Galectin-3 Inhibits Osteoblast Differentiation through Notch Signaling

Nakajima, Kosei; Kho, Dhong Hyo; Yanagawa, Takashi; Harazono, Yosuke; Gao, Xiaoge; Hogan, Victor; Raz, Avraham

doi:10.1016/j.neo.2014.09.005

Cited by 73 publications

(75 citation statements)

References 57 publications

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“…Next, we generated the cells stably transfected with N-terminal deletion mutants (33–250 aa, 63–250 aa) mimicking cleaved Gal-3 and intact Gal-3 sequence (1–250 aa) mimicking secretion by cancer cells (1, 12). In addition, we wanted to avoid the endogenous Gal-3 effect and employed LNCaP, a human prostate cancer cell line in which endogenous Gal-3 was not detected under tested conditions (1). Then, we examined how cancer-secreting truncated Gal-3 affects osteoclast differentiation in co-culture system.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, Gal-3-activating integrins possibly cross-talk with RANKL-mediated signaling pathways and transcription. Previously, we documented that secreted Gal-3 exerts an inhibitory effect on osteoblast differentiation through CRD-mediated Notch receptor binding (1). Taken together, cancer-secreted Gal-3 may exhibit dual properties in bone remodeling: 1) secreted Gal-3 enhances osteoclast fusion and 2) suppresses osteoblast differentiation, leading effectively to osteolysis.…”

Section: Discussionmentioning

confidence: 99%

“…sh-RNA against Gal-3 was created using pSilencer 3.1-H1 neo expression vector (Ambion) following previous study (16). LnCaP transfectants secreting full-length (1–250 aa) and cleaved (33–250 aa, 63–250 aa) Gal-3 were generated using Lipofectamine® LTX and Plus™ transfection reagent (Invitrogen) and p3xFLAG-MYC-CMV-25 expression vector (Sigma-Aldrich) containing a preprotrypsin leader sequence for secretion following previous study (1, 12). Recombinant Gal-3-V5 was created using the pET30as (modified pET30a) vector containing Gal-3 sequence as described (1, 13).…”

Section: Methodsmentioning

confidence: 99%

“…Bone colonization by disseminated cancer cells leads to communication with the host bone microenvironment. This causes bone remodeling and skeletal-related events such as bone pain, which reduces the patient’s quality of life (1, 2). Some patients with advanced metastatic lesions experience pathological fractures or spinal cord compression.…”

Section: Introductionmentioning

confidence: 99%

“…During the bone metastatic process, Gal-3 mediates adhesion at the interface between tumor cells and bone marrow endothelial cells (6, 7). Focusing on the bone TME, prostate and breast carcinoma secrete Gal-3, suppressing osteoblast differentiation (1), which also results in a higher serum concentration of Gal-3 in patients with breast and prostate cancer metastasis as compared with normal counterparts (8, 9). Structurally, human Gal-3 is a β-galactoside-binding protein comprising 250 amino acid residues and is a chimeric gene-product composed of three distinct structural domains: a short NH 2 -terminal domain containing a phosphorylation site, a repeated collagen α-like sequence and a C-terminal domain containing a single carbohydrate recognition domain (CRD) composed of 140 amino acids (10).…”

Section: Introductionmentioning

confidence: 99%

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Galectin-3 Cleavage Alters Bone Remodeling: Different Outcomes in Breast and Prostate Cancer Skeletal Metastasis

et al. 2016

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Management of bone metastasis remains clinically challenging and requires the identification of new molecular target(s) that can be therapeutically exploited to improve patient outcome. Galectin-3 (Gal-3) has been implicated as a secreted factor that alters the bone tumor microenvironment. Proteolytic cleavage of Gal-3 may also contribute to malignant cellular behaviors, but has not been addressed in cancer metastasis. Here, we report that Gal-3 modulates the osteolytic bone tumor microenvironment in the presence of RANKL. Gal-3 was localized on the osteoclast cell surface, and its suppression by RNAi or a specific antagonist markedly inhibited osteoclast differentiation markers, including TRAP, and reduced the number of mature osteoclasts. Structurally, the 158–175 amino acid sequence in the carbohydrate recognition domain (CRD) of Gal-3 was responsible for augmented osteoclastogenesis. During osteoclast maturation, Gal-3 interacted and co-localized with myosin-2A along the surface of cell-cell fusion. Pathologically, bone metastatic cancers expressed and released an intact form of Gal-3, mainly detected in breast cancer bone metastases, as well as a cleaved form, more abundant in prostate cancer bone metastases. Secreted intact Gal-3 interacted with myosin-2A, leading to osteoclastogenesis, whereas a shift to cleaved Gal-3 attenuated the enhancement in osteoclast differentiation. Thus, our studies demonstrate that Gal-3 shapes the bone tumor microenvironment through distinct roles contingent on its cleavage status, and highlight Gal-3 targeting through the CRD as a potential therapeutic strategy for mitigating osteolytic bone remodeling in the metastatic niche.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Galectin-3 Cleavage Alters Bone Remodeling: Different Outcomes in Breast and Prostate Cancer Skeletal Metastasis

et al. 2016

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RNF219/α‐Catenin/LGALS3 Axis Promotes Hepatocellular Carcinoma Bone Metastasis and Associated Skeletal Complications

Zhang

Xie

et al. 2020

Advanced Science

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The incidence of bone metastases in hepatocellular carcinoma (HCC) has increased prominently over the past decade owing to the prolonged overall survival of HCC patients. However, the mechanisms underlying HCC bone‐metastasis remain largely unknown. In the current study, HCC‐secreted lectin galactoside‐binding soluble 3 (LGALS3) is found to be significantly upregulated and correlates with shorter bone‐metastasis‐free survival of HCC patients. Overexpression of LGALS3 enhances the metastatic capability of HCC cells to bone and induces skeletal‐related events by forming a bone pre‐metastatic niche via promoting osteoclast fusion and podosome formation. Mechanically, ubiquitin ligaseRNF219‐meidated α‐catenin degradation prompts YAP1/β‐catenin complex‐dependent epigenetic modifications of LGALS3 promoter, resulting in LGALS3 upregulation and metastatic bone diseases. Importantly, treatment with verteporfin, a clinical drug for macular degeneration, decreases LGALS3 expression and effectively inhibits skeletal complications of HCC. These findings unveil a plausible role for HCC‐secreted LGALS3 in pre‐metastatic niche and can suggest a promising strategy for clinical intervention in HCC bone‐metastasis.

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Prostate tumor DNA methylation is associated with cigarette smoking and adverse prostate cancer outcomes

Shui

Wong

Zhao

et al. 2016

Cancer

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Background DNA methylation has been hypothesized as a mechanism to explain the association between smoking and adverse prostate cancer (PCa) outcomes. We aimed to assess whether smoking was associated with prostate tumor DNA methylation and whether these alterations may explain, in part, the association of smoking with PCa recurrence and mortality. Methods A total of 523 men had radical prostatectomy as primary treatment, detailed smoking history data, long-term follow-up for PCa outcomes and tumor tissue profiled for DNA methylation. Ninety percent of men also had matched tumor gene expression data. We conducted a methylome-wide analysis to identify differentially methylated regions (DMRs) by smoking status. To select potential functionally relevant DMRs, we evaluated their correlation with mRNA expression of corresponding genes. Finally, a smoking-related methylation score based on the top-ranked DMRs was created to assess its association with PCa outcomes. Results Forty DMRs were associated with smoking status, and ten of these were strongly correlated with mRNA expression (AOX1, CLDN5, EBF1, HOXA7, LGALS3, MAPT, PCDHGA/PCDHGB, PON3, SYCP2L, and ZSCAN12). Men who were in the highest tertile of the smoking-methylation score derived from these DMRs had a higher risk of recurrence (OR: 2.29; 95% CI: 1.42-3.72) and lethal disease (OR: 4.21; 95% CI: 1.65-11.78) compared to men in the lower two tertiles. Conclusions This integrative molecular epidemiology study supports the hypothesis that smoking-associated tumor DNA methylation changes may explain, at least a portion of the association between smoking and adverse PCa outcomes. Future studies are warranted to confirm these findings and understand the implications for improving patient outcomes.

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Galectin-3 Inhibits Osteoblast Differentiation through Notch Signaling

Cited by 73 publications

References 57 publications

Galectin-3 Cleavage Alters Bone Remodeling: Different Outcomes in Breast and Prostate Cancer Skeletal Metastasis

Galectin-3 Cleavage Alters Bone Remodeling: Different Outcomes in Breast and Prostate Cancer Skeletal Metastasis

RNF219/α‐Catenin/LGALS3 Axis Promotes Hepatocellular Carcinoma Bone Metastasis and Associated Skeletal Complications

Prostate tumor DNA methylation is associated with cigarette smoking and adverse prostate cancer outcomes

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