LGALS3

Gene Summary

Gene:LGALS3; galectin 3
Aliases: L31, GAL3, MAC2, CBP35, GALBP, GALIG, LGALS2
Location:14q22.3
Summary:This gene encodes a member of the galectin family of carbohydrate binding proteins. Members of this protein family have an affinity for beta-galactosides. The encoded protein is characterized by an N-terminal proline-rich tandem repeat domain and a single C-terminal carbohydrate recognition domain. This protein can self-associate through the N-terminal domain allowing it to bind to multivalent saccharide ligands. This protein localizes to the extracellular matrix, the cytoplasm and the nucleus. This protein plays a role in numerous cellular functions including apoptosis, innate immunity, cell adhesion and T-cell regulation. The protein exhibits antimicrobial activity against bacteria and fungi. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Oct 2014]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:galectin-3
Source:NCBIAccessed: 11 March, 2017

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: LGALS3 (cancer-related)

Dondoo TO, Fukumori T, Daizumoto K, et al.
Galectin-3 Is Implicated in Tumor Progression and Resistance to Anti-androgen Drug Through Regulation of Androgen Receptor Signaling in Prostate Cancer.
Anticancer Res. 2017; 37(1):125-134 [PubMed] Related Publications
BACKGROUND: Castration-resistant prostate cancer (CRPC)-related deaths are increasing worldwide. Therefore, clarification of the mechanisms of hormone-related tumor progression and resistance to anti-androgen drugs is useful in order to develop strategies for appropriate treatment of CRPC. Galectin-3 has been shown to be correlated with tumor progression in a variety of cancer types through the regulation of tumor proliferation, angiogenesis, and apoptosis.
MATERIALS AND METHODS: We examined tumor cell invasion and migration using the xCELLigence system. Control LNCaP and galectin-3-expressing LNCaP (LNCaP-Gal-3) cells were cultured with androgen-depleted medium with 5% charcoal-stripped serum. Cells were treated for 24 h with or without dihydrotestosterone alone or combined with MDV3100 and bicalutamide; gene profile was then analyzed by microarray analysis and mRNA expression was confirmed by quantitative real-time polymerase chain reaction (qRT-PCR). We evaluated tumor growth using spheroids and xenograft tumor growth in a mouse model.
RESULTS: In vitro, LNCaP-Gal-3 cells promoted both cell migration and invasion in an androgen-independent manner compared to control LNCaP cells. Galectin-3 also enhanced anchorage-independent growth and xenograft tumor growth even after castration. Importantly, galectin-3 greatly enhanced transcriptional activity of the androgen receptor (AR), especially on treatment with dihydrotestosterone. In microarray and qRT-PCR analyses, galectin-3 increased the expression of several AR-target genes, such as kallikrein-related peptidase 3 (KLK3), and transmembrane protease, serine 2 (TMPRSS2). These AR-target genes were not fully suppressed by anti-androgen drugs such as bicalutamide or MDV3100. Galectin-3 significantly inhibited the effect induced by anti-androgen drugs MDV3100 and bicalutamide, suggesting that galectin-3 may be involved in resistance to anti-androgen drug through enhancement of transcriptional activity of AR and expression of AR-related genes.
CONCLUSION: These results suggest that galectin-3 is a potential target molecule for future treatment of anti-androgen drug-resistant prostate cancer.

Yu Q, Shen W, Zhou H, et al.
Knockdown of LI-cadherin alters expression of matrix metalloproteinase-2 and -9 and galectin-3.
Mol Med Rep. 2016; 13(5):4469-74 [PubMed] Related Publications
Liver-intestine cadherin (LI-cadherin), a novel member of the cadherin family, has been associated with the ability of a tumor to acquire an aggressive phenotype in several types of cancer. However, the exact function of LI-cadherin in the process of tumor invasion and metastasis remains predominantly unknown. To explore the effect of LI-cadherin on the regulation of matrix metalloproteinase-2 (MMP-2), MMP-9 and galectin-3 in LoVo human colorectal cancer cells, a RNA interference technique was applied to suppress the expression of LI‑cadherin. Subsequently, the mRNA levels and activities of MMP-2 and -9 were analyzed by semi-quantitative reverse transcription-polymerase chain reaction and gelatin zymography, respectively. Additionally, the protein expression level of galectin-3 was determined by western blot analysis. The results of the present study demonstrated that short hairpin RNA (shRNA)-silencing of LI-cadherin significantly increased the mRNA levels and activities of MMP‑2 and ‑9, and significantly reduced the protein levels of galectin‑3 in LoVo cells compared with control shRNA (P<0.05). These data indicate that knockdown of LI‑cadherin facilitates the invasion of cancer cells by degrading extracellular matrix components via activation of MMP‑2 and ‑9, and increases cancer cell adhesion and migration via altered expression of galectin‑3. This suggests that LI‑cadherin serves an important role in the invasion and metastasis of colorectal cancer, and may be used as a potential therapeutic target.

Grosset AA, Labrie M, Vladoiu MC, et al.
Galectin signatures contribute to the heterogeneity of breast cancer and provide new prognostic information and therapeutic targets.
Oncotarget. 2016; 7(14):18183-203 [PubMed] Free Access to Full Article Related Publications
Because of their ability to induce local immunosuppression and to confer cancer cells with resistance to apoptosis, members of the galectin family are emerging as a new class of actionable targets in cancer. Unfortunately, we have yet to obtain a clear picture of the galectin signatures in cancer cells and the surrounding tumor microenvironment. The aim of this study was to provide the first detailed analysis of the galectin signature in molecular subtypes of breast cancer. Expression signatures of galectins were obtained at the mRNA and protein levels. A particular attention was paid to stromal versus epithelial staining and to subcellular compartmentalization. Analysis of the stromal signature showed that gal-1, -3, -9-positive stroma were preferentially found in triple-negative (TN) and HER2 subtypes. In cancer cells, gal-1, -3, -8, and -9 showed a dual expression pattern, being found either in the cytosol or in the cytosol and the nucleus. TN patients with gal-8-positive nuclei had significantly better disease-free survival (DFS), distant-disease-free survival (DDFS), and overall survival (OS). In contrast, high expression of nuclear gal-1 correlated with poor DDFS and OS. TNBC patients who were positive for both nuclear gal-1 and gal-8 had 5-year DFS and DDFS of 100%, suggesting a dominance of the gal-8 phenotype. Overall, the results indicate that specific galectin expression signatures contribute to the phenotypic heterogeneity of aggressive subtypes of breast cancer. Our data also suggest that galectins have clinical utility as indicators of disease progression and therapeutic targets in aggressive molecular subtypes of breast cancer.

Korkmaz G, Horozoglu C, Arıkan S, et al.
LGALS3 and AXIN1 gene variants playing role in the Wnt/ β-catenin signaling pathway are associated with mucinous component and tumor size in colorectal cancer.
Bosn J Basic Med Sci. 2016; 16(2):108-13 [PubMed] Free Access to Full Article Related Publications
The Wnt pathway alterations have been identified in colorectal and many other cancer types. It has been reported that galectin-3 (which is encoded by the LGALS3 gene) alters the signaling mechanism in the Wnt/ β-catenin pathway by binding to β-catenin in colon and other cancers. AXIN1 is mainly responsible for the assembly of the β-catenin destruction complex in the Wnt pathway. This study investigated the relationship of rs4644 and rs4652 variants of the LGALS3 gene and rs214250 variants of the AXIN1 gene to histopathological and clinical properties. Our study included a total of 236 patients, of whom 119 had colorectal cancer (42 women, 77 men) and 117 were healthy controls. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) and allele-specific oligonucleotide (ASO) PCR methods were used. In addition, the serum galectin-3 level was studied with the enzyme-linked immunosorbent assay (ELISA) method. For the rs4644 variant of the LGALS3 gene, the CC genotype a mucinous component was significantly more common than those without a mucinous component (p=0.026). C allele frequency of the rs214250 variant of the AXIN1 gene was significantly correlated to tumor size in the advanced tumor stage (p=0.022). The CCAACT haplotype was more common in colorectal cancer patients (p=0.022). Serum galectin-3 level was higher in the patient group compared to the control group (5.9± 0.69 ng/ml vs. 0.79±0.01 ng/ml; p<0.001). In conclusion, variants of LGALS3 and AXIN1 genes affect tumor sizes and the mucinous component via Wnt/ β-catenin pathway in the pathogenesis of colorectal cancer.

Qiao L, Liang N, Xie J, et al.
Gene silencing of galectin-3 changes the biological behavior of Eca109 human esophageal cancer cells.
Mol Med Rep. 2016; 13(1):160-6 [PubMed] Free Access to Full Article Related Publications
Galectin-3 is a multifunctional β-galactoside‑binding lectin that is involved in multiple biological functions which are upregulated in malignancies, including cell growth, adhesion, proliferation, progression and metastasis, as well as apoptosis. A previous study has confirmed the roles of galecin-3 overexpression in the biological behavior of Eca109 human esophageal cancer (EC) cells. In the present study, small interfering (si)RNA-mediated galectin-3 silencing was performed to analyze the effects of decreased galectin-3 expression on the biological behavior of EC cells. Western blot and quantitative polymerase chain reaction analyses were utilized to confirm galectin-3 knockdown at the protein and mRNA level (P<0.05 vs. siRNA-control and untransfected groups). Cell proliferation was assessed using the Cell Counting Kit-8 assay. At 72 and 96 h after transfection, the proliferation of Eca109 cells in the siRNA-Gal-3 group was decreased compared with that in the siRNA-Control and untransfected groups (P<0.001 and P=0.004, respectively). Furthermore, Transwell assays demonstrated that inhibition of galecin-3 significantly reduced the migration and invasion of Eca109 cells compared with that in the other groups (P<0.05). Finally, apoptosis of Eca109 cells was detected using Annexin V/7-amino‑actinomycin double-staining and flow cytometric analysis. Galectin-3 knockdown significantly enhanced the apoptotic rate of Eca109 cells compared with that in the siRNA-control and untreated groups (P=0.031 and P=0.047, respectively). In conclusion, following successful knockdown of galecin-3 expression in Eca109 cells, the cell proliferation, migration and invasion were reduced, while the apoptosis was enhanced, which indicates that galectin silencing may represent a therapeutic strategy for EC.

Agarwal A, Pradhan R, Kumari N, et al.
Molecular Characteristics of Large Parathyroid Adenomas.
World J Surg. 2016; 40(3):607-14 [PubMed] Related Publications
INTRODUCTION: The clinical entity of large parathyroid adenomas (LPTAs) has not been well defined. It is speculated that LPTAs would have biochemical, histological, and molecular characteristics different from small adenomas. Our study aimed to find out occurrence of atypia and carcinomas in large parathyroid lesions and the presence of distinct molecular abnormalities in LPTAs.
MATERIALS AND METHODS: We divided the parathyroid lesions into large (>7 g, i.e., LPTAs) and small (<7 g) adenomas. We performed parafibromin, APC (adenomatous polyposis coli), galectin 3, and PGP9.5 (protein gene product 9.5) analysis by immunohistochemistry in adenomas without atypia, atypical adenomas, and carcinomas.
RESULTS: Mean serum calcium, alkaline phosphatase, and intact PTH were significantly higher in large parathyroid tumor group. The presence of both atypical adenoma and carcinoma was higher in large parathyroid tumor group. There was higher percentage of atypia in patients with LPTAs >10 g (33%), and 68% of tumors showed at least one marker suggestive of malignancy in this group. Detailed analysis of immunohistochemical features of LPTA >10 g revealed that six patients showed complete loss of parafibromin immunoreactivity (out of these four showed atypia), while seven showed partial loss. In histopathologically proven malignancy (n = 9), six patients showed complete loss of parafibromin staining, 5 (55%) APC negativity, and 45% showed both galectin 3 and PGP9.5 positivity. Three out of these showed all IHC markers s/o malignancy, and all of them had evidence of metastases or recurrence. 32% of atypical adenoma and 13% of atypical adenoma showed complete loss of parafibromin staining, however none developed metastases or recurrence in follow-up (median follow-up 40 months). Loss of parafibromin staining (complete or partial) was higher in LPTA group (56%) than that in small adenoma (39%); however, it was not statistically significant. APC, galectin 3, and PGP9.5 markers suggestive were higher in LPTA group but were not significant.
CONCLUSION: LPTAs may show some morphological and immunohistochemical features suggestive of malignancy and can be considered a separate entity. However, the immunohistochemical markers are unable to clearly segregate those LPTAs that may show premalignant potential. Further, we would like to recommend that LPTAs showing complete parafibromin loss together with atypia should be kept under close follow-up.

Botti G, Marra L, Anniciello A, et al.
Immune-phenotypical markers for the differential diagnosis of melanocytic lesions.
Int J Clin Exp Pathol. 2015; 8(9):9742-51 [PubMed] Free Access to Full Article Related Publications
For specific subsets of melanocytic proliferations, there are morphologic limitations in the histological diagnosis, especially for borderline melanocytic tumors. In particular, Spitzoid proliferations can be difficult to diagnose. For these reasons, in the last years, clinic research has focused attention on discovery of new diagnostic markers. Published gene expression and proteomic profiling data indicate new candidate molecules involved in melanoma pathogenesis, and useful in differential diagnosis of difficult melanocytic lesions. Recently, the diagnostic power of galectin-3 was demonstrated in series of melanocytic lesions, with a strong increasing of expression in malignant lesions compared with benign lesions. Similarly, the accumulation of Collagen XVII antibody was detected in vertical melanoma fronts and associated with invasive phenotype. Moreover, overexpression of cyclin D1 and p21 was detected in Spitz nevi compared with non-spitzoid melanomas; Ki-67 appears highly expressed in deep areas of non-spitzoid melanomas. In this review, we overview of the main molecular markers that a useful tool for the differential diagnosis of benign, borderline and malignant melanocytic lesions, related to their biological behavior, useful also for predicting the evolution of the disease.

Coppin L, Benomar K, Corfiotti F, et al.
CA-125, but not galectin-3, complements CA 19-9 for discriminating ductal adenocarcinoma versus non-malignant pancreatic diseases.
Pancreatology. 2016 Jan-Feb; 16(1):115-20 [PubMed] Related Publications
BACKGROUND/OBJECTIVES: CA 19-9 is the gold standard biomarker of pancreatic adenocarcinoma despite several weaknesses in particular a high rate of false positives or negatives. CA-125 corresponding to MUC16 and galectin-3, a lectin able to interact with mucin-associated carbohydrates, are tumor-associated proteins. We investigated whether combined measurement of CA 19-9, galectin-3 and CA-125 may help to better discriminate pancreatic adenocarcinoma versus non-malignant pancreatic diseases.
METHODS: We evaluated by immunohistochemistry the expression of MUC4, MUC16 (CA-125) and galectin-3 in 31 pancreatic adenocarcinomas. We measured CA 19-9, CA-125 and Gal-3 in the serum from patients with pancreatic benign diseases (n = 58) or adenocarcinoma (n = 44). Clinical performance of the 3 biomarkers for cancer diagnosis and prognosis was analyzed.
RESULTS: By immunohistochemistry, MUC16 and Gal-3 were expressed in 74% and 84% of adenocarcinomas versus 0% and 3.2% in peri-tumoral regions, respectively. At the serum level, CA 19-9 and CA125 were significantly higher in patients with pancreatic adenocarcinoma whereas Gal-3 levels did not differ. The performance of CA 19-9 for cancer detection was higher than those of CA-125 or Gal-3 by ROC analysis. However, CA-125 offers the highest specificity for malignancy (81%) because of an absence of false positives among type 2 diabetic patients. Cancer deaths assessed 6 or 12 months after diagnosis varied according to the initial CA-125 level (p < 0.006).
CONCLUSION: Gal-3 is not an interesting biomarker for pancreatic adenocarcinoma detection. CA 19-9 alone exhibits the best performance but measuring CA-125 provides complementary information in terms of diagnosis and prognosis.

Kuo HY, Hsu HT, Chen YC, et al.
Galectin-3 modulates the EGFR signalling-mediated regulation of Sox2 expression via c-Myc in lung cancer.
Glycobiology. 2016; 26(2):155-65 [PubMed] Related Publications
Galectin-3 is a ubiquitous lectin exerting multiple cellular functions such as RNA splicing, protein trafficking and apoptosis. Its expression is positively correlated with the poor prognosis in lung cancer patients. Galectin-3 can promote cancer progression through its effects on cell proliferation, cell survival or cancer metastasis. However, the role of galectin-3 in the regulation of cancer stem-like cells (CSCs) is still unclear. Here, we investigated the hypothesis that galectin-3 might regulate lung CSCs via the EGF receptor (EGFR) signaling pathway. In our study, galectin-3 facilitated EGFR activation and enhanced the sphere formation activity of lung cancer cells. Furthermore, galectin-3 promoted Sox2 expression in an EGFR activation-dependent manner; importantly, forced expression of Sox2 blunted the effect of galectin-3 knockdown on lung cancer sphere formation ability. These results suggest that galectin-3 promotes EGFR activation leading to the upregulation of Sox2 expression and lung CSCs properties. Moreover, we showed that the carbohydrate-binding activity of galectin-3 was important for the regulation of EGFR activation, Sox2 expression and sphere formation. We have recently reported that c-Myc is a transcriptional activator of Sox2. We further found that galectin-3 enhanced c-Myc protein stability leading to increased c-Myc binding to the Sox2 gene promoter. We also examined the effect of the stemness factors, Oct4, Nanog and Sox2 on the expression of galectin-3. We found that Oct4 enhanced galectin-3 expression. Our results together suggest that galectin-3 enhances lung cancer stemness through the EGFR/c-Myc/Sox2 axis; Oct4, in turn, promotes galectin-3 expression, forming a positive regulatory loop in lung CSCs.

Shetty P, Bargale A, Patil BR, et al.
Cell surface interaction of annexin A2 and galectin-3 modulates epidermal growth factor receptor signaling in Her-2 negative breast cancer cells.
Mol Cell Biochem. 2016; 411(1-2):221-33 [PubMed] Related Publications
Overexpression and activation of tyrosine kinase receptors like EGFR and Src regulate the progression and metastasis of Her-2 negative breast cancer. Recently we have reported the role of cell membrane interaction of phospholipid-binding protein annexin A2 (AnxA2) and EGFR in regulating cellular signaling in the activation of angiogenesis, matrix degradation, invasion, and cancer metastasis. Beta-galactoside-specific animal lectin galectin-3 is an apoptosis inhibitor, and cell surface-associated extracellular galectin-3 also has a role in cell migration, cancer progression, and metastasis. Similar expression pattern and membrane co-localization of these two proteins made us to hypothesize in the current study that galectin-3 and AnxA2 interaction is critical for Her-2 negative breast cancer progression. By various experimental analyses, we confirm that glycosylated AnxA2 at the membrane surface interacts with galectin-3. N-linked glycosylation inhibitor tunicamycin treatment convincingly blocked AnxA2 membrane translocation and its association with galectin-3. To analyze whether this interaction has any functional relevance, we tried to dissociate this interaction with purified plant lectin from chickpea (Cicer arietinum agglutinin). This highly specific 30 kDa plant lectin could dissociate AnxA2 from endogenous lectin galectin-3 interaction at the cell surface. This dissociation could down-regulate Bcl-2 family proteins, cell proliferation, and migration simultaneously triggering cell apoptosis. Targeting this interaction of membrane surface glycoprotein and its animal lectin in Her-2 negative breast cancer may be of therapeutic value.

Zeinali M, Adelinik A, Papian S, et al.
Role of galectin-3 in the pathogenesis of bladder transitional cell carcinoma.
Hum Immunol. 2015; 76(10):770-4 [PubMed] Related Publications
Galectins constitute an evolutionary conserved family that binds to β-galactosides. There is growing evidence that galectins are implicated in essential biological processes such as cellular communication, inflammation, differentiation and apoptosis. Galectin-3 is one of the best-known galectins, which is found in vertebrates. Galectin-3 has been shown to be expressed in some cell lines and plays important roles in several physiological and pathological processes, including cell adhesion, cell activation and chemoattraction, cell cycle, apoptosis, cell growth, and differentiation. Moreover, this galectin is of interest due to its involvement in regulation of cancer. Changes in galectin-3 expression are commonly seen in cancerous and pre-cancerous conditions and galectin-3 may be involved in the regulation of cancer cell activities that contribute to tumourigenesis, cancer progression and metastasis. Finally, galectin-3 seems to be involved in cell events in tumor microenvironment, and therefore it could be considered as a target in transitional cell carcinoma therapies. This review aims to describe recent progress in understanding the role of galectin-3 in cancer biology, with emphasis on bladder tumor progression and metastasis.

Manzoni M, Roversi G, Di Bella C, et al.
Solid cell nests of the thyroid gland: morphological, immunohistochemical and genetic features.
Histopathology. 2016; 68(6):866-74 [PubMed] Related Publications
AIMS: The correct identification of solid cell nests (SCNs) is an important issue in thyroid pathology because of the spectrum of differential diagnoses of this type of lesion.
METHODS AND RESULTS: Ten cases of 295 consecutive thyroidectomies showed the presence of SCNs at histological examination. The identification of the exact SCN type required the distinction of the cystic and solid pattern; SCNs were usually composed of a mixture of main cells (MCs) and C-cells (CCs). The immunohistochemical calcitonin stain identified CCs easily, both inside SCNs and dispersed in islets at the periphery. For the characterization of MCs, we added the utility of p40 to p63. The use of thyroid transcription factor-1 (TTF-1) helped in their identification, as MCs did not react with this marker; the combination of TTF-1 and p40 or p63 IHC stains was useful for the characterization of cystic SCNs of both types 3 and 4. The negativity of mouse monoclonal mesothelioma antibody (HMBE-1) and a very low proliferative index (MIB-1) supported the diagnosis. [Correction added on 23 November 2015, after online publication: MIB-1 was incorrectly defined, the expanded form was deleted.] We discourage the use of galectin-3 (Gal-3) and cytokeratin-19 (CK-19), as they have an important overlap with papillary thyroid carcinoma. The complete absence of any B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutations is an additional fundamental finding.
CONCLUSIONS: We reviewed the most relevant morphological and immunohistochemical features of SCNs and have provided a genetic analysis of the BRAF gene because of its expanding use in thyroid pathology.

Zuo X, Chen L, Liu L, et al.
Identification of a panel of complex autoantigens (LGALS3, PHB2, MUC1, and GK2) in combination with CA15-3 for the diagnosis of early-stage breast cancer.
Tumour Biol. 2016; 37(1):1309-17 [PubMed] Related Publications
Currently, there is no effective single antigen and there are only a very limited number of complex antigens for the diagnosis of early-stage breast cancer (BC). In this study, we used serological analysis of recombinant cDNA expression libraries (SEREX) in combination with phage display technology to screen complex autoantigens from the sera of BC patients. The cDNA expression library was constructed using tissue samples of three patients with BC at as early as stage T1N0M0. The serum samples of ten patients, including the three patients who provided tissue samples, as well as five healthy human subjects as controls were used to screen the library. All seven autoantigens were identified from the library by four rounds of screening and matched the existing genes after a blast search using NCBI-BLAST. Then, the expression conditions of the autoantibodies of the seven autoantigens and anti-CA15-3 in the sera from 100 BC patients and 50 healthy donors were examined by gray values. The data were analyzed by the area under the receiver operating characteristic (ROC) curve and logistic regression diagnostic models. In the end, a panel of complex autoantigens consisting of B11 (LGALS3), B18 (PHB2), B119 (MUC1), B130 (GK2), and CA15-3, which had a sensitivity of 87 % and a specificity of 76 %, were identified. The area under the curve (AUC) of the complex antigens was 0.872, which is significantly greater than that of anti-CA15-3 alone (AUC = 0.634) for the diagnosis of BC. Thus, this panel of complex antigens provides a promising strategy for the diagnosis of early-stage BC.

Ruvolo PP
Galectin 3 as a guardian of the tumor microenvironment.
Biochim Biophys Acta. 2016; 1863(3):427-37 [PubMed] Related Publications
Galectin 3 is a member of a family of β-galactoside binding proteins and has emerged as an important regulator of diverse functions critical in cancer biology including apoptosis, metastasis, immune surveillance, molecular trafficking, mRNA splicing, gene expression, and inflammation. Galectin 3's ability to support cancer cell survival by intra-cellular and extra-cellular mechanisms suggests this molecule is an important component of the tumor microenvironment that potentially could be targeted for therapy. Data is emerging that Galectin 3 is elevated in many cancers including solid tumors and the cancers of the blood. Galectin 3 also appears to be a key molecule produced by tumor microenvironment support cells including mesenchymal stromal cells (MSC) to suppress immune surveillance by killing T cells and interfering with NK cell function and by supporting metastasis. Levels of Galectin 3 increase in the MSC of aging mice and perhaps this contributes to the development of cancer in the elderly. Galectin 3 modulates surface protein expression of a diverse set of glycoproteins including CD44 by regulating endocytosis of these proteins. In addition, Galectin 3 binding to receptor kinases such as CD45 and the T cell receptor is critical in the regulation of their function. In this review I will examine the various mechanisms how Galectin 3 supports chemoresistance and metastasis in solid tumors and in leukemia and lymphoma. I will also discuss possible therapeutic strategies to target this Galectin for cancer therapy. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza.

Lei P, He H, Hu Y, Liao Z
Small interfering RNA-induced silencing of galectin-3 inhibits the malignant phenotypes of osteosarcoma in vitro.
Mol Med Rep. 2015; 12(4):6316-22 [PubMed] Related Publications
Osteosarcoma (OS) is the most common malignant tumor of bone. It has recently been demonstrated that galectin-3, a multifunctional β-galactoside-binding, is significantly upregulated in OS tissues, and is correlated with its progression and metastasis. However, the detailed role of galectin‑3 in the regulation of cellular biological processes in OS cells has remained to be elucidated. The present study reported that the mRNA and protein levels of galectin‑3 were significantly increased in OS tissues compared to those in their matched normal adjacent tissues. Furthermore, galectin‑3 was upregulated in three OS cell lines, Saos‑2, MG63 and U2OS, when compared with that in the human osteoblast cell line hFOB1.19. Knockdown of galectin‑3 by galectin‑3‑specific small interfering RNA markedly inhibited OS‑cell proliferation and induced cell apoptosis. Furthermore, silencing of galectin‑3 expression significantly inhibited OS cell migration and invasion, accompanied with a marked decrease in the protein expression of matrix metalloproteinase 2 and ‑9. Mechanistic investigation suggested that the mitogen‑activated protein kinase kinase/extracellular signal‑regulated protein kinase signaling pathway may be involved in the galectin‑3‑mediated OS cell invasion. In conclusion, the present study was the first to report that silencing of galectin‑3 inhibited the malignant phenotypes of osteosarcoma in vitro. Therefore, galectin-3 may serve as a potential therapeutic target for OS.

Harazono Y, Kho DH, Balan V, et al.
Extracellular galectin-3 programs multidrug resistance through Na+/K+-ATPase and P-glycoprotein signaling.
Oncotarget. 2015; 6(23):19592-604 [PubMed] Free Access to Full Article Related Publications
Galectin-3 (Gal-3, LGALS3) is a pleotropic versatile, 29-35 kDa chimeric gene product, and involved in diverse physiological and pathological processes, including cell growth, homeostasis, apoptosis, pre-mRNA splicing, cell-cell and cell-matrix adhesion, cellular polarity, motility, adhesion, activation, differentiation, transformation, signaling, regulation of innate/adaptive immunity, and angiogenesis. In multiple diseases, it was found that the level of circulating Gal-3 is markedly elevated, suggesting that Gal-3-dependent function is mediated by specific interaction with yet an unknown ubiquitous cell-surface protein. Recently, we showed that Gal-3 attenuated drug-induced apoptosis, which is one of the mechanisms underlying multidrug resistance (MDR). Here, we document that MDR could be mediated by Gal-3 interaction with the house-keeping gene product e.g., Na+/K+-ATPase, and P-glycoprotein (P-gp). Gal-3 interacts with Na+/K+-ATPase and induces the phosphorylation of P-gp. We also find that Gal-3 binds P-gp and enhances its ATPase activity. Furthermore Gal-3 antagonist suppresses this interaction and results in a decrease of the phosphorylation and the ATPase activity of P-gp, leading to an increased sensitivity to doxorubicin-mediated cell death. Taken together, these findings may explain the reported roles of Gal-3 in diverse diseases and suggest that a combined therapy of inhibitors of Na+/K+-ATPase and Gal-3, and a disease specific drug(s) might be superior to a single therapeutic modality.

Montesinos-Rongen M, Purschke FG, Brunn A, et al.
Primary Central Nervous System (CNS) Lymphoma B Cell Receptors Recognize CNS Proteins.
J Immunol. 2015; 195(3):1312-9 [PubMed] Related Publications
Primary lymphoma of the CNS (PCNSL) is a diffuse large B cell lymphoma confined to the CNS. To elucidate its peculiar organ tropism, we generated recombinant Abs (recAbs) identical to the BCR of 23 PCNSLs from immunocompetent patients. Although none of the recAbs showed self-reactivity upon testing with common autoantigens, they recognized 1547 proteins present on a large-scale protein microarray, indicating polyreactivity. Interestingly, proteins (GRINL1A, centaurin-α, BAIAP2) recognized by the recAbs are physiologically expressed by CNS neurons. Furthermore, 87% (20/23) of the recAbs, including all Abs derived from IGHV4-34 using PCNSL, recognized galectin-3, which was upregulated on microglia/macrophages, astrocytes, and cerebral endothelial cells upon CNS invasion by PCNSL. Thus, PCNSL Ig may recognize CNS proteins as self-Ags. Their interaction may contribute to BCR signaling with sustained NF-κB activation and, ultimately, may foster tumor cell proliferation and survival. These data may also explain, at least in part, the affinity of PCNSL cells for the CNS.

Meng F, Joshi B, Nabi IR
Galectin-3 Overrides PTRF/Cavin-1 Reduction of PC3 Prostate Cancer Cell Migration.
PLoS One. 2015; 10(5):e0126056 [PubMed] Free Access to Full Article Related Publications
Expression of Caveolin-1 (Cav1), a key component of cell surface caveolae, is elevated in prostate cancer (PCa) and associated with PCa metastasis and a poor prognosis for PCa patients. Polymerase I and Transcript Release Factor (PTRF)/cavin-1 is a cytoplasmic protein required for Cav1-dependent formation of caveolae. Expression of PTRF reduces the motility of PC3 cells, a metastatic prostate cancer cell line that endogenously expresses abundant Cav1 but no PTRF and no caveolae, suggesting a role for non-caveolar Cav1 domains, or Cav1 scaffolds, in PCa cell migration. Tyrosine phosphorylated Cav1 (pCav1) functions in concert with Galectin-3 (Gal3) and the galectin lattice to stabilize focal adhesion kinase (FAK) within focal adhesions (FAs) and promote cancer cell motility. However, whether PTRF regulation of Cav1 function in PCa cell migration is related to Gal3 expression and functionality has yet to be determined. Here we show that PTRF expression in PC3 cells reduces FAK stabilization in focal adhesions and reduces cell motility without affecting pCav1 levels. Exogenous Gal3 stabilized FAK in focal adhesions of PTRF-expressing cells and restored cell motility of PTRF-expressing PC3 cells to levels of PC3 cells in a dose-dependent manner, with an optimal concentration of 2 µg/ml. Exogenous Gal3 stabilized FAK in focal adhesions of Gal3 knockdown PC3 cells but not in Cav1 knockdown PC3 cells. Cav1 knockdown also prevented Gal3 rescue of FA-associated FAK stabilization in PTRF-expressing PC3 cells. Our data support a role for PTRF/cavin-1, through caveolae formation, as an attenuator of the non-caveolar functionality of Cav1 in Gal3-Cav1 signalling and regulation of focal adhesion dynamics and cancer cell migration.

Lamba Saini M, Weynand B, Rahier J, et al.
Cyclin D1 in well differentiated thyroid tumour of uncertain malignant potential.
Diagn Pathol. 2015; 10:32 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Encapsulated follicular tumours with equivocal papillary thyroid carcinoma (PTC) type nuclear features continue to remain a challenge despite the recent attempts to classify these borderline lesions. The term 'well differentiated tumour of uncertain malignant potential (WDT-UMP)' was introduced to classify these tumours. The present study aimed to evaluate the role of a cell cycle regulator like cyclin D1 in these tumours along with assessment of other well established PTC markers like galectin-3, HBME-1, CK19.
METHODS: Thirteen cases of metastatic PTC, papillary microcarcinoma and follicular variant of PTC (FVPTC) were identified from a histological review of 510 cases. In addition, 13 cases of a subset of follicular adenomatoid nodules with focal areas showing nuclear features characteristic of PTC, identified as WDT-UMP, were also analyzed. Immunohistochemical analysis of galectin-3, HBME-1, CK19 and the proliferation markers Ki67 and cyclin D1 was performed. Lesions were analyzed for cyclin D1 gene amplification by fluorescent in-situ hybridization.
RESULTS: All WDT-UMP lesions showed immunolabelling of cyclin D1, Ki67; 11/ 13 cases showed immunolabelling of CK19; 10/13 cases showed immunolabelling of HBME-1 and 4/13 cases showed immunolabelling of galectin-3. Surrounding benign adenomatoid areas showed no to faint focal staining in all thirteen cases of cyclin D1, HBME-1 and galectin-3. A low rate of cyclin D1 gene amplification was identified in a significant proportion of cells in the WDT-UMP lesions as compared to surrounding benign adenomatoid areas.
CONCLUSIONS: Increased expression of cyclin D1 and amplification of its gene along with immunolabelling of HBME-1 in WDT-UMP lesions showing cytological features of papillary thyroid carcinoma within follicular adenomatoid nodules suggest that these areas could correspond to a precursor lesion of follicular variant of PTC. Overexpression of cyclin D1, associated with the amplification of the gene suggests that these WDT-UMP lesions are an intermediate between the benign and malignant groups making this group of lesions a reliable precursor of FVPTC.
VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1851820807142117.

Fei F, Joo EJ, Tarighat SS, et al.
B-cell precursor acute lymphoblastic leukemia and stromal cells communicate through Galectin-3.
Oncotarget. 2015; 6(13):11378-94 [PubMed] Free Access to Full Article Related Publications
The molecular interactions between B-cell precursor acute lymphoblastic leukemia (pre-B ALL) cells and stromal cells in the bone marrow that provide microenvironmentally-mediated protection against therapeutic drugs are not well-defined. Galectin-3 (Lgals3) is a multifunctional galactose-binding lectin with reported location in the nucleus, cytoplasm and extracellular space in different cell types. We previously reported that ALL cells co-cultured with stroma contain high levels of Galectin-3. We here establish that, in contrast to more mature B-lineage cancers, Galectin-3 detected in and on the ALL cells originates from stromal cells, which express it on their surface, secrete it as soluble protein and also in exosomes. Soluble and stromal-bound Galectin-3 is internalized by ALL cells, transported to the nucleus and stimulates transcription of endogenous LGALS3 mRNA. When human and mouse ALL cells develop tolerance to different drugs while in contact with protective stromal cells, Galectin-3 protein levels are consistently increased. This correlates with induction of Galectin-3 transcription in the ALL cells. Thus Galectin-3 sourced from stroma becomes supplemented by endogenous Galectin-3 production in the pre-B ALL cells that are under continuous stress from drug treatment. Our data suggest that stromal Galectin-3 may protect ALL cells through auto-induction of Galectin-3 mRNA and tonic NFκB pathway activation. Since endogenously synthesized Galectin-3 protects pre-B ALL cells against drug treatment, we identify Galectin-3 as one possible target to counteract the protective effects of stroma.

Thijssen VL, Heusschen R, Caers J, Griffioen AW
Galectin expression in cancer diagnosis and prognosis: A systematic review.
Biochim Biophys Acta. 2015; 1855(2):235-47 [PubMed] Related Publications
Galectins are a family of proteins that bind to specific glycans thereby deciphering the information captured within the glycome. In the last two decades, several galectin family members have emerged as versatile modulators of tumor progression. This has initiated the development and preclinical assessment of galectin-targeting compounds. With the first compounds now entering clinical trials it is pivotal to gain insight in the diagnostic and prognostic value of galectins in cancer as this will allow a more rational selection of the patients that might benefit most from galectin-targeted therapies. Here, we present a systematic review of galectin expression in human cancer patients. Malignant transformation is frequently associated with altered galectin expression, most notably of galectin-1 and galectin-3. In most cancers, increased galectin-1 expression is associated with poor prognosis while elevated galectin-9 expression is emerging as a marker of favorable disease outcome. The prognostic value of galectin-3 appears to be tumor type dependent and the other galectins require further investigation. Regarding the latter, additional studies using larger patient cohorts are essential to fully unravel the diagnostic and prognostic value of galectin expression. Furthermore, to better compare different findings, consensus should be reached on how to assess galectin expression, not only with regard to localization within the tissue and within cellular compartments but also regarding alternative splicing and genomic variations. Finally, linking galectin expression and function to aberrant glycosylation in cancer cells will improve our understanding of how these versatile proteins can be exploited for diagnostic, prognostic and even therapeutic purposes in cancer patients.

Dange MC, Agarwal AK, Kalraiya RD
Extracellular galectin-3 induces MMP9 expression by activating p38 MAPK pathway via lysosome-associated membrane protein-1 (LAMP1).
Mol Cell Biochem. 2015; 404(1-2):79-86 [PubMed] Related Publications
Matrix metalloproteinases (MMPs) play a key role in matrix remodelling and thus invasion and metastasis. Extracellular galectin-3 has been shown to induce MMP9 secretion. Here, we demonstrate that galectin-3 induces MMP9 at transcript level and it is dependent on the surface levels of poly-N-acetyllactosamine (polyLacNAc). By employing signalling pathway inhibitors, MMP9 expression was shown to be induced via p38 MAP-kinase pathway. Using clones of melanoma cells expressing shRNAs to lysosome-associated membrane protein-1 (LAMP1), a major carrier of polyLacNAc, surface LAMP1 was demonstrated to serve as one of the key mediators of galectin-3-induced MMP9 expression via p38 MAPK pathway.

Kouo T, Huang L, Pucsek AB, et al.
Galectin-3 Shapes Antitumor Immune Responses by Suppressing CD8+ T Cells via LAG-3 and Inhibiting Expansion of Plasmacytoid Dendritic Cells.
Cancer Immunol Res. 2015; 3(4):412-23 [PubMed] Free Access to Full Article Related Publications
Galectin-3 is a 31-kDa lectin that modulates T-cell responses through several mechanisms, including apoptosis, T-cell receptor (TCR) cross-linking, and TCR downregulation. We found that patients with pancreatic ductal adenocarcinoma (PDA) who responded to a granulocyte-macrophage colony-stimulating factor-secreting allogeneic PDA vaccine developed neutralizing antibodies to galectin-3 after immunization. We show that galectin-3 binds activated antigen-committed CD8(+) T cells only in the tumor microenvironment. Galectin-3-deficient mice exhibit improved CD8(+) T-cell effector function and increased expression of several inflammatory genes. Galectin-3 binds to LAG-3, and LAG-3 expression is necessary for galectin-3-mediated suppression of CD8(+) T cells in vitro. Lastly, galectin-3-deficient mice have elevated levels of circulating plasmacytoid dendritic cells, which are superior to conventional dendritic cells in activating CD8(+) T cells. Thus, inhibiting galectin-3 in conjunction with CD8(+) T-cell-directed immunotherapies should enhance the tumor-specific immune response.

Chung LY, Tang SJ, Wu YC, et al.
Galectin-3 augments tumor initiating property and tumorigenicity of lung cancer through interaction with β-catenin.
Oncotarget. 2015; 6(7):4936-52 [PubMed] Free Access to Full Article Related Publications
Cancer stem cells (CSCs) are comprised of a rare sub-population of cells in tumors that have been proposed to be responsible for high recurrence rates and resistance to chemotherapy. Galectins are highly expressed in cancers that correlate with the aggressiveness of tumors. Galectins may also promote the resistance of cancer cells to chemotherapy. However, the role of galectins in CSCs remains unknown. In this study, sphere formation was used to enrich H1299 human lung CSCs that had self-renewal ability, advanced tumorigenic potential, and that highly expressed stem/progenitor cell markers such as Oct4, Sox2, Nanog, and CD133. A novel candidate molecule, galectin-3, for stemness was found in lung CSCs. The expression of galectin-3 robustly increased in lung cancer spheres over serial passages, but its suppression in the H1299 monolayer or spheres resulted in reduced expression of stemness-related genes, sphere-forming ability, tumorigenicity, chemoresistance, and tumor initiation in mice. Notably, the overexpression of galectin-3 in A549 lung cancer cells, which have low capability to grow as tumor spheres, promoted CSC formation. β-catenin activity was increased in H1299 spheres and counteracted by galectin-3 suppression. Thus, galectin-3 may act as a cofactor by interacting with β-catenin to augment the transcriptional activities of stemness-related genes. Furthermore, galectin-3 expression correlated with tumor progression and expressions of β-catenin and CSC marker CD133 in lung cancer tissues. Targeting galectin-3 signaling may provide a new strategy for lung cancer treatment by inhibiting stem-like properties.

Aggarwal S, Sharma SC, Das SN
Galectin-1 and galectin-3: plausible tumour markers for oral squamous cell carcinoma and suitable targets for screening high-risk population.
Clin Chim Acta. 2015; 442:13-21 [PubMed] Related Publications
BACKGROUND: Galectins are a family of carbohydrate binding proteins that regulate several cellular functions such as growth, migration, adhesion and apoptosis.
METHODS: We investigated the expression of galectin (gal)-1 and galectin (gal)-3 in patients with oral squamous cell carcinoma (OSCC) and observed their effects on growth and survival of OSCC cell lines.
RESULTS: OSCC patients expressed significantly higher levels of gal-1 and gal-3 in circulation (p<0.0001) and at the tumour sites (p<0.01) as compared to controls. Patients with higher tumour load showed significantly higher expression of both galectins than those with lower tumour load. In ROC analysis, serum levels of gal-1 and gal-3 at cut-off values of 4.875 and 0.871ng/ml respectively, discriminated between healthy subjects and patients with more than 80% sensitivity and specificity. Similarly, logistic regression analysis revealed about 3-times higher risk of OSCC in subjects over expressing these proteins. Further, exogenous gal-1 and gal-3 significantly increased survival, proliferation and angiogenesis in OSCC cell lines.
CONCLUSIONS: Serum levels of gal-1 and gal-3 may serve as plausible markers for oral squamous cell carcinoma and may be useful in screening population at a higher risk.

Pillai S, Gopalan V, Smith RA, Lam AK
Diffuse sclerosing variant of papillary thyroid carcinoma--an update of its clinicopathological features and molecular biology.
Crit Rev Oncol Hematol. 2015; 94(1):64-73 [PubMed] Related Publications
Diffuse sclerosing variant of papillary thyroid carcinoma (DSVPTC) is an uncommon variant of papillary thyroid carcinoma. The aim of this review is to critically analyse the features of this entity. A search of the literature revealed 25 clinicopathological studies with in-depth analysis of features of DSVPTC. Overall, the prevalence of DSVPTC varies from 0.7-6.6% of all papillary thyroid carcinoma. Higher prevalence of DSVPTC was noted in paediatric patients and in patients affected by irradiation. DSVPTC tends to occur more frequently in women and in patients in the third decade of life. Macroscopically, DSVPTC can involve the thyroid gland extensively without forming a dominant mass. Microscopic examination of DSVPTC revealed extensive fibrosis, squamous metaplasia and numerous psammoma bodies. The latter pathological feature can aid in the pre-operative diagnosis of the entity by fine needle aspiration and ultrasound. Compared to conventional papillary thyroid carcinoma, DSVPTC had a higher incidence of lymph node metastases at presentation. Distant metastases were noted in approximately 5% of the cases. Patients with DSVPTC were recommended to be managed by aggressive treatment protocols. It is likely that as a result of this, the prognosis of the patients with DSVPTC was noted to be similar to conventional papillary thyroid carcinoma. Overall, cancer recurrence and cancer related mortality have been reported in 14% and 3%, respectively, of patients with DSVPTC. In immunohistochemical studies, DSVPTC showed different expression patterns of epithelial membrane antigen, galectin 3, cell adhesion molecules, p53 and p63 when compared to conventional papillary thyroid carcinoma. On genetic analysis, the occurrence of BRAF and RAS mutations are uncommon events in DSVPTC and activation of RET/PTC rearrangements are common. To conclude, DSVPTC has different clinical, pathological and molecular profiles when compared to conventional papillary thyroid carcinoma.

Selemetjev SA, Savin SB, Paunovic IR, et al.
Changes in the expression pattern of apoptotic molecules (galectin-3, Bcl-2, Bax, survivin) during progression of thyroid malignancy and their clinical significance.
Wien Klin Wochenschr. 2015; 127(9-10):337-44 [PubMed] Related Publications
BACKGROUND: Papillary carcinoma of the thyroid (PTC) is generally a slow growing tumor with favorable prognosis, while anaplastic thyroid carcinoma (ATC) is highly aggressive malignancy. Genetic defects in apoptotic pathways may contribute to differences in their biological behavior.
METHODS: In this study, we analyzed immunohistochemically the expression of apoptosis-related molecules: galectin-3, Bcl-2, survivin (antiapoptotic), and Bax (pro-apoptotic), in archival tissue sections of PTC (n = 69) and ATC (n = 30) and correlated the results with clinicopathological parameters of these tumors.
RESULTS: Galectin-3 and Bcl-2 showed a similar trend of down-regulation from high levels of both in PTC to low levels in ATC (p < 0.05). Bax was expressed at high levels in both type of thyroid carcinoma. Expression of survivin increased from PTC to ATC (p < 0.05), which may, at least in part, further facilitate the ability of malignant thyroid cell of ATC to escape programmed cell death despite high Bax expression. Only survivin, but not galectin-3, Bcl-2, or Bax, correlated significantly with lymph node metastasis presence and advanced stages of malignancy.
CONCLUSIONS: In conclusion, this study documented down-regulation of galectin-3 and Bcl-2 (antiapoptotic molecules) and stepwise increase of survivin (inhibitor of apoptosis), during thyroid tumor progression from PTC to ATC. Correlation of high survivin expression with aggressive behavior implies its role in progression of thyroid tumor malignancy and suggests that survivin could be a useful tool in the prediction of aggressiveness of a subset of papillary carcinomas and a possible target for molecular therapy for ATC patients.

Krause S, Pfeiffer C, Strube S, et al.
Mer tyrosine kinase promotes the survival of t(1;19)-positive acute lymphoblastic leukemia (ALL) in the central nervous system (CNS).
Blood. 2015; 125(5):820-30 [PubMed] Related Publications
Patients with t(1;19)-positive acute lymphoblastic leukemia (ALL) are prone to central nervous system (CNS) relapses, and expression of the TAM (Tyro3, Axl, and Mer) receptor Mer is upregulated in these leukemias. We examined the functional role of Mer in the CNS in preclinical models and performed correlative studies in 64 t(1;19)-positive and 93 control pediatric ALL patients. ALL cells were analyzed in coculture with human glioma cells and normal rat astrocytes: CNS coculture caused quiescence and protection from methotrexate toxicity in Mer(high) ALL cell lines, which was antagonized by short hairpin RNA-mediated knockdown of Mer. Mer expression was upregulated, prosurvival Akt and mitogen-activated protein kinase signaling were activated, and secretion of the Mer ligand Galectin-3 was stimulated. Mer(high) t(1;19) primary cells caused CNS involvement to a larger extent in murine xenografts than in their Mer(low) counterparts. Leukemic cells from Mer(high) xenografts showed enhanced survival in coculture. Treatment of Mer(high) patient cells with the Mer-specific inhibitor UNC-569 in vivo delayed leukemia onset, reduced CNS infiltration, and prolonged survival of mice. Finally, a correlation between high Mer expression and CNS positivity upon initial diagnosis was observed in t(1;19) patients. Our data provide evidence that Mer is associated with survival in the CNS in t(1;19)-positive ALL, suggesting a role as a diagnostic marker and therapeutic target.

Ikemori RY, Machado CM, Furuzawa KM, et al.
Galectin-3 up-regulation in hypoxic and nutrient deprived microenvironments promotes cell survival.
PLoS One. 2014; 9(11):e111592 [PubMed] Free Access to Full Article Related Publications
Galectin-3 (gal-3) is a β-galactoside binding protein related to many tumoral aspects, e.g. angiogenesis, cell growth and motility and resistance to cell death. Evidence has shown its upregulation upon hypoxia, a common feature in solid tumors such as glioblastoma multiformes (GBM). This tumor presents a unique feature described as pseudopalisading cells, which accumulate large amounts of gal-3. Tumor cells far from hypoxic/nutrient deprived areas express little, if any gal-3. Here, we have shown that the hybrid glioma cell line, NG97ht, recapitulates GBM growth forming gal-3 positive pseudopalisades even when cells are grafted subcutaneously in nude mice. In vitro experiments were performed exposing these cells to conditions mimicking tumor areas that display oxygen and nutrient deprivation. Results indicated that gal-3 transcription under hypoxic conditions requires previous protein synthesis and is triggered in a HIF-1α and NF-κB dependent manner. In addition, a significant proportion of cells die only when exposed simultaneously to hypoxia and nutrient deprivation and demonstrate ROS induction. Inhibition of gal-3 expression using siRNA led to protein knockdown followed by a 1.7-2.2 fold increase in cell death. Similar results were also found in a human GBM cell line, T98G. In vivo, U87MG gal-3 knockdown cells inoculated subcutaneously in nude mice demonstrated decreased tumor growth and increased time for tumor engraftment. These results indicate that gal-3 protected cells from cell death under hypoxia and nutrient deprivation in vitro and that gal-3 is a key factor in tumor growth and engraftment in hypoxic and nutrient-deprived microenvironments. Overexpression of gal-3, thus, is part of an adaptive program leading to tumor cell survival under these stressing conditions.

Grosset AA, Labrie M, Gagné D, et al.
Cytosolic galectin-7 impairs p53 functions and induces chemoresistance in breast cancer cells.
BMC Cancer. 2014; 14:801 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Resistance to apoptosis induced by anti-cancer drugs is a major obstacle for the treatment of aggressive forms of breast cancer. Galectin-7 (gal-7) was recently shown to be specifically expressed in basal-like but not in luminal subtypes of human breast cancer.
METHODS: We generated a mutant form of gal-7 (R74S). Arginine 74 is the structural equivalent of arginine 186 found in human galectin-3. Mutation R186S was previously shown to abolish the biological function of galectin-3.
RESULTS: Mutation of arginine 74 induced only limited and local changes to the gal-7 fold. Recombinant forms of R74S and wtgal-7 were also equally effective at forming dimers in solution. Analysis of the thermodynamic parameters by isothermal titration calorimetry (ITC) indicated, however, that binding of lactose to gal-7 was inhibited by the R74S mutation. Using confocal microscopy and electron microscopy, we confirmed the expression of gal-7 in the cytosolic and nuclear compartments of breast cancer cells and the ability of gal-7 to translocate to mitochondria. The mutation at position 74, however, greatly reduced the expression of gal-7 in the nuclear and mitochondrial compartments. Interestingly, cells expressing mutated gal-7 were equally if not even more resistant to drug-induced apoptosis when compared to cells expressing wtgal-7. We also found that both wtgal-7 and R74S inhibited dox-induced PARP-1 cleavage and p53 protein expression. The inhibition of p53 correlated with a decrease in p21 protein expression and CDKN1A mRNA. Furthermore, analysis of nuclear and cytoplasmic fractions showed that both wild type and R74S mutant gal-7 inhibited p53 nuclear translocation, possibly by increasing degradation of cytosolic p53.
CONCLUSIONS: These findings pose a challenge to the paradigm that has guided the design of galectin-specific inhibitors for the treatment of cancer. This study suggests that targeting CRD-independent cytosolic gal-7 in breast cancer cells may be a valuable strategy for the treatment of this disease. Our study will thus complement efforts towards improving selectivity of targeted anticancer agents.

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Cite this page: Cotterill SJ. LGALS3, Cancer Genetics Web: http://www.cancer-genetics.org/LGALS3.htm Accessed:

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