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Targeted disruption of the galectin-3 gene results in decreased susceptibility to NNK-induced lung tumorigenesis: an oligonucleotide microarray study

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Abstract

Purpose

Galectin-3, a β-galactoside-binding animal lectin is a multifunctional protein, which regulates cell growth, cell adhesion, cell proliferation, angiogenesis, and apoptosis, and in turn contributes to tumorigenesis and metastasis. The aim of this study was to clarify the role or related mechanisms of galectin-3 in lung carcinogenesis.

Methods

We administrated 4-(methylnitrosamino)-1-(3-pyridyle)-1-butanone (NNK), a powerful chemical carcinogen into galectin-3 wild-type (gal3+/+) and galectin-3 knock-out (gal3−/−) CD1 mice by intraperitoneal injection, examined the expression status of 22,690 mouse genes of the NNK-induced tumors using Affymetrix GeneChip mouse expression 430 A arrays, and then analyzed functional network and gene ontology by Ingenuity Pathway Analysis. Real-time PCR was also employed to partially confirm the genechip data.

Results

Compared with the gal3+/+ mice, the incidence of lung tumors was significantly low in gal3−/− mice after 32 weeks (28.6 vs 52.1%, P < 0.05). Pathway analysis indicated that galectin-3 up-regulated carcinogenesis-related genes (e.g. B-cell receptor, ERK/MAPK, and PPAR signalings) in normal condition, and lung cancer and NNK-induced gene expression associated with cellular growth (e.g. Wnt/β-catenin signaling) or immunological disease (e.g. EGF and PDGF signalings) in lung carcinogenesis with or without the galectin-3 control, respectively.

Conclusion

Disrupted galectin-3 may attenuate the lung carcinogenesis due to its regulatory role in the B-cell receptor, ERK/MAPK, and PPAR signal pathways.

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References

  • Abdel-Aziz HO, Takasaki I, Tabuchi Y, Nomoto K, Murai Y, Tsuneyama K, Takano Y (2007) High-density oligonucleotide microarrays and functional network analysis reveal extended lung carcinogenesis pathway maps and multiple interacting genes in NNK [4-(methylnitrosamino)-1-(3-pyridyle)-1-butanone] induced CD1 mouse lung tumor. J Cancer Res Clin Oncol 133:107–115

    Article  PubMed  CAS  Google Scholar 

  • Alberg AJ, Brock MV, Samet JM (2005) Epidemiology of lung cancer: looking to the future. J Clin Oncol 23:3175–3185

    Article  PubMed  Google Scholar 

  • Baldus SE, Zirbes TK, Weingarten M, Fromm S, Glossmann J, Hanisch FG, Mönig SP, Schröder W, Flucke U, Thiele J, Hölscher AH, Dienes HP (2000) Increased galectin-3 expression in gastric cancer: correlations with histopathological subtypes, galactosylated antigens and tumor cell proliferation. Tumour Biol 21:258–266

    Article  PubMed  CAS  Google Scholar 

  • Barondes SH, Cooper DN, Gitt MA, Leffler H (1994) Structure and function of a large family of animal lectins. J Biol Chem 269:20807–20810

    PubMed  CAS  Google Scholar 

  • Bhattacharjee A, Richards WG, Staunton J, Li C, Monti S, Vasa P, Ladd C, Beheshti J, Bueno R, Gillette M, Loda M, Weber G, Mark EJ, Lander ES, Wong W, Johnson BE, Golub TR, Sugarbaker DJ, Meyerson M (2001) Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proc Natl Acad Sci USA 98:13790–13795

    Article  PubMed  CAS  Google Scholar 

  • Bianco R, Melisi D, Ciardiello F, Tortora G (2006) Key cancer cell signal transduction pathways as therapeutic targets. Eur J Cancer 42:290–294

    Article  PubMed  CAS  Google Scholar 

  • Bresalier RS, Mazurek N, Sternberg LR, Byrd JC, Yunker CK, Nangia-Makker P, Raz A (1998) Metastasis of human colon cancer is altered by modifying expression of the beta-galactoside-binding protein galectin 3. Gastroenterology 115:287–296

    Article  PubMed  CAS  Google Scholar 

  • Buttery R, Monaghan H, Salter DM, Sethi T (2004) Galectin-3: differential expression between small-cell and non-small-cell lung cancer. Histopathology 44:339–344

    Article  PubMed  CAS  Google Scholar 

  • Castronovo V, Campo E, van den Brule FA, Claysmith AP, Cioce V, Liu FT, Fernandez PL, Sobel ME (1992) Inverse modulation of steady-state messenger RNA levels of two non-integrin laminin-binding proteins in human colon carcinoma. J Nat Cancer Inst 84:1161–1169

    Google Scholar 

  • Chen HY, Liu FT, Yang RY (2005) Roles of galectin-3 in immune responses. Arch Immunol Ther Exp (Warsz) 53:497–504

    CAS  Google Scholar 

  • Chen HY, Sharma BB, Yu L, Zuberi R, Weng IC, Kawakami Y, Kawakami T, Hsu DK, Liu FT (2006) Role of galectin-3 in mast cell functions: galectin-3-deficient mast cells exhibit impaired mediator release and defective JNK expression. J Immunol 177:4991–4997

    PubMed  CAS  Google Scholar 

  • Danguy A, Camby I, Kiss R (2002) Galectins and cancer. Biochim Biophys Acta 1572:285–293

    PubMed  CAS  Google Scholar 

  • Daya-Makin M, Sanghera JS, Mogentale TL, Lipp M, Parchomchuk J, Hogg JC, Pelech SL (1994) Activation of a tumor-associated protein kinase (p40TAK) and casein kinase 2 in human squamous cell carcinomas and adenocarcinomas of the lung. Cancer Res 54:2262–2268

    PubMed  CAS  Google Scholar 

  • Dungworth DL, Rittinghausen S, Schwartz L, Harkema JR, Hayashi Y, Kittel B, Lewis D, Miller RA, Mohr U, Morgan KT, Rehm S, Slayter MV (2001). Respiratory system and mesothelium. In: Mohr U (ed) International classification of rodent tumors-the mouse. Springer, Berlin/WHO-International Agency for Research on Cancer, pp 87–137

  • Fukumoto K, Yano Y, Virgona N, Hagiwara H, Sato H, Senba H, Suzuki K, Asano R, Yamada K, Yano T (2005) Peroxisome proliferator-activated receptor delta as a molecular target to regulate lung cancer cell growth. FEBS Lett 579:3829–3836

    Article  PubMed  CAS  Google Scholar 

  • Greenlee RT, Hill-Harmon MB, Murray T, Thun M (2001) Cancer statistics, 2001. CA Cancer J Clin 51:15–36

    Article  PubMed  CAS  Google Scholar 

  • Gururajan M, Jennings CD, Bondada S (2006) Cutting edge: constitutive B cell receptor signaling is critical for basal growth of B lymphoma. J Immunol 176:7789

    CAS  Google Scholar 

  • Hittelet H, Legendre N, Nagy Y, Bronckart Y, Pector JC, Salmon I, Yeaton P, Gabius HJ, Kiss R, Camby I (2003) Upregulation of galectins-1 and -3 in human colon cancer and their role in regulating cell migration. Int J Cancer 103:370–379

    Article  PubMed  CAS  Google Scholar 

  • Honjo Y, Inohara H, Akahani S, Yoshii T, Takenaka Y, Yoshida J, Hattori K, Tomiyama Y, Raz A, Kubo T (2000) Expression of cytoplasmic galectin-3 as a prognostic marker in tongue carcinoma. Clin Cancer Res 6:4635–4640

    PubMed  CAS  Google Scholar 

  • Hsu DK, Yang RY, Pan Z, Yu L, Salomon DR, Fung-Leung WP, Liu FT (2000) Targeted disruption of the galectin-3 gene results in attenuated peritoneal inflammatory responses. Am J Pathol 156:1073–1083

    PubMed  CAS  Google Scholar 

  • Hughes RC (2001) Galectins as modulators of cell adhesion. Biochimie 83:667–676

    Article  PubMed  CAS  Google Scholar 

  • Kawai T, Hiroi S, Torikata C (1997) Expression in lung carcinomas of platelet-derived growth factor and its receptors. Lab Invest 77:431–436

    PubMed  CAS  Google Scholar 

  • Kim K, Mayer EP, Nachtigal M (2003a) Galectin-3 expression in macrophages is signaled by Ras/MAP kinase pathway and up-regulated by modified lipoproteins. Biochim Biophys Acta 641:13–23

    Google Scholar 

  • Kim SJ, Uehara H, Karashima T, Shepherd DL, Killion JJ, Fidler IJ (2003b) Blockade of epidermal growth factor receptor signaling in tumor cells and tumor-associated endothelial cells for therapy of androgen-independent human prostate cancer growing in the bone of nude mice. Clin Cancer Res 9:1200–1210

    PubMed  CAS  Google Scholar 

  • Kim SJ, Uehara H, Yazici S, Langley RR, He J, Tsan R, Fan D, Killion JJ, Fidler IJ (2004) Simultaneous blockade of platelet-derived growth factor-receptor and epidermal growth factor-receptor signaling and systemic administration of paclitaxel as therapy for human prostate cancer metastasis in bone of nude mice. Cancer Res 64:4201–4208

    Article  PubMed  CAS  Google Scholar 

  • Landesman-Bollag E, Romieu-Mourez R, Song DH, Sonenshein GE, Cardiff RD, Seldin DC (2001) Protein kinase CK2 in mammary gland tumorigenesis. Oncogene 20:3247–3257

    Article  PubMed  CAS  Google Scholar 

  • Liu FT (2000) Galectins: a new family of regulators of inflammation. Clin Immunol 97:79–88

    Article  PubMed  CAS  Google Scholar 

  • Liu FT (2005) Regulatory roles of galectins in the immune response. Int Arch Allergy Immunol 136:385–400

    Article  PubMed  CAS  Google Scholar 

  • Liu FT, Patterson RJ, Whang JL (2002) Intracellular functions of galectins. Biochim Biophys Acta 1572:263–273

    PubMed  CAS  Google Scholar 

  • Lotz MM, Andrews CW, Korzelius CA, Lee EC, Steele GD Jr, Clarke A, Mercurio AM (1993) Decreased expression of Mac-2 (carbohydrate binding protein 35) and loss of its nuclear localization are associated with the neoplastic progression of colon carcinoma. Proc Nat Acad Sci 90:3466–3470

    Article  PubMed  CAS  Google Scholar 

  • Mathieu A, Saal I, Vuckovic A, Ransy V, Vereerstraten P, Kaltner H, Gabius HJ, Kiss R, Decaestecker C, Salmon I, Remmelink M (2005) Nuclear galectin-3 expression is an independent predictive factor of recurrence for adenocarcinoma and squamous cell carcinoma of the lung. Mod Pathol 18:1264–1271

    Article  PubMed  CAS  Google Scholar 

  • McPherson JD, Marra M, Hillier L, Waterston RH, Chinwalla A, Wallis J, Sekhon M, Wylie K, Mardis ER, Wilson RK, Fulton R, Kucaba TA, Wagner-McPherson C, Barbazuk WB, Gregory SG, Humphray SJ, French L, Evans RS, Bethel G, Whittaker A, Holden JL, McCann OT, Dunham A, Soderlund C, Scott CE, Bentley DR, Schuler G, Chen HC, Jang W, Green ED, Idol JR, Maduro VV, Montgomery KT, Lee E, Miller A, Emerling S, Kucherlapati, Gibbs R, Scherer S, Gorrell JH, Sodergren E, Clerc-Blankenburg K, Tabor P, Naylor S, Garcia D, de Jong PJ, Catanese JJ, Nowak N, Osoegawa K, Qin S, Rowen L, Madan A, Dors M, Hood L, Trask B, Friedman C, Massa H, Cheung VG, Kirsch IR, Reid T, Yonescu R, Weissenbach J, Bruls T, Heilig R, Branscomb E, Olsen A, Doggett N, Cheng JF, Hawkins T, Myers RM, Shang J, Ramirez L, Schmutz J, Velasquez O, Dixon K, Stone NE, Cox DR, Haussler D, Kent WJ, Furey T, Rogic S, Kennedy S, Jones S, Rosenthal A, Wen G, Schilhabel M, Gloeckner G, Nyakatura G, Siebert R, Schlegelberger B, Korenberg J, Chen XN, Fujiyama A, Hattori M, Toyoda A, Yada T, Park HS, Sakaki Y, Shimizu N, Asakawa S, Kawasaki K, Sasaki T, Shintani A, Shimizu A, Shibuya K, Kudoh J, Minoshima S, Ramser J, Seranski P, Hoff C, Poustka A, Reinhardt R, Lehrach H, International Human Genome Mapping Consortium (2001) A physical map of the human genome. Nature 409:934–941

    Article  PubMed  CAS  Google Scholar 

  • Miglietta A, Bozzo F, Bocca C, Trombetta A, Belotti S, Canuto RA (2006) Conjugated linoleic acid induces apoptosis in MDA-MB-231 breast cancer cells through ERK/MAPK signalling and mitochondrial pathway. Cancer Lett 234:149–157

    Article  PubMed  CAS  Google Scholar 

  • Mori M, Tezuka F, Chiba R, Funae Y, Watanabe M, Nukiwa T, Takahashi T (1996) Atypical adenomatous hyperplasia and adenocarcinoma of the human lung: their heterology in form and analogy in immunohistochemical characteristics. Cancer 77:665–674

    Article  PubMed  CAS  Google Scholar 

  • Nakamura M, Inufusa H, Adachi T, Aga M, Kurimoto M, Nakatani Y, Wakano T, Nakajima A, Hida JI, Miyake M, Shindo K, Yasutomi M (1999) Involvement of galectin-3 expression in colorectal cancer progression and metastasis. Int J Oncol 15:143–148

    PubMed  CAS  Google Scholar 

  • Nangia-Makker P, Hogan V, Honjo Y, Baccarini S, Tait L, Bresalier R, Raz A (2002) Inhibition of human cancer cell growth and metastasis in nude mice by oral intake of modified citrus pectin. J Natl Cancer Inst 94:1854–1862

    PubMed  CAS  Google Scholar 

  • Nettesheim P (1991) Cells of origin of primary neoplasm in mice. Exp Lung Res 17:215–217

    Article  PubMed  CAS  Google Scholar 

  • Nomoto K, Tsuneyama K, Abdel Aziz HO, Takahashi H, Murai Y, Cui ZG, Fujimoto M, Kato I, Hiraga K, Hsu DK, Liu FT, Takano Y (2006) Disrupted galectin-3 causes non-alcoholic fatty liver disease in male mice. J Pathol 210:469–477

    Article  PubMed  CAS  Google Scholar 

  • Normanno N, De Luca A, Bianco C, Strizzi L, Mancino M, Maiello MR, Carotenuto A, De Feo G, Caponigro F, Salomon DS (2006) Epidermal growth factor receptor (EGFR) signaling in cancer. Gene 366:2–16

    Article  PubMed  CAS  Google Scholar 

  • O-charoenrat P, Rusch V, Talbot SG, Sarkaria I, Viale A, Socci N, Ngai I, Rao P, Singh B (2004) Casein kinase II alpha subunit and C1-inhibitor are independent predictors of outcome in patients with squamous cell carcinoma of the lung. Clin Cancer Res 10:5792–5803

    Article  PubMed  CAS  Google Scholar 

  • Paterlini-Brechot P, Saigo K, Murakami Y, Chami M, Gozuacik D, Mugnier C, Lagorce D, Brechot C (2003) Hepatitis B virus-related insertional mutagenesis occurs frequently in human liver cancers and recurrently targets human telomerase gene. Oncogene 22:3911–3916

    Article  PubMed  CAS  Google Scholar 

  • Perillo NL, Marcus ME, Baum LG (1998) Galectins: versatile modulators of cell adhesion, cell proliferation, and cell death. J Mol Med 76:402–412

    Article  PubMed  CAS  Google Scholar 

  • Piantelli M, Iacobelli S, Almadori G, Iezzi M, Tinari N, Natoli C, Cadoni G, Lauriola L, Ranelletti FO (2002) Lack of expression of galectin-3 is associated with a poor outcome in node-negative patients with laryngeal squamous-cell carcinoma. J Clin Oncol 20:3850–3856

    Article  PubMed  CAS  Google Scholar 

  • Pugliese G, Pricci F, Iacobini C, Leto G, Amadio L, Barsotti P, Frigeri L, Hsu DK, Vlassara H, Liu FT, Di Mario U (2001) Accelerated diabetic glomerulopathy in galectin-3/AGE receptor 3 knockout mice. FASEB J 15:2471–2479

    Article  PubMed  CAS  Google Scholar 

  • Rehm S, Word JM, Sass B (1994) Tumours of the lungs. In: Turusov VS, Mohrs U (eds) Pathology of tumours in laboratory animals. Tumours of the mouse, vol. 2. IARC, Lyon, pp 325–356

    Google Scholar 

  • Sano H, Hsu DK, Apgar JR, Yu L, Sharma BB, Kuwabara I, Izui S, Liu FT (2003) Critical role of galectin-3 in phagocytosis by macrophages. J Clin Invest 112:389–397

    PubMed  CAS  Google Scholar 

  • Shimamura T, Sakamoto M, Ino Y, Shimada K, Kosuge T, Sato Y, Tanaka K, Sekihara H, Hirohashi S (2002) Clinicopathological significance of galectin-3 expression in ductal adenocarcinoma of the pancreas. Clin Cancer Res 8:2570–2575

    PubMed  CAS  Google Scholar 

  • Silva-Monteiro E, Reis Lorenzato L, Kenji Nihei O, Junqueira M, Rabinovich GA, Hsu DK, Liu FT, Savino W, Chammas R, Villa-Verde DM (2007) Altered expression of galectin-3 induces cortical thymocyte depletion and premature exit of immature thymocytes during trypanosoma cruzi infection. Am J Pathol 170:546–556

    Article  PubMed  CAS  Google Scholar 

  • Stabile LP, Siegfried JM (2004) Estrogen receptor pathways in lung cancer. Curr Oncol Rep 6:259–267

    Article  PubMed  Google Scholar 

  • Stitt AW, McGoldrick C, Rice-McCaldin A, McCance DR, Glenn JV, Hsu DK, Liu FT, Thorpe SR, Gardiner TA (2005) Impaired retinal angiogenesis in diabetes: role of advanced glycation end products and galectin-3. Diabetes 54:785–794

    Article  PubMed  CAS  Google Scholar 

  • Tejada ML, Yu L, Dong J, Jung K, Meng G, Peale FV, Frantz GD, Hall L, Liang X, Gerber HP, Ferrara N (2006) Tumor-driven paracrine platelet-derived growth factor receptor alpha signaling is a key determinant of stromal cell recruitment in a model of human lung carcinoma. Clin Cancer Res 12:2676–2688

    Article  PubMed  CAS  Google Scholar 

  • Warmka JK, Mauro LJ, Wattenberg EV (2004) Mitogen-activated protein kinase phosphatase-3 is a tumor promoter target in initiated cells that express oncogenic Ras. J Biol Chem 279:33085–33092

    Article  PubMed  CAS  Google Scholar 

  • Xi S, Dyer KF, Kimak M, Zhang Q, Gooding WE, Chaillet JR, Chai RL, Ferrell RE, Zamboni B, Hunt J, Grandis JR (2006) Decreased STAT1 expression by promoter methylation in squamous cell carcinogenesis. Natl Cancer Inst 98:181–189

    Article  CAS  Google Scholar 

  • Yoshimura A, Gemma A, Hosoya Y, Komaki E, Hosomi Y, Okano T, Takenaka K, Matuda K, Seike M, Uematsu K, Hibino S, Shibuya M, Yamada T, Hirohashi S, Kudoh S (2003) Increased expression of the LGALS3 (galectin 3) gene in human non-small-cell lung cancer. Genes Chromosomes Cancer 37:159–164

    Article  PubMed  CAS  Google Scholar 

  • Yuen T, Wurmbach E, Pfeffer RL, Ebersole BJ, Sealfon SC (2002) Accuracy and calibration of commercial oligonucleotide and custom cDNA microarrays. Nucleic Acids Res 30:e48

    Article  PubMed  Google Scholar 

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Acknowledgments

We appreciate Tokimasa Kumada, Hideki Hatta, and Kanako Yasuyoshi for their expert technical assistance. This work was supported by Fund of Smoking Research Society and Shenyang Outstanding Scholar Foundation.

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Authors and Affiliations

  1. Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, Toyama, Japan

    Hekmat Osman Abdel-Aziz, Yoshihiro Murai, Kazuhiro Nomoto, Hiroyuki Takahashi, Koichi Tsuneyama & Yasuo Takano

  2. Division of Molecular Genetics Research, Life Science Research Center, University of Toyama, Toyama, Japan

    Ichiro Takasaki & Yoshiaki Tabuchi

  3. Department of Biochemistry and Molecular Biology, College of Basic Medicine, China Medical University, Shenyang, China

    Hua-chuan Zheng

  4. Department of Biochemistry, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, Toyama, Japan

    Ichiro Kato & Koichi Hiraga

  5. Department of Dermatology, University of California, Davis, School of Medicine, Sacramento, CA, USA

    Daniel K. Hsu & Fu-tong Liu

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  1. Hekmat Osman Abdel-Aziz
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  2. Yoshihiro Murai
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Correspondence to Yoshihiro Murai.

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Abdel-Aziz, H.O., Murai, Y., Takasaki, I. et al. Targeted disruption of the galectin-3 gene results in decreased susceptibility to NNK-induced lung tumorigenesis: an oligonucleotide microarray study. J Cancer Res Clin Oncol 134, 777–788 (2008). https://doi.org/10.1007/s00432-007-0345-3

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