Galectin Family Members: Emerging Novel Targets for Lymphoma Therapy?

Shi, Yuanwei; Tang, Danting; Li, Xiaoqi; Xie, Xiaoli; Ye, Yufu; Wang, Limin

doi:10.3389/fonc.2022.889034

Cited by 6 publications

(6 citation statements)

References 142 publications

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“…The FGF/FGFR signaling units and galectins govern critical cellular processes and are ultimately implicated in human diseases, especially cancers [4,14,16,17,[41][42][43][44][45][46]. For a long time, these diverse groups of proteins were treated separately.…”

Section: Discussionmentioning

confidence: 99%

Receptor clustering by a precise set of extracellular galectins initiates FGFR signaling

Zukowska

Gedaj

Porębska

et al. 2023

Cell. Mol. Life Sci.

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FGF/FGFR signaling is critical for the development and homeostasis of the human body and imbalanced FGF/FGFR contributes to the progression of severe diseases, including cancers. FGFRs are N-glycosylated, but the role of these modifications is largely unknown. Galectins are extracellular carbohydrate-binding proteins implicated in a plethora of processes in heathy and malignant cells. Here, we identified a precise set of galectins (galectin-1, -3, -7, and -8) that directly interact with N-glycans of FGFRs. We demonstrated that galectins bind N-glycan chains of the membrane-proximal D3 domain of FGFR1 and trigger differential clustering of FGFR1, resulting in activation of the receptor and initiation of downstream signaling cascades. Using engineered galectins with controlled valency, we provide evidence that N-glycosylation-dependent clustering of FGFR1 constitutes a mechanism for FGFR1 stimulation by galectins. We revealed that the consequences of galectin/FGFR signaling for cell physiology are markedly different from the effects induced by canonical FGF/FGFR units, with galectin/FGFR signaling affecting cell viability and metabolic activity. Furthermore, we showed that galectins are capable of activating an FGFR pool inaccessible for FGF1, enhancing the amplitude of transduced signals. Summarizing, our data identify a novel mechanism of FGFR activation, in which the information stored in the N-glycans of FGFRs provides previously unanticipated information about FGFRs’ spatial distribution, which is differentially deciphered by distinct multivalent galectins, affecting signal transmission and cell fate.

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Section: Discussionmentioning

confidence: 99%

Receptor clustering by a precise set of extracellular galectins initiates FGFR signaling

Zukowska

Gedaj

Porębska

et al. 2023

Cell. Mol. Life Sci.

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“…For instance, in acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and classical Hodgkin’s lymphoma (cHL), Gal-3 overexpression is associated with poor survival and prognosis [ 124 , 125 , 126 ]. Similarly, in DLBCL, multiple studies associated overexpressed Gal-3 with increased cell proliferation, survival, and disease aggressiveness and identified GAL-3 as a prognostic factor and potential target for therapy [ 127 , 128 , 129 , 130 , 131 , 132 , 133 ]. Interestingly, Gal-3 binds lymphocyte-activation gene 3 (LAG3), the immune checkpoint of immune effector cells, and anti-LAG-3 (relatlimab) represents a novel FDA-approved inhibitor for combinational checkpoint therapy in melanoma [ 134 ].…”

Section: Discussionmentioning

confidence: 99%

Transcriptome Analysis of Diffuse Large B-Cell Lymphoma Cells Inducibly Expressing MyD88 L265P Mutation Identifies Upregulated CD44, LGALS3, NFKBIZ, and BATF as Downstream Targets of Oncogenic NF-κB Signaling

Turi

Sithara

Hofmanová

et al. 2023

IJMS

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During innate immune responses, myeloid differentiation primary response 88 (MyD88) functions as a critical signaling adaptor protein integrating stimuli from toll-like receptors (TLR) and the interleukin-1 receptor (IL-1R) family and translates them into specific cellular outcomes. In B cells, somatic mutations in MyD88 trigger oncogenic NF-κB signaling independent of receptor stimulation, which leads to the development of B-cell malignancies. However, the exact molecular mechanisms and downstream signaling targets remain unresolved. We established an inducible system to introduce MyD88 to lymphoma cell lines and performed transcriptomic analysis (RNA-seq) to identify genes differentially expressed by MyD88 bearing the L265P oncogenic mutation. We show that MyD88L265P activates NF-κB signaling and upregulates genes that might contribute to lymphomagenesis, including CD44, LGALS3 (coding Galectin-3), NFKBIZ (coding IkBƺ), and BATF. Moreover, we demonstrate that CD44 can serve as a marker of the activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) and that CD44 expression is correlated with overall survival in DLBCL patients. Our results shed new light on the downstream outcomes of MyD88L265P oncogenic signaling that might be involved in cellular transformation and provide novel therapeutical targets.

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“…The changes in the immune microenvironment are closely related to the occurrence and progression of the disease. Galectin-3 plays a role in many cellular functions, including apoptosis, innate immunity, and T-cell regulation, and is a vital component of the immune microenvironment ( 24 , 25 ). HBV has multiple immunosuppressive effects, a key factor in the progression of HBV infection from chronic infection to HCC ( 26 ).…”

Section: Discussionmentioning

confidence: 99%

The necroptosis related gene LGALS3 can be used as a biomarker for the adverse progression from chronic HBV infection to HCC

et al. 2023

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The number of patients with hepatocellular carcinoma (HCC) caused by hepatitis B virus (HBV) infection remains large, despite the remarkable effectiveness of antiviral drugs and vaccines for HBV in preventing and treating HBV infection. Necroptosis is closely related to the occurrence of inflammation, clearance of viral infection, and tumor progression. Presently, little is known about the changes in necroptosis-related genes in the progression from chronic HBV infection (CHI) to HBV-related hepatic fibrosis (HBV-HF) and HBV-related hepatocellular carcinoma (HBV-HCC). In this study, Cox regression analysis was performed using GSE14520 chip data and a necroptosis-related genes survival prognosis score (NRGPS) was established for HBV-HCC patients. NRGPS was constructed using three model genes (G6PD, PINK1 and LGALS3), and verified by data sequencing in the TCGA database. The HBV-HCC cell model was established by transfection of pAAV/HBV1.2C2, constructed by homologous recombination, into HUH7 and HEPG2 cells. The expression levels of G6PD, PINK1, and LGALS3 were detected using RT-qPCR. We further analyzed the expression of the model genes in GSE83148, GSE84044, and GSE14520 and found that LGALS3 was consistently highly expressed in CHI, high fibrosis score and high NRGPS. In addition, immune microenvironment analysis showed that LGALS3 was not only associated with the infiltration of regulatory T cells in the immune microenvironment but also with expression of CCL20 and CCR6. The expression levels of model genes, FOXP3 and CCR6, were analyzed using RT-qPCR in peripheral blood mononuclear cells of 31 hepatitis B surface antibody positive patients, 30 CHI, 21 HBV-HF, and 20 HBV-HCC. In further cell-model experiments, we analyzed the expression of CCL20 by RT-qPCR and the changes in cell proliferation and migration by CCK8 and transwell assays, respectively, in HBV-HCC cell models after LGALS3 knockdown. The findings of this study suggest that LGALS3 could be a biomarker for adverse progression following chronic HBV infection and may also be involved in the regulation of the immune microenvironment, making it a potential therapeutic target.

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Galectin Family Members: Emerging Novel Targets for Lymphoma Therapy?

Cited by 6 publications

References 142 publications

Receptor clustering by a precise set of extracellular galectins initiates FGFR signaling

Receptor clustering by a precise set of extracellular galectins initiates FGFR signaling

Transcriptome Analysis of Diffuse Large B-Cell Lymphoma Cells Inducibly Expressing MyD88 L265P Mutation Identifies Upregulated CD44, LGALS3, NFKBIZ, and BATF as Downstream Targets of Oncogenic NF-κB Signaling

The necroptosis related gene LGALS3 can be used as a biomarker for the adverse progression from chronic HBV infection to HCC

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