LGALS1

Gene Summary

Gene:LGALS1; galectin 1
Aliases: GBP, GAL1
Location:22q13.1
Summary:The galectins are a family of beta-galactoside-binding proteins implicated in modulating cell-cell and cell-matrix interactions. This gene product may act as an autocrine negative growth factor that regulates cell proliferation. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:galectin-1
Source:NCBIAccessed: 13 March, 2017

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 13 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 13 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: LGALS1 (cancer-related)

Park GB, Kim D
TLR4-mediated galectin-1 production triggers epithelial-mesenchymal transition in colon cancer cells through ADAM10- and ADAM17-associated lactate production.
Mol Cell Biochem. 2017; 425(1-2):191-202 [PubMed] Related Publications
Toll-like receptor 4 (TLR4) activation is a key contributor to the carcinogenesis of colon cancer. Overexpression of galectin-1 (Gal-1) also correlates with increased invasive activity of colorectal cancer. Lactate production is a critical predictive factor of risk of metastasis, but the functional relationship between intracellular lactate and Gal-1 expression in TLR4-activated colon cancer remains unknown. In this study, we investigated the underlying mechanism and role of Gal-1 in metastasis and invasion of colorectal cancer (CRC) cells after TLR4 stimulation. Exposure to the TLR4 ligand lipopolysaccharide (LPS) increased expression of Gal-1, induced EMT-related cytokines, triggered the activation of glycolysis-related enzymes, and promoted lactate production. Gene silencing of TLR4 and Gal-1 in CRC cells inhibited lactate-mediated epithelial-mesenchymal transition (EMT) after TLR4 stimulation. Gal-1-mediated activation of a disintegrin and metalloproteinase 10 (ADAM10) and ADAM 17 increased the invasion activity and expression of mesenchymal characteristics in LPS-activated CRC cells. Conversely, inhibition of ADAM10 or ADAM17 effectively blocked the generation of lactate and the migration capacity of LPS-treated CRC cells. Thus, the TLR4/Gal-1 signaling pathway regulates lactate-mediated EMT processes through the activation of ADAM10 and ADAM17 in CRC cells.

Shen KH, Li CF, Chien LH, et al.
Role of galectin-1 in urinary bladder urothelial carcinoma cell invasion through the JNK pathway.
Cancer Sci. 2016; 107(10):1390-1398 [PubMed] Free Access to Full Article Related Publications
Human galectin-1 is a member of the galectin family, proteins with conserved carbohydrate-recognition domains that bind galactoside. Galectin-1 is highly expressed in various tumors and participates in various oncogenic processes. However, detailed descriptions of the function of galectin-1 in urinary bladder urothelial carcinoma have not been reported. Our previous cohort investigation showed that galectin-1 is associated with tumor invasiveness and is a possible independent prognostic marker of urinary bladder urothelial carcinoma. The present study aimed to clarify the relevance of galectin-1 expression level to tumor progression and invasion. In order to decipher a mechanism for the contribution of galectin-1 to the malignant behavior of urinary bladder urothelial carcinoma, two bladder cancer cell lines (T24 and J82) were established with knockdown of galectin-1 expression by shRNA. Bladder cancer cells with LGALS1 gene silencing showed reduced cell proliferation, lower invasive capability, and lower clonogenicity. Extensive signaling pathway studies indicated that galectin-1 participated in bladder cancer cell invasion by mediating the activity of MMP9 through the Ras-Rac1-MEKK4-JNK-AP1 signaling pathway. Our functional analyses of galectin-1 in urinary bladder urothelial carcinoma provided novel insights into the critical role of galectin-1 in tumor progression and invasion. These results revealed that silencing the galectin-1-mediated MAPK signaling pathway presented a novel strategy for bladder cancer therapy.

Zhang L, Liu X, Tang Z, et al.
Reversal of galectin-1 gene silencing on resistance to cisplatin in human lung adenocarcinoma A549 cells.
Biomed Pharmacother. 2016; 83:265-270 [PubMed] Related Publications
This study aims to investigate reversal of Galectin-1 gene silencing on resistance to cisplatin in human lung adenocarcinoma A549 (or A549/DDP) in vivo and in vitro. The stably transfected lentivirus vector was used to silence Galectin-1 in human lung adenocarcinoma cell line A549 and A549/DDP cells and the cell lines were cultured and passaged. RT-PCR and western blot assay were used to test A549, A549/DDP cells, silenced Galectin-1A549 (A549/I) cells, Galectin-1 mRNA and protein expression levels, respectively, in A549/DDP (A549/DDP/I) cells. CCK8 assay was used to measure median inhibitory concentration (IC50) in each group and resistant index of A549/DDP cells and A549/DDP/I cells. Tumor model in nude mice was established by armpit injection of A549, A549/DDP, A549/I, A549/DDP/I cells. Cisplatin was injected intraperitoneally in tumor models and growth of tumor was observed in vivo model. Four weeks later, nude mice were killed and tumor weight and diameter was measured. mRNA and protein expression of Galectin-1 in A549/DDP cells was higher than that in A549 cells. mRNA and protein expression of Galectin-1 in A549/DDP/I cells was lower than that in A549/DDP cells. Moreover, IC50 values ​​and resistance index in A549/DDP cells was higher than that in A549 cells group and IC50 values ​​and resistance index A549/DDP/I cell group were lower than that in A549/DDP cells. Additionally, tumor weight and volume in A549/DDP/I cell group were lower than that in A549/DDP. In conclusion, Galectin-1 gene silencing would improve the sensitivity of A549/DDP cells to cisplatin in vivo and in vitro.

Tian H, Zhou Y, Yang G, et al.
Sulforaphane-cysteine suppresses invasion via downregulation of galectin-1 in human prostate cancer DU145 and PC3 cells.
Oncol Rep. 2016; 36(3):1361-8 [PubMed] Related Publications
Our previous study showed that sulforaphane (SFN) inhibits invasion in human prostate cancer DU145 cells; however, the underlying mechanisms were not profoundly investigated. In the present study, we found that sulforaphane-cysteine (SFN-Cys), as a metabolite of SFN, inhibits invasion and possesses a novel mechanism in prostate cancer DU145 and PC3 cells. The scratch and Transwell assays showed that SFN-Cys (15 µM) inhibited both migration and invasion, with cell morphological changes, such as cell shrinkage and pseudopodia shortening. The cell proliferation (MTS) assay indicated that cell viability was markedly suppressed with increasing concentrations of SFN‑Cys. Furthermore, the Transwell assay showed that inhibition of SFN‑Cys‑triggered invasion was tightly linked to the sustained extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. Western blot analysis revealed that SFN-Cys downregulated galectin-1 protein, an invasion‑related protein, and that the galectin‑1 reduction could be blocked by ERK1/2 inhibitor PD98059 (25 µM). Moreover, immunofluorescence staining showed that the expression level of galectin-1 protein was significantly reduced in the cells treated with SFN‑Cys. Hence, SFN‑Cys‑inhibited invasion resulted from the sustained ERK1/2 phosphorylation and ERK1/2‑triggered galectin-1 downregulation, suggesting that galectin-1 is a new SFN-Cys target inhibiting invasion apart from ERK1/2, in the treatment of prostate cancer.

Zhang PF, Li KS, Shen YH, et al.
Galectin-1 induces hepatocellular carcinoma EMT and sorafenib resistance by activating FAK/PI3K/AKT signaling.
Cell Death Dis. 2016; 7:e2201 [PubMed] Free Access to Full Article Related Publications
Galectin-1 (Gal-1) is involved in several pathological activities associated with tumor progression and chemoresistance, however, the role and molecular mechanism of Gal-1 activity in hepatocellular carcinoma (HCC) epithelial-mesenchymal transition (EMT) and sorafenib resistance remain enigmatic. In the present study, forced Gal-1 expression promoted HCC progression and sorafenib resistance. Gal-1 elevated αvβ3-integrin expression, leading to AKT activation. Moreover, Gal-1 overexpression induced HCC cell EMT via PI3K/AKT cascade activation. Clinically, our data revealed that Gal-1 overexpression is correlated with poor HCC survival outcomes and sorafenib response. These data suggest that Gal-1 may be a potential therapeutic target for HCC and a biomarker for predicting response to sorafenib treatment.

Zhu X, Wang K, Zhang K, et al.
Galectin-1 knockdown in carcinoma-associated fibroblasts inhibits migration and invasion of human MDA-MB-231 breast cancer cells by modulating MMP-9 expression.
Acta Biochim Biophys Sin (Shanghai). 2016; 48(5):462-7 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
Carcinoma-associated fibroblasts (CAFs) play central roles in facilitating tumor progression and metastasis in breast cancer. Galectin-1 (Gal-1), a marker of CAFs, was previously reported to be associated with tumorigenesis and metastasis of various types of tumors. The aim of this study is to investigate the role of Gal-1 in CAF-mediated breast cancer metastasis and its underlying molecular mechanisms. Our results showed that CAFs isolated from human breast tumor tissues expressed higher level of Gal-1 compared with paired normal fibroblasts, and the conditioned medium (CM) of CAFs significantly induced the migration and invasion of human MDA-MB-231 breast cancer cells. Knockdown of Gal-1 in CAFs dramatically inhibited CAF-CM-induced cell migration and invasion, probably by inhibiting the expression of matrix metalloprotein 9 (MMP-9). Our findings demonstrate that Gal-1-regulated CAFs activation promotes breast cancer cell metastasis by upregulating MMP-9 expression, which indicated that Gal-1 in CAFs might be a potential novel target for breast cancer therapy.

Blanchard H, Bum-Erdene K, Bohari MH, Yu X
Galectin-1 inhibitors and their potential therapeutic applications: a patent review.
Expert Opin Ther Pat. 2016; 26(5):537-54 [PubMed] Related Publications
INTRODUCTION: Galectins have affinity for β-galactosides. Human galectin-1 is ubiquitously expressed in the body and its expression level can be a marker in disease. Targeted inhibition of galectin-1 gives potential for treatment of inflammatory disorders and anti-cancer therapeutics.
AREAS COVERED: This review discusses progress in galectin-1 inhibitor discovery and development. Patent applications pertaining to galectin-1 inhibitors are categorised as monovalent- and multivalent-carbohydrate-based inhibitors, peptides- and peptidomimetics. Furthermore, the potential of galectin-1 protein as a therapeutic is discussed along with consideration of the unique challenges that galectin-1 presents, including its monomer-dimer equilibrium and oxidized and reduced forms, with regard to delivering an intact protein to a pathologically relevant site.
EXPERT OPINION: Significant evidence implicates galectin-1's involvement in cancer progression, inflammation, and host-pathogen interactions. Conserved sequence similarity of the carbohydrate-binding sites of different galectins makes design of specific antagonists (blocking agents/inhibitors of function) difficult. Key challenges pertaining to the therapeutic use of galectin-1 are its monomer-dimer equilibrium, its redox state, and delivery of intact galectin-1 to the desired site. Developing modified forms of galectin-1 has resulted in increased stability and functional potency. Gene and protein therapy approaches that deliver the protein toward the target are under exploration as is exploitation of different inhibitor scaffolds.

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] Article available free on PMC after 01/05/2017 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.

Tesone AJ, Rutkowski MR, Brencicova E, et al.
Satb1 Overexpression Drives Tumor-Promoting Activities in Cancer-Associated Dendritic Cells.
Cell Rep. 2016; 14(7):1774-86 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
Special AT-rich sequence-binding protein 1 (Satb1) governs genome-wide transcriptional programs. Using a conditional knockout mouse, we find that Satb1 is required for normal differentiation of conventional dendritic cells (DCs). Furthermore, Satb1 governs the differentiation of inflammatory DCs by regulating major histocompatibility complex class II (MHC II) expression through Notch1 signaling. Mechanistically, Satb1 binds to the Notch1 promoter, activating Notch expression and driving RBPJ occupancy of the H2-Ab1 promoter, which activates MHC II transcription. However, tumor-driven, unremitting expression of Satb1 in activated Zbtb46(+) inflammatory DCs that infiltrate ovarian tumors results in an immunosuppressive phenotype characterized by increased secretion of tumor-promoting Galectin-1 and IL-6. In vivo silencing of Satb1 in tumor-associated DCs reverses their tumorigenic activity and boosts protective immunity. Therefore, dynamic fluctuations in Satb1 expression govern the generation and immunostimulatory activity of steady-state and inflammatory DCs, but continuous Satb1 overexpression in differentiated DCs converts them into tolerogenic/pro-inflammatory cells that contribute to malignant progression.

Gölz L, Buerfent BC, Hofmann A, et al.
Genome-wide transcriptome induced by Porphyromonas gingivalis LPS supports the notion of host-derived periodontal destruction and its association with systemic diseases.
Innate Immun. 2016; 22(1):72-84 [PubMed] Related Publications
Chronic periodontitis (CP) is a prevalent pathogen-associated inflammatory disorder characterized by the destruction of tooth-supporting tissues, and linked to several systemic diseases. Both the periodontopathogen Porphyromonas gingivalis (Pg), and the genetically determined host immune response, are hypothesized to play a crucial role in this association. To identify new target genes for CP and its associated systemic diseases, we investigated the transcriptome induced by Pg in human monocytes using a genome-wide approach. Monocytes were isolated from healthy male volunteers of European origin and challenged with the Pg virulence factor LPS. Array-based gene expression analysis comprising >47,000 transcripts was performed followed by pathway analyses. Transcriptional data were validated by protein and cell surface markers. LPS Pg challenge led to the significant induction of 902 transcripts. Besides known periodontitis-associated targets, several new candidates were identified (CCL23↑, INDO↑, GBP 1/4↑, CFB↑, ISG20↑, MIR155HG↑, DHRS9↓). Moreover, various transcripts correspond to the host immune response, and have been linked to cancer, atherosclerosis and arthritis, thus highlighting the systemic impact of CP. Protein data of immunological markers validated our results. The present findings expand understanding of Pg elicited immune responses, and indicate new target genes and pathways of relevance to diagnostic and therapeutic strategies.

Manzi M, Bacigalupo ML, Carabias P, et al.
Galectin-1 Controls the Proliferation and Migration of Liver Sinusoidal Endothelial Cells and Their Interaction With Hepatocarcinoma Cells.
J Cell Physiol. 2016; 231(7):1522-33 [PubMed] Related Publications
Galectin-1 (Gal1), a β-galactoside-binding protein elevated in hepatocellular carcinoma (HCC), promotes epithelial-mesenchymal transition (EMT) and its expression correlates with HCC growth, invasiveness, and metastasis. During the early stages of HCC, transforming growth factor β1 (TGF-β1 ) acts as a tumor suppressor; however in advanced stages, HCC cells lose their cytostatic response to TGF-β1 and undergo EMT. Here, we investigated the role of Gal1 on liver endothelial cell biology, and the interplay between Gal1 and TGF-β1 in HCC progression. By Western blot and immunofluorescence, we analyzed Gal1 expression, secretion and localization in HepG2 and HuH-7 human HCC cells, and in SK-HEP-1 human liver sinusoidal endothelial cells (SECs). We used loss-of-function and gain-of-function experiments to down- or up-regulate Gal1 expression, respectively, in HepG2 cells. We cultured SK-HEP-1 cells with conditioned media from HCC cells secreting different levels of Gal1, and demonstrated that Gal1 derived from tumor hepatocytes induced its own expression in SECs. Colorimetric and scratch-wound assays revealed that secretion of Gal1 by HCC cells induced SEC proliferation and migration. Moreover, by fluorescence microscopy we demonstrated that Gal1 promoted glycan-dependent heterotypic adhesion of HepG2 cells to SK-HEP-1 SECs. Furthermore, TGF-β1 induced Gal1 expression and secretion by HCC cells, and promoted HepG2 cell adhesion to SK-HEP-1 SECs through a Gal1-dependent mechanism. Finally, Gal1 modulated HepG2 cell proliferation and sensitivity to TGF-β1 -induced growth inhibition. Our results suggest that Gal1 and TGF-β1 might function coordinately within the HCC microenvironment to regulate tumor growth, invasion, metastasis, and angiogenesis.

Wu Y, Liu M, Li Z, et al.
LYAR promotes colorectal cancer cell mobility by activating galectin-1 expression.
Oncotarget. 2015; 6(32):32890-901 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. However, the molecular mechanisms of CRC pathogenesis are not fully understood. In this study, we report the characterization of LYAR (Ly-1 antibody reactive clone) as a key regulator of the migration and invasion of human CRC cells. Immunohistochemistry analysis demonstrated that LYAR is expressed at a higher level in metastatic CRC tissues. We found that LYAR promoted the migratory and invasive capabilities of CRC cells. Gene expression profile analysis of CRC cells showed that LGALS1, which encodes the galectin-1 protein, was a potential target of LYAR. The ChIP assay and gene reporter assays indicated that LYAR directly bound to the LGALS1 promoter. The ectopic expression of galectin-1 partially restored the mobile potential of LYAR knocked-down cells, which suggests that galectin-1 contributed to the LYAR-promoted cell migration and invasion of CRC cells. Thus, this study revealed a novel mechanism by which the transcription factor LYAR may promote tumor cell migration and invasion by upregulating galectin-1 gene expression in CRC.

Lee YS, Hwang SG, Kim JK, et al.
Identification of novel therapeutic target genes in acquired lapatinib-resistant breast cancer by integrative meta-analysis.
Tumour Biol. 2016; 37(2):2285-97 [PubMed] Related Publications
Acquired resistance to lapatinib is a highly problematic clinical barrier that has to be overcome for a successful cancer treatment. Despite efforts to determine the mechanisms underlying acquired lapatinib resistance (ALR), no definitive genetic factors have been reported to be solely responsible for the acquired resistance in breast cancer. Therefore, we performed a cross-platform meta-analysis of three publically available microarray datasets related to breast cancer with ALR, using the R-based RankProd package. From the meta-analysis, we were able to identify a total of 990 differentially expressed genes (DEGs, 406 upregulated, 584 downregulated) that are potentially associated with ALR. Gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the DEGs showed that "response to organic substance" and "p53 signaling pathway" may be largely involved in ALR process. Of these, many of the top 50 upregulated and downregulated DEGs were found in oncogenesis of various tumors and cancers. For the top 50 DEGs, we constructed the gene coexpression and protein-protein interaction networks from a huge database of well-known molecular interactions. By integrative analysis of two systemic networks, we condensed the total number of DEGs to six common genes (LGALS1, PRSS23, PTRF, FHL2, TOB1, and SOCS2). Furthermore, these genes were confirmed in functional module eigens obtained from the weighted gene correlation network analysis of total DEGs in the microarray datasets ("GSE16179" and "GSE52707"). Our integrative meta-analysis could provide a comprehensive perspective into complex mechanisms underlying ALR in breast cancer and a theoretical support for further chemotherapeutic studies.

Li J, Sun RR, Yu ZJ, et al.
Galectin-1 Modulates the Survival and Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) Sensitivity in Human Hepatocellular Carcinoma Cells.
Cancer Biother Radiopharm. 2015; 30(8):336-41 [PubMed] Related Publications
Galectin-1 is a member of carbohydrate-binding proteins and plays critical roles in tumor growth and progression. It has been reported that galectin-1 is upregulated in human hepatocellular carcinoma (HCC) and facilitates HCC cell migration and invasion. In this study, the authors aimed to explore the effects of the knockdown of galectin-1 on HCC cell survival and sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Human HCC cells were transfected with galectin-1-targeting small interfering RNA (siRNA) with or without 100 ng/mL TRAIL treatment and tested for apoptosis and gene expression changes. Cotransfection of Bcl-2- and survivin-expressing plasmids with galectin-1 siRNA was done, before TRAIL exposure, cell viability, and apoptosis were assessed. The authors found that siRNA-mediated downregulation of galectin-1 caused apoptosis in HCC cells, which was coupled with reduced Bcl-2 and survivin and increased Bax expression. Overexpression of Bcl-2 and survivin significantly blocked galectin-1 silencing-induced apoptosis of HCC cells. Knockdown of galectin-1 significantly enhanced TRAIL cytotoxicity against HCC cells, as determined by the MTT assay. Moreover, galectin-1 downregulation significantly induced apoptosis in TRAIL-treated HCC cells. Such effects were almost completely counteracted by the enforced expression of Bcl-2 and survivin. Taken together, these data first show that galectin-1 downregulation induces apoptosis in and augments TRAIL cytotoxicity to HCC cells largely through regulation of Bcl-2 and survivin expression. These findings provide a rationale for preclinical and clinical evaluation of targeting galectin-1 for improving TRAIL-based therapy against HCC.

Kolundžić N, Ćujić D, Abu Rabi T, et al.
Galectin signature of the choriocarcinoma JAr cells: Galectin-1 as a modulator of invasiveness in vitro.
Mol Reprod Dev. 2015; 82(10):765-73 [PubMed] Related Publications
Our previous findings showed that galectin-1 (LGALS1) plays an important role in the in vitro invasion of normal human trophoblast cells. In the present study, choriocarcinoma JAr cells were found to express LGALS1, -2, -3, -8, -10, and -13 mRNA and at least LGALS1, -3, and -8 protein, as determined by reverse-transcriptase PCR and Western blot, respectively. The galectin mRNA signature of JAr cells thus differed from that of normal first-trimester extravillous trophoblasts. A Matrigel migration assay was also used to investigate and confirm the relevance and effect of LGALS1 on the invasive potential of JAr cells, as observed in other trophoblast models. This modulation in behavior was achieved by specific lectin-glycan binding.

Zu S, Ma W, Xiao P, et al.
Evaluation of Docetaxel-Sensitive and Docetaxel-Resistant Proteomes in PC-3 Cells.
Urol Int. 2015; 95(1):114-9 [PubMed] Related Publications
OBJECTIVES: Docetaxel was the first drug with proven survival benefit in men with castration-resistant prostate cancer. Acquired resistance to docetaxel precedes fatality in castration-resistant prostate cancer. The aims of this study were to evaluate docetaxel-sensitive and docetaxel-resistant proteomes in PC-3 cells, and to investigate the molecular mechanism of docetaxel-resistant PC-3 cells.
METHODS: Docetaxel-resistant PC-3 cells were developed by docetaxel dose escalation. The global profiling of the protein expression was investigated in docetaxel-sensitive and docetaxel-resistant proteomes in PC-3 cells using 2-dimensional polyacrylamide gel electrophoresis/matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.
RESULTS: Forty-nine differential proteins were found in docetaxel-resistant PC-3 cells in comparison with docetaxel-sensitive PC-3 cells. Expression in 29 proteins was upregulated, whereas expression in 20 proteins was downregulated. ATP synthase and galectin-1 were involved in the formation of tumor vessels; calreticulin, cathepsin D, and cofilin were involved in tumor metastasis, and GRP78 (78-kDa glucose-regulated protein) and microtubule-associated protein-6 were involved in drug resistance of tumor.
CONCLUSION: It is suggested that a proteomic expression difference exists between docetaxel-sensitive and docetaxel-resistant PC-3 cells, which would be helpful for further understanding the molecular mechanisms of docetaxel resistance in PC-3 cells.

El Leithy AA, Helwa R, Assem MM, Hassan NH
Expression profiling of cancer-related galectins in acute myeloid leukemia.
Tumour Biol. 2015; 36(10):7929-39 [PubMed] Related Publications
Acute myeloid leukemia (AML) is the most common type of leukemia in adults with the lowest survival rate of all the leukemias. It is a heterogeneous disease in which a variety of cytogenetic and molecular alterations have been identified. Some galectins were previously reported to have important roles in cancer-like neoplastic transformation, tumor cell survival, angiogenesis, and tumor metastasis. Previous studies have showed that some galectin family members play a role in various types of leukemia. The present study aims at evaluating and clarifying the diagnostic and prognostic value of the expression of cancer-related galectins in relation to the clinicopathological characters of AML patients. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect expression profile of eight galectin family members (galectin-1, -2, -3, -4, -8, -9, -12, and -13) in 53 newly diagnosed de novo AML patients. The samples were collected from the inpatient clinic at National Cancer Institute (NCI), Cairo University (CU), diagnosed between July 2012 and May 2013. Our results show that patients with lower LGALS12 gene expression have a lower overall survival than those with higher expression (P value <0.026). Moreover, a statistically significant association between the LGALS4 gene expression and patient age is found. Hence, the higher expression of LGALS4 gene is associated with younger age (adjusted P value <0.001). In conclusion, galectin-12 may be a potential prognostic marker for AML.

Yeh CC, Hsu CH, Shao YY, et al.
Integrated Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) and Isobaric Tags for Relative and Absolute Quantitation (iTRAQ) Quantitative Proteomic Analysis Identifies Galectin-1 as a Potential Biomarker for Predicting Sorafenib Resistance in Liver Cancer.
Mol Cell Proteomics. 2015; 14(6):1527-45 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
Sorafenib has become the standard therapy for patients with advanced hepatocellular carcinoma (HCC). Unfortunately, most patients eventually develop acquired resistance. Therefore, it is important to identify potential biomarkers that could predict the efficacy of sorafenib. To identify target proteins associated with the development of sorafenib resistance, we applied stable isotope labelling with amino acids in cell culture (SILAC)-based quantitative proteomic approach to analyze differences in protein expression levels between parental HuH-7 and sorafenib-acquired resistance HuH-7 (HuH-7(R)) cells in vitro, combined with an isobaric tags for relative and absolute quantitation (iTRAQ) quantitative analysis of HuH-7 and HuH-7(R) tumors in vivo. In total, 2,450 quantified proteins were identified in common in SILAC and iTRAQ experiments, with 81 showing increased expression (>2.0-fold) with sorafenib resistance and 75 showing decreased expression (<0.5-fold). In silico analyses of these differentially expressed proteins predicted that 10 proteins were related to cancer with involvements in cell adhesion, migration, and invasion. Knockdown of one of these candidate proteins, galectin-1, decreased cell proliferation and metastasis in HuH-7(R) cells and restored sensitivity to sorafenib. We verified galectin-1 as a predictive marker of sorafenib resistance and a downstream target of the AKT/mTOR/HIF-1α signaling pathway. In addition, increased galectin-1 expression in HCC patients' serum was associated with poor tumor control and low response rate. We also found that a high serum galectin-1 level was an independent factor associated with poor progression-free survival and overall survival. In conclusion, these results suggest that galectin-1 is a possible biomarker for predicting the response of HCC patients to treatment with sorafenib. As such, it may assist in the stratification of HCC and help direct personalized therapy.

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.

Yazawa EM, Geddes-Sweeney JE, Cedeno-Laurent F, et al.
Melanoma Cell Galectin-1 Ligands Functionally Correlate with Malignant Potential.
J Invest Dermatol. 2015; 135(7):1849-62 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
Galectin-1 (Gal-1)-binding to Gal-1 ligands on immune and endothelial cells can influence melanoma development through dampening antitumor immune responses and promoting angiogenesis. However, whether Gal-1 ligands are functionally expressed on melanoma cells to help control intrinsic malignant features remains poorly understood. Here, we analyzed expression, identity, and function of Gal-1 ligands in melanoma progression. Immunofluorescent analysis of benign and malignant human melanocytic neoplasms revealed that Gal-1 ligands were abundant in severely dysplastic nevi, as well as in primary and metastatic melanomas. Biochemical assessments indicated that melanoma cell adhesion molecule (MCAM) was a major Gal-1 ligand on melanoma cells that was largely dependent on its N-glycans. Other melanoma cell Gal-1 ligand activity conferred by O-glycans was negatively regulated by α2,6 sialyltransferase ST6GalNAc2. In Gal-1-deficient mice, MCAM-silenced (MCAM(KD)) or ST6GalNAc2-overexpressing (ST6(O/E)) melanoma cells exhibited slower growth rates, underscoring a key role for melanoma cell Gal-1 ligands and host Gal-1 in melanoma growth. Further analysis of MCAM(KD) or ST6(O/E) melanoma cells in cell migration assays indicated that Gal-1 ligand-dependent melanoma cell migration was severely inhibited. These findings provide a refined perspective on Gal-1/melanoma cell Gal-1 ligand interactions as contributors to melanoma malignancy.

Tang D, Gao J, Wang S, et al.
Apoptosis and anergy of T cell induced by pancreatic stellate cells-derived galectin-1 in pancreatic cancer.
Tumour Biol. 2015; 36(7):5617-26 [PubMed] Related Publications
Galectin-1, a β-galactoside-binding protein implicated in cancer cell immune privilege, was highly expressed in activated pancreatic stellate cells (PSCs). This study was designed to investigate the relationship between PSC-derived galectin-1 and tumor immunity in pancreatic cancer. Isolated PSCs were identified as normal pancreas cells (hNPSCs) or pancreatic cancer cells (hCaPSCs) by immunohistochemical staining for α-SMA and vimentin, and galectin-1 expression was evaluated by Western blotting and quantitative RT-PCR. Apoptosis, caspase activity, and cytokine production (IL-6, IL-10, TNF-β, and IFN-γ) of T cells co-cultured with PSCs were evaluated, and immunohistochemical staining of galectin-1 was correlated with CD3 and clinicopathological variables in 66 pancreatic cancer and 10 normal pancreatic tissue samples. hCaPSCs exhibited higher galectin-1 expression than did hNPSCs, and hCaPSCs induced higher levels of apoptosis in T cells following co-culture. hCaPSCs activated caspase-9 and caspase-3 in the mitochondrial apoptotic pathway and stimulated secretion of Th2 cytokines (IL-6 and IL-10) but decreased secretion of Th1 cytokines (TNF-β and IFN-γ), compared with hNPSCs. Immunohistochemical staining indicated that galectin-1 and CD3 were more highly expressed in pancreatic cancer tissue. Galectin-1 expression was highest in poorly differentiated pancreatic cancer cells and lowest in well-differentiated pancreatic cancer cells and was associated with tumor size, lymph node metastasis, differentiation, and UICC stage. However, CD3 expression showed the opposite trend and was highest in well-differentiated pancreatic cancer cells and was associated with tumor differentiation and UICC stage. High expression of galectin-1 was associated with short survival, as was low expression of CD3. hCaPSC-derived galectin-1 enhanced apoptosis and anergy of T cells in pancreatic cancer, which contributes to the immune escape of pancreatic cancer cells.

Danhier F, Messaoudi K, Lemaire L, et al.
Combined anti-Galectin-1 and anti-EGFR siRNA-loaded chitosan-lipid nanocapsules decrease temozolomide resistance in glioblastoma: in vivo evaluation.
Int J Pharm. 2015; 481(1-2):154-61 [PubMed] Related Publications
Glioblastoma is the most frequent primary malignant brain tumor in adults. Despite treatments including surgery, radiotherapy and chemotherapy by oral Temozolomide (TMZ), the prognosis of patients with glioblastoma remains very poor. This is partly due to the resistance of malignant cells to therapy particularly TMZ. Overexpression of epidermal growth factor receptor (EGFR) and Galectin-1 by tumor cells significantly contributes to TMZ resistance. The purpose of this study was to evaluate in vivo, the effect of local administration by convection enhanced delivery (CED) of the anti-EGFR and anti-Galectin-1 siRNAs administered separately or in combination on (i) the survival of nude mice-bearing orthotopic U87MG glioblastoma cells and on (ii) the EGFR and Galectin-1 expression in excised U87MG tumor tissue. Both siRNAs were carried by chitosan lipid nanocapsules (LNCs). Survival of mice treated 14 days after tumor implantation by the combination of anti-EGFR and anti-Galectin-1 siRNAs and TMZ (40 mg/kg) was significantly increased compared to animals treated by single anti-EGFR or anti-Galectin-1 siRNAs carried by chitosan-LNCs. This was confirmed by a decreased EGFR and Galectin-1 expression at the protein level in excised U87MG tumor tissue, 8 days post-transfection, visualized by immunofluorescence. This study demonstrates the potential of our strategy in glioblastoma therapy.

Zhou X, Li D, Wang X, et al.
Galectin-1 is overexpressed in CD133+ human lung adenocarcinoma cells and promotes their growth and invasiveness.
Oncotarget. 2015; 6(5):3111-22 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
Previous studies demonstrated that a subpopulation of cancer cells, which are CD133 positive (CD133+) feature higher invasive and metastatic abilities, are called cancer stem cells (CSCs). By using tumor cells derived from patients with lung adenocarcinoma, we found that galectin-1 is highly overexpressed in the CD133+ cancer cells as compared to the normal cancer cells (CD133-) from the same patients. We overexpressed galectin-1 in CD133- cancer cells and downregulated it in CSCs. We found that overexpression of galectin-1 promoted invasiveness of CD133- cells, while knockdown of galectin-1 suppressed proliferation, colony formation and invasiveness of CSCs. Furthermore, tumor growth was significantly inhibited in CSCs xenografts with knockdown of galectin-1 as compared to CSCs treated with scramble siRNAs. Biochemical studies revealed that galectin-1 knockdown led to the suppression of COX-2/PGE2 and AKT/mTOR pathways, indicating galectin-1 might control the phenotypes of CSCs by regulating these signaling pathways. Finally, a retrospective study revealed that galectin-1 levels in blood circulation negatively correlates with overall survival and positively correlates with lymph node metastasis of the patients. Taken together, these findings suggested that galectin-1 plays a major role on the tumorigenesis and invasiveness of CD133+ cancer cells and might serve as a potential therapeutic target for treatment of human patients with lung adenocarcinoma.

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.

Castells X, Acebes JJ, Majós C, et al.
Robustness of equations that define molecular subtypes of glioblastoma tumors based on five transcripts measured by RT-PCR.
OMICS. 2015; 19(1):41-51 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
Glioblastoma (Gb) is one of the most deadly tumors. Its molecular subtypes are yet to be fully characterized while the attendant efforts for personalized medicine need to be intensified in relation to glioblastoma diagnosis, treatment, and prognosis. Several molecular signatures based on gene expression microarrays were reported, but the use of microarrays for routine clinical practice is challenged by attendant economic costs. Several authors have proposed discriminant equations based on RT-PCR. Still, the discriminant threshold is often incompletely described, which makes proper validation difficult. In a previous work, we have reported two Gb subtypes based on the expression levels of four genes: CHI3L1, LDHA, LGALS1, and IGFBP3. One Gb subtype presented with low expression of the four genes mentioned, and of MGMT in a large portion of the patients (with anticipated high methylation of its promoter), and mutated IDH1. Here, we evaluate the robustness of the equations fitted with these genes using RT-PCR values in a set of 64 cases and importantly, define an unequivocal discriminant threshold with a view to prognostic implications. We developed two approaches to generate the discriminant equations: 1) using the expression level of the four genes mentioned above, and 2) using those genes displaying the highest correlation with survival among the aforementioned four ones, plus MGMT, as an attempt to further reduce the number of genes. The ease of equations' applicability, reduction in cost for raw data, and robustness in terms of resampling-based classification accuracy warrant further evaluation of these equations to discern Gb tumor biopsy heterogeneity at molecular level, diagnose potential malignancy, and prognosis of individual patients with glioblastomas.

Rutkowski MR, Stephen TL, Svoronos N, et al.
Microbially driven TLR5-dependent signaling governs distal malignant progression through tumor-promoting inflammation.
Cancer Cell. 2015; 27(1):27-40 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
The dominant TLR5(R392X) polymorphism abrogates flagellin responses in >7% of humans. We report that TLR5-dependent commensal bacteria drive malignant progression at extramucosal locations by increasing systemic IL-6, which drives mobilization of myeloid-derived suppressor cells (MDSCs). Mechanistically, expanded granulocytic MDSCs cause γδ lymphocytes in TLR5-responsive tumors to secrete galectin-1, dampening antitumor immunity and accelerating malignant progression. In contrast, IL-17 is consistently upregulated in TLR5-unresponsive tumor-bearing mice but only accelerates malignant progression in IL-6-unresponsive tumors. Importantly, depletion of commensal bacteria abrogates TLR5-dependent differences in tumor growth. Contrasting differences in inflammatory cytokines and malignant evolution are recapitulated in TLR5-responsive/unresponsive ovarian and breast cancer patients. Therefore, inflammation, antitumor immunity, and the clinical outcome of cancer patients are influenced by a common TLR5 polymorphism.

Coumans JV, Gau D, Poljak A, et al.
Profilin-1 overexpression in MDA-MB-231 breast cancer cells is associated with alterations in proteomics biomarkers of cell proliferation, survival, and motility as revealed by global proteomics analyses.
OMICS. 2014; 18(12):778-91 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
Despite early screening programs and new therapeutic strategies, metastatic breast cancer is still the leading cause of cancer death in women in industrialized countries and regions. There is a need for novel biomarkers of susceptibility, progression, and therapeutic response. Global analyses or systems science approaches with omics technologies offer concrete ways forward in biomarker discovery for breast cancer. Previous studies have shown that expression of profilin-1 (PFN1), a ubiquitously expressed actin-binding protein, is downregulated in invasive and metastatic breast cancer. It has also been reported that PFN1 overexpression can suppress tumorigenic ability and motility/invasiveness of breast cancer cells. To obtain insights into the underlying molecular mechanisms of how elevating PFN1 level induces these phenotypic changes in breast cancer cells, we investigated the alteration in global protein expression profiles of breast cancer cells upon stable overexpression of PFN1 by a combination of three different proteome analysis methods (2-DE, iTRAQ, label-free). Using MDA-MB-231 as a model breast cancer cell line, we provide evidence that PFN1 overexpression is associated with alterations in the expression of proteins that have been functionally linked to cell proliferation (FKPB1A, HDGF, MIF, PRDX1, TXNRD1, LGALS1, STMN1, LASP1, S100A11, S100A6), survival (HSPE1, HSPB1, HSPD1, HSPA5 and PPIA, YWHAZ, CFL1, NME1) and motility (CFL1, CORO1B, PFN2, PLS3, FLNA, FLNB, NME2, ARHGDIB). In view of the pleotropic effects of PFN1 overexpression in breast cancer cells as suggested by these new findings, we propose that PFN1-induced phenotypic changes in cancer cells involve multiple mechanisms. Our data reported here might also offer innovative strategies for identification and validation of novel therapeutic targets and companion diagnostics for persons with, or susceptibility to, breast cancer.

Wu TF, Li CF, Chien LH, et al.
Galectin-1 dysregulation independently predicts disease specific survival in bladder urothelial carcinoma.
J Urol. 2015; 193(3):1002-8 [PubMed] Related Publications
PURPOSE: Galectin-1 is highly expressed in various tumors and participates in various oncogenic processes. Our previous proteomics investigation demonstrated that galectin-1 is up-regulated in high compared to nonhigh grade lesions. Thus, in the current cohort study we clarified the correlation of galectin-1 over expression with various clinicopathological features and prognosis.
MATERIALS AND METHODS: We selected 185 cases of consecutively treated primary localized bladder urothelial carcinoma for study. Transurethral resection of bladder tumor was performed in all patients followed by radical cystectomy in those with T2 to T4 tumors. Pathological slides were examined to determine cytoplasmic galectin-1 immuno-expression and correlate galectin-1 dysregulation with various clinicopathological factors and disease specific survival.
RESULTS: Positive galectin-1 immuno-expression in tumors was significantly linked to pT status (p = 0.0295), histological grade (p = 0.037), vascular invasion (p = 0.0287) and nodal status (p = 0.0012). Galectin-1 over expression in tumors significantly predicted disease specific survival at the univariate (p = 0.0002) and multivariate levels (p = 0.03, HR 2.438, 95% CI 1.090-5.451). In situ hybridization indicated that the LGALS1 gene was amplified in 43 specimens in an independent cohort of 56 snap frozen tumor specimens. Association analysis showed that an increased LGALS1 mRNA level was linked to bladder urothelial carcinoma invasiveness (p = 0.016) and LGALS1 gene amplification was significantly associated the amount of GAL-1 protein in tumors (p <0.0001). On the univariate level gene amplification was also closely linked to disease specific survival (p = 0.0006).
CONCLUSIONS: These results reveal that galectin-1 over expression is a possible independent factor for bladder cancer prognosis.

Katzenmaier EM, André S, Kopitz J, Gabius HJ
Impact of sodium butyrate on the network of adhesion/growth-regulatory galectins in human colon cancer in vitro.
Anticancer Res. 2014; 34(10):5429-38 [PubMed] Related Publications
BACKGROUND/AIM: The physiological compound sodium butyrate can induce differentiation in colon cancer cells in vitro. Due to the role of galectins in growth control we explored its effect on this network beyond galectins-1 and -3, with deliberate consideration of the status of microsatellite stability, for nine cell lines.
MATERIALS AND METHODS: Microscopical monitoring and measurement of alkaline phosphatase activity ascertained butyrate's impact on cells. Monitoring by reverse transcriptase-polymerase chain reaction (RT-PCR) and western blotting with galectin-type-specific probes characterized galectin expression.
RESULTS: Controlled by expectable strong up-regulation of galectin-1 and comparatively small effects on galectin-3 regulation for galectins-4, -7, -8 and -9 were reported with no obvious association to microsatellite stability status. Neoexpression of the GAL-12 gene was observed in eight out of nine tested lines.
CONCLUSION: Butyrate affects the galectin network beyond galectins-1 and -3, warranting further cell biological and histochemical studies.

Schulkens IA, Heusschen R, van den Boogaart V, et al.
Galectin expression profiling identifies galectin-1 and Galectin-9Δ5 as prognostic factors in stage I/II non-small cell lung cancer.
PLoS One. 2014; 9(9):e107988 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
Approximately 30-40% of the patients with early stage non-small cell lung cancer (NSCLC) will present with recurrent disease within two years of resection. Here, we performed extensive galectin expression profiling in a retrospective study using frozen and paraffin embedded tumor tissues from 87 stage I/II NSCLC patients. Our data show that galectin mRNA expression in NSCLC is confined to galectin-1, -3, -4, -7, -8, and -9. Next to stage, univariable Cox regression analysis identified galectin-1, galectin-9FL and galectin-9Δ5 as possible prognostic markers. Kaplan-Meier survival estimates revealed that overall survival was significantly shorter in patients that express galectin-1 above median levels, i.e., 23.0 (2.9-43.1) vs. 59.9 (47.7-72.1) months (p = 0.020) as well as in patients that express galectin-9Δ5 or galectin-9FL below the median, resp. 59.9 (41.9-75.9) vs. 32.8 (8.7-56.9) months (p = 0.014) or 23.2 (-0.4-46.8) vs. 58.9 (42.9-74.9) months (p = 0.042). All three galectins were also prognostic for disease free survival. Multivariable Cox regression analysis showed that for OS, the most significant prognostic model included stage, age, gal-1 and gal-9Δ5 while the model for DFS included stage, age and gal-9Δ5. In conclusion, the current study confirms the prognostic value of galectin-1 and identifies galectin-9Δ5 as novel potential prognostic markers in early stage NSCLC. These findings could help to identify early stage NSCLC patients that might benefit most from adjuvant chemotherapy.

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