Research progress on the mechanism of LGALS1 in the occurrence and development of non-small cell lung cancer

LGALS1 (Galactin 1) is an important member of the galectin family. As a conserved sugar chain binding protein, its encoding gene is located in a specific region of the human chromosome. The protein structure contains a typical carbohydrate recognition domain (CRD), which can specifically bind to sugar chain structures containing β - galactosides.

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I. Overview of Molecular Characteristics and Biological Functions of LGALS1

LGALS1 (Galectin-1), an important member of the galectin family, is a conserved glycan-binding protein. Its encoding gene is located in a specific region of human chromosomes, and its protein structure contains a typical carbohydrate recognition domain (CRD) that can specifically bind to β-galactoside-containing glycan structures. As a soluble protein, LGALS1 can function both intracellularly and extracellularly after secretion to participate in intercellular signal transmission. Its expression is regulated by various transcription factors and epigenetic mechanisms, showing specific expression patterns in different tissues and pathological states.

Under physiological conditions, LGALS1 is involved in various biological processes such as immune regulation, cell adhesion, and angiogenesis. In the immune system, it maintains immune tolerance by regulating T cell activity; during embryonic development, it participates in tissue and organ formation by regulating cell proliferation and differentiation; in adult individuals, it plays an important role in maintaining tissue homeostasis and injury repair. These functions are achieved through its interaction with cell surface glycoproteins, extracellular matrix components, and cytokines, influencing cell fate decisions by activating downstream signaling pathways.

II. Expression Characteristics of LGALS1 in Non-Small Cell Lung Cancer

(I) Expression Differences in Clinical Samples

Analysis of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases revealed that LGALS1 is significantly overexpressed in non-small cell lung cancer (NSCLC) tumor tissues, with mRNA and protein levels being 2-3 times higher than those in adjacent normal lung tissues. Clinical correlation analysis showed that high LGALS1 expression is closely associated with adverse clinicopathological features of patients, including tumor size, lymph node metastasis, and clinical stage, and is an independent risk factor for shortened overall survival.

Among different NSCLC subtypes, LGALS1 expression is slightly higher in lung squamous cell carcinoma than in lung adenocarcinoma, but both are significantly higher than in normal tissues. Immunohistochemistry showed that it is mainly localized in the cytoplasm and cell membrane of tumor cells, with positive expression in the tumor stroma in some cases, suggesting that it may function through autocrine or paracrine mechanisms and has potential as a diagnostic marker.

(II) Expression Regulation Mechanisms

The overexpression of LGALS1 in NSCLC is regulated by multiple levels of mechanisms. At the epigenetic level, hypomethylation of its gene promoter region is an important reason for upregulated expression, and treatment with DNA methyltransferase inhibitors can further enhance its expression. In terms of transcriptional regulation, transcription factors such as NF-κB and HIF-1α bind to its promoter region to promote transcription under inflammatory or hypoxic conditions. In addition, non-coding RNAs are involved in regulation; some oncogenic miRNAs inhibit expression by targeting its 3' untranslated region, while the downregulation of these miRNAs in NSCLC may release this inhibition. Cytokines in the tumor microenvironment such as TGF-β and IL-6 can also induce LGALS1 expression, forming a positive feedback regulatory loop.

III. Interaction and Functional Synergy Between LGALS1 and NCAPG

(I) Identification of Protein Interaction

Recent studies have found that LGALS1 directly interacts with non-smooth muscle cell condensin I complex subunit G (NCAPG). As a core component of the condensin complex, NCAPG is involved in regulating chromosome condensation and segregation during mitosis, and has been confirmed to play an oncogenic role in various tumors in recent years. Through co-immunoprecipitation and mass spectrometry analysis, it was confirmed that LGALS1 and NCAPG form a protein complex in NSCLC cells, and their interaction depends on the carbohydrate recognition domain of LGALS1 and specific functional regions of NCAPG. Confocal microscopy showed co-localization of the two in cells, with significantly enhanced co-localization signals during mitosis, suggesting a potential association with cell cycle regulation. This interaction exhibits dose dependence and specificity.

(II) Functional Synergistic Effects

The interaction between LGALS1 and NCAPG significantly affects NSCLC cell functions. In terms of cell proliferation, their co-expression can synergistically promote the in vitro proliferation of NSCLC cells, characterized by shortened G1 phase of the cell cycle, increased proportion of S phase cells, and significantly elevated expression of the cell proliferation marker Ki-67. In vivo experiments showed that xenograft tumors in nude mice with co-expression of LGALS1 and NCAPG grew faster than those with single overexpression or control groups, with significantly increased proliferation index in tumor tissues.

In terms of tumor metastasis, cells with co-expression showed increased migration distance and number of transmembrane cells, with obvious changes in epithelial-mesenchymal transition (EMT) markers, including downregulated E-cadherin and upregulated N-cadherin and vimentin. These findings suggest that LGALS1 and NCAPG synergistically promote the EMT process, playing an important role in the malignant progression of NSCLC.

IV. Mechanisms of LGALS1-Mediated Signaling Pathways

(I) Role of the LGALS1/SPARC Axis

LGALS1 exerts oncogenic functions by regulating the expression of SPARC (Secreted Protein Acidic and Cysteine Rich). It can bind to the SPARC promoter or enhance transcriptional activity through protein interaction, leading to SPARC upregulation in NSCLC. As a secreted glycoprotein, SPARC regulates extracellular matrix remodeling and vascular permeability, and its high expression can enhance tumor invasive ability and promote angiogenesis. Experiments showed that LGALS1-mediated SPARC upregulation increases tumor vascular permeability, facilitating tumor cells to enter the bloodstream and form metastatic lesions. In urethane-induced mouse lung cancer models, LGALS1 knockout significantly reduced SPARC expression, and the metastatic ability of lung tumors was obviously weakened. Additionally, SPARC can activate the PI3K/Akt pathway to enhance the survival and proliferation of tumor cells.

(II) Regulation of EMT Signaling Pathways

LGALS1 promotes the malignant progression of NSCLC by regulating EMT-related signaling pathways. Mechanistically, it can activate the Smad2/3 signaling pathway, promoting the nuclear translocation of transcription factors Snail and Twist, thereby inhibiting E-cadherin expression and enhancing the mesenchymal phenotype of tumor cells. Meanwhile, LGALS1 can activate the FAK/Src signaling pathway by binding to integrins on the cell membrane, promoting cytoskeletal reorganization and pseudopodia formation, and enhancing migration ability. In the presence of NCAPG, the activating effect of LGALS1 on EMT signaling pathways is more significant, with further increased expression of downstream target genes, suggesting that their interaction may amplify the pro-metastatic effect by enhancing signal transduction efficiency.

V. Functional Verification of LGALS1 in Non-Small Cell Lung Cancer

In vitro experiments confirmed that LGALS1 knockout significantly inhibits the proliferation of NSCLC cells, arresting the cell cycle at G1 phase, increasing the proportion of apoptotic cells, and reducing clonogenic efficiency by more than 50%. In migration and invasion experiments, knockout cells showed decreased motility and matrix degradation ability, with reduced expression of MMP2 and MMP9. Rescue experiments showed that exogenous supplementation of LGALS1 can restore the malignant phenotype of knockout cells, verifying its direct role.

In vivo experiments, nude mouse subcutaneous xenograft models showed that tumors with high LGALS1 expression grew faster with increased microvessel density. In tail vein injection metastasis models, cells with high LGALS1 expression formed more lung metastatic lesions. In urethane-induced spontaneous lung cancer models, LGALS1 knockout mice showed reduced incidence and number of lung tumors, delayed progression, and prolonged survival. These in vitro and in vivo experiments collectively confirm the important role of LGALS1 in the oncogenesis and progression of NSCLC.

VI. Clinical Value and Research Prospects of LGALS1

(I) Diagnostic and Prognostic Value

As a potential biomarker, LGALS1 can assist in the early diagnosis of NSCLC through immunohistochemistry or blood tests. Clinical data showed that its expression level can serve as an independent prognostic indicator, with patients with high expression having increased recurrence risk and shortened overall survival. Combined with other parameters, it can improve the accuracy of prognostic evaluation. In therapeutic monitoring, changes in LGALS1 expression can reflect treatment response, with responsive patients often showing decreased expression levels, making it a dynamic monitoring indicator for treatment efficacy.

(II) Therapeutic Target Potential and Future Directions

LGALS1 has potential as a therapeutic target, with targeting strategies including the development of specific neutralizing antibodies, small molecule inhibitors, and oligonucleotide drugs. In vitro experiments showed that neutralizing antibodies against LGALS1 can significantly inhibit the proliferation and invasion of NSCLC cells and enhance chemotherapy sensitivity. In animal models, LGALS1-targeted therapy can reduce tumor volume, decrease metastatic lesions, and no serious side effects were observed. Combined inhibition of the interaction between LGALS1 and NCAPG or simultaneous targeting of the LGALS1/SPARC axis may produce synergistic anti-tumor effects.

Future research should focus on: analyzing the molecular details of the interaction between LGALS1 and NCAPG to identify key binding sites; exploring functional differences among different NSCLC subtypes to achieve individualized treatment; investigating its interaction with other cells in the tumor microenvironment; and developing combined treatment regimens to overcome drug resistance. With the development of technology, the mechanism of LGALS1 will be more comprehensively revealed, and its clinical translation is expected to bring new hope for NSCLC patients.

Disclaimer: This article partially utilizes artificial intelligence assistance in its creation. If any content involves copyright or intellectual property issues, please let us know and we promise to verify and remove it as soon as possible.

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