteosarcoma (OS). However, the expression of LOXL1 in colorectal cancer (CRC) remains controversial, with reports suggesting both upregulation and downregulation (Ye et al., 2020; Barker, Cox & Erler, 2012) (Table 1).

The tumor-promoting mechanism of LOXL1 can be categorized into two main effects: extracellular and intracellular: (1) Extracellular effect: TGF-β secreted by non-small cell lung cancer (NSCLC) cells promotes the expression of integrin α11 (ITG α11) in cancer-associated fibroblasts (CAFs) through the Smad signaling pathway, which in turn upregulates LOXL1 expression in CAFs. This process induces ECM remodeling, fostering the proliferation and invasion of NSCLC cells. Additionally, LOXL1 secreted by tumor cells interacts with other cell types in the tumor microenvironment (TME), accelerating tumor progression. In intrahepatic cholangiocarcinoma (ICC), elevated LOXL1 expression interacts with fibulin-5 (FBLN5), an extracellular matrix glycoprotein containing the Arg-Gly-Asp (RGD) motif. LOXL1, FBLN5, and ITG-αvβ3 on the surface of vascular endothelial cells (VECs) may form a complex that regulates the FAK and MAPK pathways in VECs, promoting tumor angiogenesis (Wang et al., 2022a) (Fig. 3A). (2) Intracellular effect: The VEGFR/Src/CCAAT enhancer binding protein α (CEBPA) axis increases LOXL1 expression in glioma cells. LOXL1 stabilizes BAG family molecular chaperone regulator 2 (BAG2) by preventing K186 ubiquitination, thereby inhibiting tumor apoptosis (Wang et al., 2022a) (Fig. 3B).

The expression of LOXL1 in various human cancers was analyzed using data from The Cancer Genome Atlas (TCGA) database via a browser (https://portal.gdc.cancer.gov) (Fig. 4). LOXL1 transcripts are notably overexpressed in several cancers, including invasive breast carcinoma, cholangiocarcinoma, diffuse large B-cell lymphoma, esophageal carcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, kidney renal papillary cell carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, pheochromocytoma and paraganglioma, sarcoma, stomach adenocarcinoma, thymoma, uterine corpus endometrial carcinoma, and uterine carcinosarcoma (Fig. 4A). Furthermore, the cBioPortal database (https://www.cbioportal.org/) revealed that the LOXL1 gene frequently undergoes mutations and amplifications in tumors, with varying frequencies of gene mutations, structural variants, amplifications, and deep deletions across different cancer types. Among these, the mutation frequency of LOXL1 is highest in uterine corpus endometrial carcinoma, while the amplification frequency is highest in uterine carcinosarcoma (Fig. 4B). Analysis of TCGA tumor samples shows that the most common point mutations in LOXL1 are D525N and R562H/C (Fig. 4C).

Conclusions and future perspectives

With the advancements in modern medicine, cancer treatment options, including surgery, radiofrequency ablation, hepatic artery chemoembolization, systemic chemotherapy, targeted therapy, and immunotherapy, are becoming increasingly diverse. As a result, the patient prognosis has improved. However, cancer treatment remains a challenging issue in the medical field. The LOXL1 gene serves as a potential therapeutic target and plays a significant role in the occurrence and development of various types of cancer (Schlötzer-Schrehardt & Zenkel, 2019). This finding may be related to the origin of the tumour cells, degree of differentiation, and genetic factors. Moreover, differences in LOXL1 expression across different cancers may also be associated with interactions between tumour stromal cells, ECM stability, and the diverse biological activities of LOXL1 itself. LOXL1 is a crucial gene that plays a diverse and significant role in maintaining cellular homeostasis. LOXL1 participates in several fundamental processes in tumor progression, especially in invasion and metastasis, while proliferation, apoptosis, chemoresistance, and other aspects also have preliminary progress. However, more studies are still required because of the tissue-specific, spatial, and temporal differences in the expression of LOXL1.

This review highlights that LOXL1 plays a key role in crosslinking collagen and elastin through oxidation, thereby preserving the rigidity and structural integrity of the ECM. The ECM is crucial in the tumor microenvironment, influencing invasiveness and metastasis. Consequently, developing drugs that target LOXL1 may offer therapeutic potential for preventing and treating tumor metastasis. In addition, considering the pivotal role of LOXL1 in various physiological processes, its systemic inhibition will inevitably cause numerous side effects. Therefore, developing novel delivery systems, such as enzyme-catalyzed responsive nanoparticles combined with specific enzyme inhibitors and standard cancer therapeutics, should be another promising direction for future exploration (Loser et al., 2023). New methods for cancer prevention and metastasis control are needed. Given the shared characteristics among LOX family members and the ongoing quest for a deeper understanding of their intricate structures, it is imperative to urgently devise specialized inhibitors tailored to LOXL1. The current availability of non-selective inhibitors, such as beta-aminopropionitrile (β-APN), which target the broader LOX family, underscores the pressing need for tailored solutions specific to LOXL1 (Zhao, Liu & Luo, 2025).

In essence, this review not only illuminates the role of LOXL1 in cancer progression but also beckons toward a future where innovative LOXL1-targeted therapeutics may reshape the landscape of cancer treatment, offering renewed hope and prospects for improved patient outcomes (Zhao, Liu & Luo, 2025). This review also has certain limitations. Currently, research on the specific mechanisms through which the LOX family influences tumor progression is still insufficient, so the summary of these mechanisms in this review is not comprehensive. Further research should be conducted in this area in the future.