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http://dx.doi.org/10.5483/BMBRep.2020.53.4.020

Non-classical role of Galectin-3 in cancer progression: translocation to nucleus by carbohydrate-recognition independent manner  

Kim, Seok-Jun (Department of Biomedical Science, College of Natural Science, Chosun University)
Chun, Kyung-Hee (Department of Biochemistry & Molecular Biology, Yonsei University College of Medicine)
Publication Information
BMB Reports / v.53, no.4, 2020 , pp. 173-180 More about this Journal
Abstract
Galectin-3 is a carbohydrate-binding protein and regulates diverse functions, including cell proliferation and differentiation, mRNA splicing, apoptosis induction, immune surveillance and inflammation, cell adhesion, angiogenesis, and cancer-cell metastasis. Galectin-3 is also recommended as a diagnostic or prognostic biomarker of various diseases, including heart disease, kidney disease, and cancer. Galectin-3 exists as a cytosol, is secreted in extracellular spaces on cells, and is also detected in nuclei. It has been found that galectin-3 has different functions in cellular localization: (i) Extracellular galectin-3 mediates cell attachment and detachment. (ii) cytosolic galectin-3 regulates cell survival by blocking the intrinsic apoptotic pathway, and (iii) nuclear galectin-3 supports the ability of the transcriptional factor for target gene expression. In this review, we focused on the role of galectin-3 on translocation from cytosol to nucleus, because it happens in a way independent of carbohydrate recognition and accelerates cancer progression. We also suggested here that intracellular galecin-3 could be a potent therapeutic target in cancer therapy.
Keywords
Cancer progression; Carbohydrate-binding; Cellular localization; Galectin-3;
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1 Pacis RA, Pilat MJ, Pienta KJ et al (2000) Decreased galectin-3 expression in prostate cancer. Prostate 44, 118-123   DOI
2 Brustmann H, Riss D and Naude S (2003) Galectin-3 expression in normal, hyperplastic, and neoplastic endometrial tissues. Pathol Res Pract 199, 151-158   DOI
3 Shimonishi T, Miyazaki K, Kono N et al (2001) Expression of endogenous galectin-1 and galectin-3 in intrahepatic cholangiocarcinoma. Hum Pathol 32, 302-310   DOI
4 van den Brule FA, Waltregny D, Liu FT and Castronovo V (2000) Alteration of the cytoplasmic/nuclear expression pattern of galectin-3 correlates with prostate carcinoma progression. Int J Cancer 89, 361-367   DOI
5 Jin L, Riss D, Ruebel K et al (2005) Galectin-3 Expression in Functioning and Silent ACTH-Producing Adenomas. Endocr Pathol 16, 107-114   DOI
6 Shimura T, Takenaka Y, Fukumori T et al (2005) Implication of galectin-3 in Wnt signaling. Cancer Res 65, 3535-3537   DOI
7 Shimamura T, Sakamoto M, Ino Y et al (2002) Clinicopathological significance of galectin-3 expression in ductal adenocarcinoma of the pancreas. Clin Cancer Res 8, 2570-2575
8 Balan V, Nangia-Makker P, Schwartz AG et al (2008) Racial disparity in breast cancer and functional germ line mutation in galectin-3 (rs4644): a pilot study. Cancer Res 68, 10045-10050   DOI
9 Hashimoto Y, Ito T, Inoue H et al (2005) Prognostic significance of fascin overexpression in human esophageal squamous cell carcinoma. Clin Cancer Res 11, 2597-2605   DOI
10 Jawhari AU, Buda A, Jenkins M et al (2003) Fascin, an actin-bundling protein, modulates colonic epithelial cell invasiveness and differentiation in vitro. Am J Pathol 162, 69-80   DOI
11 Fortuna-Costa A, Gomes AM, Kozlowski EO, Stelling MP and Pavao MS (2014) Extracellular galectin-3 in tumor progression and metastasis. Front Oncol 4, 138
12 Grothey A, Hashizume R, Ji H et al (2000) C-erbB-2/HER-2 upregulates fascin, an actin-bundling protein associated with cell motility, in human breast cancer cell lines. Oncogene 19, 4864-4875   DOI
13 Hashimoto Y, Shimada Y, Kawamura J, Yamasaki S and Imamura M (2004) The prognostic relevance of fascin expression in human gastric carcinoma. Oncology 67, 262-270   DOI
14 Leffler H, Carlsson S, Hedlund M, Qian Y and Poirier F (2002) Introduction to galectins. Glycoconj J 19, 433-440   DOI
15 Drickamer K and Fadden AJ (2002) Genomic analysis of C-type lectins. Biochem Soc Symp 69, 59-72   DOI
16 Liu FT and Rabinovich GA (2005) Galectins as modulators of tumour progression. Nat Rev Cancer 5, 29-41   DOI
17 Hirabayashi J and Kasai K (1993) The family of metazoan metal-independent beta-galactoside-binding lectins: structure, function and molecular evolution. Glycobiology 3, 297-304   DOI
18 Johannes L, Jacob R and Leffler H (2018) Galectins at a glance. J Cell Sci 131
19 Argueso P and Panjwani N (2011) Focus on molecules: galectin-3. Exp Eye Res 92, 2-3   DOI
20 Dumic J, Dabelic S and Flogel M (2006) Galectin-3: an open-ended story. Biochim Biophys Acta 1760, 616-635   DOI
21 Ruvolo PP (2016) Galectin 3 as a guardian of the tumor microenvironment. Biochim Biophys Acta 1863, 427-437   DOI
22 Kadrofske MM, Openo KP and Wang JL (1998) The human LGALS3 (galectin-3) gene: determination of the gene structure and functional characterization of the promoter. Arch Biochem Biophys 349, 7-20   DOI
23 Wang L and Guo XL (2016) Molecular regulation of galectin-3 expression and therapeutic implication in cancer progression. Biomed Pharmacother 78, 165-171   DOI
24 Krzeslak A and Lipinska A (2004) Galectin-3 as a multifunctional protein. Cell Mol Biol Lett 9, 305-328
25 Macfarlane SR, Seatter MJ, Kanke T, Hunter GD and Plevin R (2001) Proteinase-activated receptors. Pharmacol Rev 53, 245-282
26 Yamashiro S, Yamakita Y, Ono S and Matsumura F (1998) Fascin, an actin-bundling protein, induces membrane protrusions and increases cell motility of epithelial cells. Mol Biol Cell 9, 993-1006   DOI
27 Shonukan O, Bagayogo I, McCrea P, Chao M and Hempstead B (2003) Neurotrophin-induced melanoma cell migration is mediated through the actin-bundling protein fascin. Oncogene 22, 3616-3623   DOI
28 Shimura T, Takenaka Y, Tsutsumi S, Hogan V, Kikuchi A and Raz A (2004) Galectin-3, a novel binding partner of beta-catenin. Cancer Res 64, 6363-6367   DOI
29 Tellez C and Bar-Eli M (2003) Role and regulation of the thrombin receptor (PAR-1) in human melanoma. Oncogene 22, 3130-3137   DOI
30 Arora P, Ricks TK and Trejo J (2007) Protease-activated receptor signalling, endocytic sorting and dysregulation in cancer. J Cell Sci 120, 921-928   DOI
31 Pei D (2005) Matrix metalloproteinases target proteaseactivated receptors on the tumor cell surface. Cancer Cell 7, 207-208   DOI
32 Blackburn JS, Liu I, Coon CI and Brinckerhoff CE (2009) A matrix metalloproteinase-1/protease activated receptor-1 signaling axis promotes melanoma invasion and metastasis. Oncogene 28, 4237-4248   DOI
33 Ochieng J, Furtak V and Lukyanov P (2002) Extracellular functions of galectin-3. Glycoconj J 19, 527-535   DOI
34 Nangia-Makker P, Balan V and Raz A (2008) Regulation of tumor progression by extracellular galectin-3. Cancer Microenviron 1, 43-51   DOI
35 Raimond J, Zimonjic DB, Mignon C et al (1997) Mapping of the galectin-3 gene (LGALS3) to human chromosome 14 at region 14q21-22. Mamm Genome 8, 706-707   DOI
36 Hughes RC (1999) Secretion of the galectin family of mammalian carbohydrate-binding proteins. Biochim Biophys Acta 1473, 172-185   DOI
37 Yu F, Finley RL Jr, Raz A and Kim HR (2002) Galectin-3 translocates to the perinuclear membranes and inhibits cytochrome c release from the mitochondria. A role for synexin in galectin-3 translocation. J Biol Chem 277, 15819-15827   DOI
38 van den Brule F, Califice S and Castronovo V (2002) Expression of galectins in cancer: a critical review. Glycoconj J 19, 537-542   DOI
39 Inohara H and Raz A (1994) Identification of human melanoma cellular and secreted ligands for galectin-3. Biochem Biophys Res Commun 201, 1366-1375   DOI
40 Yang RY, Rabinovich GA and Liu FT (2008) Galectins: structure, function and therapeutic potential. Expert Rev Mol Med 10, e17   DOI
41 Haudek KC, Spronk KJ, Voss PG, Patterson RJ, Wang JL and Arnoys EJ (2010) Dynamics of galectin-3 in the nucleus and cytoplasm. Biochim Biophys Acta 1800, 181-189   DOI
42 Thijssen VL, Heusschen R, Caers J and Griffioen AW (2015) Galectin expression in cancer diagnosis and prognosis: A systematic review. Biochim Biophys Acta 1855, 235-247
43 Zetterberg FR, Peterson K, Johnsson RE et al (2018) Monosaccharide Derivatives with Low-Nanomolar Lectin Affinity and High Selectivity Based on Combined Fluorine-Amide, Phenyl-Arginine, Sulfur-pi, and Halogen Bond Interactions. Chem Med Chem 13, 133-137   DOI
44 Chen WS, Cao Z, Leffler H, Nilsson UJ and Panjwani N (2017) Galectin-3 Inhibition by a Small-Molecule Inhibitor Reduces Both Pathological Corneal Neovascularization and Fibrosis. Invest. Ophthalmol Vis Sci 58, 9-20   DOI
45 Glinskii OV, Sud S, Mossine VV et al (2012) Inhibition of prostate cancer bone metastasis by synthetic TF antigen mimic/galectin-3 inhibitor lactulose-L-leucine. Neoplasia 14, 65-73   DOI
46 Campo VL, Marchiori MF, Rodrigues LC and Dias-Baruffi M (2016) Synthetic glycoconjugates inhibitors of tumor-related galectin-3: an update. Glycoconj J 33, 853-876   DOI
47 Hughes RC (2001) Galectins as modulators of cell adhesion. Biochimie 83, 667-676   DOI
48 Ebrahim AH, Alalawi Z, Mirandola L et al (2014) Galectins in cancer: carcinogenesis, diagnosis and therapy. Ann Transl Med 2, 88
49 Takenaka Y, Inohara H, Yoshii T et al (2003) Malignant transformation of thyroid follicular cells by galectin-3. Cancer Lett 195, 111-119   DOI
50 Markowska AI, Jefferies KC and Panjwani N (2011) Galectin-3 protein modulates cell surface expression and activation of vascular endothelial growth factor receptor 2 in human endothelial cells. J Biol Chem 286, 29913-29921   DOI
51 Kim HR, Lin HM, Biliran H and Raz A (1999) Cell cycle arrest and inhibition of anoikis by galectin-3 in human breast epithelial cells. Cancer Res 59, 4148-4154
52 Zhao Q, Barclay M, Hilkens J et al (2010) Interaction between circulating galectin-3 and cancer-associated MUC1 enhances tumour cell homotypic aggregation and prevents anoikis. Mol Cancer 9, 154   DOI
53 Yang RY, Hsu DK and Liu FT (1996) Expression of galectin-3 modulates T-cell growth and apoptosis. Proc Natl Acad Sci U S A 93, 6737-6742   DOI
54 Harazono Y, Kho DH, Balan V et al (2014) Galectin-3 leads to attenuation of apoptosis through Bax heterodimerization in human thyroid carcinoma cells. Oncotarget 5, 9992-10001   DOI
55 Nakahara S, Oka N and Raz A (2005) On the role of galectin-3 in cancer apoptosis. Apoptosis 10, 267-275   DOI
56 Davidson PJ, Davis MJ, Patterson RJ, Ripoche MA, Poirier F and Wang JL (2002) Shuttling of galectin-3 between the nucleus and cytoplasm. Glycobiology 12, 329-337   DOI
57 Itoh K, Brott BK, Bae GU, Ratcliffe MJ and Sokol SY (2005) Nuclear localization is required for Dishevelled function in Wnt/beta-catenin signaling. J Biol 4, 3   DOI
58 Kang HG, Kim DH, Kim SJ et al (2016) Galectin-3 supports stemness in ovarian cancer stem cells by activation of the Notch1 intracellular domain. Oncotarget 7, 68229-68241   DOI
59 Pikarsky E, Porat RM, Stein I et al (2004) NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 431, 461-466   DOI
60 Arnoys EJ, Ackerman CM and Wang JL (2015) Nucleocytoplasmic shuttling of galectin-3. Methods Mol Biol 1207, 465-483   DOI
61 Nakahara S, Oka N, Wang Y, Hogan V, Inohara H and Raz A (2006) Characterization of the nuclear import pathways of galectin-3. Cancer Res 66, 9995-10006   DOI
62 Nakahara S, Hogan V, Inohara H and Raz A (2006) Importin-mediated nuclear translocation of galectin-3. J Biol Chem 281, 39649-39659   DOI
63 Davidson PJ, Li SY, Lohse AG et al (2006) Transport of galectin-3 between the nucleus and cytoplasm. I. Conditions and signals for nuclear import. Glycobiology 16, 602-611   DOI
64 Li SY, Davidson PJ, Lin NY, Patterson RJ, Wang JL and Arnoys EJ (2006) Transport of galectin-3 between the nucleus and cytoplasm. II. Identification of the signal for nuclear export. Glycobiology 16, 612-622   DOI
65 Kim SJ, Shin JY, Cheong TC et al (2011) Galectin-3 germline variant at position 191 enhances nuclear accumulation and activation of beta-catenin in gastric cancer. Clin Exp Metastasis 28, 743-750   DOI
66 Wilson NH and Key B (2007) Neogenin: one receptor, many functions. Int J Biochem Cell Biol 39, 874-878   DOI
67 Nangia-Makker P, Wang Y, Raz T et al (2010) Cleavage of galectin-3 by matrix metalloproteases induces angiogenesis in breast cancer. Int J Cancer 127, 2530-2541   DOI
68 Wang LF, Liu YS, Yang B et al (2018) The extracellular matrix protein mindin attenuates colon cancer progression by blocking angiogenesis via Egr-1-mediated regulation. Oncogene 37, 601-615   DOI
69 Nangia-Makker P, Honjo Y, Sarvis R et al (2000) Galectin-3 induces endothelial cell morphogenesis and angiogenesis. Am J Pathol 156, 899-909   DOI
70 Song S, Byrd JC, Mazurek N, Liu K, Koo JS and Bresalier RS (2005) Galectin-3 modulates MUC2 mucin expression in human colon cancer cells at the level of transcription via AP-1 activation. Gastroenterology 129, 1581-1591   DOI
71 Kim SJ, Wang YG, Lee HW et al (2014) Up-regulation of neogenin-1 increases cell proliferation and motility in gastric cancer. Oncotarget 5, 3386-3398   DOI
72 Li J, Shima H, Nishizawa H et al (2018) Phosphorylation of BACH1 switches its function from transcription factor to mitotic chromosome regulator and promotes its interaction with HMMR. Biochem J 475, 981-1002   DOI
73 Yeh MH, Tzeng YJ, Fu TY et al (2018) Extracellular Matrix-receptor Interaction Signaling Genes Associated with Inferior Breast Cancer Survival. Anticancer Res 38, 4593-4605   DOI
74 Casini P, Nardi I and Ori M (2010) RHAMM mRNA expression in proliferating and migrating cells of the developing central nervous system. Gene Expr Patterns 10, 93-97   DOI
75 Bahrami SB, Tolg C, Peart T et al (2017) Receptor for hyaluronan mediated motility (RHAMM/HMMR) is a novel target for promoting subcutaneous adipogenesis. Integr Biol (Camb) 9, 223-237   DOI
76 Connell M, Chen H, Jiang J et al (2017) HMMR acts in the PLK1-dependent spindle positioning pathway and supports neural development. Elife 6, pii: e28672
77 Silverman AM, Nakata R, Shimada H, Sposto R and DeClerck YA (2012) A galectin-3-dependent pathway upregulates interleukin-6 in the microenvironment of human neuroblastoma. Cancer Res 72, 2228-2238   DOI
78 Kim SJ, Lee HW, Gu Kang H et al (2014) Ablation of galectin-3 induces p27(KIP1)-dependent premature senescence without oncogenic stress. Cell Death Differ 21, 1769-1779   DOI
79 Vaught JB (2006) Biorepository and biospecimen science: a new focus for CEBP. Cancer Epidemiol Biomarkers Prev 15, 1572-1573   DOI
80 Kuilman T, Michaloglou C, Mooi WJ and Peeper DS (2010) The essence of senescence. Genes Dev 24, 2463-2479   DOI
81 La SH, Kim SJ, Kang HG, Lee HW and Chun KH (2016) Ablation of human telomerase reverse transcriptase (hTERT) induces cellular senescence in gastric cancer through a galectin-3 dependent mechanism. Oncotarget 7, 57117-57130   DOI
82 Nangia-Makker P, Hogan V and Raz A (2018) Galectin-3 and cancer stemness. Glycobiology 28, 172-181   DOI
83 Yoshii T, Inohara H, Takenaka Y et al (2001) Galectin-3 maintains the transformed phenotype of thyroid papillary carcinoma cells. Int J Oncol 18, 787-792
84 Regalo G, Forster S, Resende C et al (2016) C/EBPbeta regulates homeostatic and oncogenic gastric cell proliferation. J Mol Med (Berl) 94, 1385-1395   DOI
85 Ma J, Yao Y, Wang P et al (2014) MiR-152 functions as a tumor suppressor in glioblastoma stem cells by targeting Kruppel-like factor 4. Cancer Lett 355, 85-95   DOI
86 Seguin L, Kato S, Franovic A et al (2014) An integrin beta(3)-KRAS-RalB complex drives tumour stemness and resistance to EGFR inhibition. Nat Cell Biol 16, 457-468   DOI
87 Shekhar MP, Nangia-Makker P, Tait L, Miller F and Raz A (2004) Alterations in galectin-3 expression and distribution correlate with breast cancer progression: functional analysis of galectin-3 in breast epithelial-endothelial interactions. Am J Pathol 165, 1931-1941   DOI
88 El Gendy H, Madkour B, Abdelaty S et al (2014) Galectin 3 for the diagnosis of bladder cancer. Arab J Urol 12, 178-181   DOI
89 Kim SJ, Choi IJ, Cheong TC et al (2010) Galectin-3 increases gastric cancer cell motility by up-regulating fascin-1 expression. Gastroenterology 138, 1035-1045 e1031-1032   DOI
90 Kim SJ, Shin JY, Lee KD et al (2011) Galectin-3 facilitates cell motility in gastric cancer by up-regulating protease-activated receptor-1 (PAR-1) and matrix metalloproteinase-1 (MMP-1). PLoS One 6, e25103   DOI
91 Kang HG, Kim WJ, Kang HG, Chun KH and Kim SJ (2020) Galectin-3 interacts with C/EBPbeta and upregulates hyaluronan-mediated motility receptor expression in gastric cancer. Mol Cancer Res 18, 403-413   DOI
92 Dong R, Zhang M, Hu Q et al (2018) Galectin-3 as a novel biomarker for disease diagnosis and a target for therapy (Review). Int J Mol Med 41, 599-614
93 Califice S, Castronovo V and Van Den Brule F (2004) Galectin-3 and cancer (Review). Int J Oncol 25, 983-992
94 Baldus SE, Zirbes TK, Weingarten M et al (2000) Increased galectin-3 expression in gastric cancer: correlations with histopathological subtypes, galactosylated antigens and tumor cell proliferation. Tumour Biol 21, 258-266   DOI
95 Volante M, Bozzalla-Cassione F, Orlandi F and Papotti M (2004) Diagnostic role of galectin-3 in follicular thyroid tumors. Virchows Arch 444, 309-312   DOI
96 Gudowska M, Gruszewska E, Cylwik B et al (2015) Galectin-3 Concentration in Liver Diseases. Ann Clin Lab Sci 45, 669-673
97 Castronovo V, Van Den Brule FA, Jackers P et al (1996) Decreased expression of galectin-3 is associated with progression of human breast cancer. J Pathol 179, 43-48   DOI
98 Inufusa H, Nakamura M, Adachi T et al (2001) Role of galectin-3 in adenocarcinoma liver metastasis. Int J Oncol 19, 913-919
99 Honjo Y, Inohara H, Akahani S et al (2000) Expression of cytoplasmic galectin-3 as a prognostic marker in tongue carcinoma. Clin Cancer Res 6, 4635-4640
100 Sciacchitano S, Lavra L, Morgante A et al (2018) Galectin-3: One Molecule for an Alphabet of Diseases, from A to Z. Int J Mol Sci 19, pii: E379
101 Honjo Y, Nangia-Makker P, Inohara H and Raz A (2001) Down-regulation of galectin-3 suppresses tumorigenicity of human breast carcinoma cells. Clin Cancer Res 7, 661-668
102 Takenaka Y, Fukumori T and Raz A (2004) Galectin-3 and metastasis. Glycoconj J 19, 543-549   DOI
103 Dagher SF, Wang JL and Patterson RJ (1995) Identification of galectin-3 as a factor in pre-mRNA splicing. Proc Natl Acad Sci U S A 92, 1213-1217   DOI
104 Inohara H, Akahani S and Raz A (1998) Galectin-3 stimulates cell proliferation. Exp Cell Res 245, 294-302   DOI
105 Bresalier RS, Mazurek N, Sternberg LR et al (1998) Metastasis of human colon cancer is altered by modifying expression of the beta-galactoside-binding protein galectin 3. Gastroenterology 115, 287-296   DOI
106 Raz A, Zhu DG, Hogan V et al (1990) Evidence for the role of 34-kDa galactoside-binding lectin in transformation and metastasis. Int J Cancer 46, 871-877   DOI
107 Hood JD and Cheresh DA (2002) Role of integrins in cell invasion and migration. Nat Rev Cancer 2, 91-100   DOI
108 Yoder BJ, Tso E, Skacel M et al (2005) The expression of fascin, an actin-bundling motility protein, correlates with hormone receptor-negative breast cancer and a more aggressive clinical course. Clin Cancer Res 11, 186-192
109 Kureishy N, Sapountzi V, Prag S, Anilkumar N and Adams JC (2002) Fascins, and their roles in cell structure and function. Bioessays 24, 350-361   DOI