Overexpression of Galectin-3 Enhances Migration of Colon Cancer Cells Related to Activation of the K-Ras-Raf-Erk1/2 Pathway

Overview

Journal J Gastroenterol

Specialty Gastroenterology

Date 2012 Sep 28

PMID 23015305

Citations 27

Authors

Keng-Liang Wu

Eng-Yen Huang

En-Wei Jhu

Ya-Hui Huang

Wen-Hong Su

Pei-Chin Chuang

Kuender D Yang

Affiliations

Soon will be listed here.

Abstract

Background: Galectin-3 has been independently correlated with malignant behavior in human colon cancer. The involvement of galectin-3 in the invasiveness of colon cancer cells remains to be determined. We investigated whether galectin-3 was involved in the colon cancer cell migration mediated by certain kinase pathways.

Methods: We studied 2 colon cancer cell lines (DLD-1 and Caco2) and clinical samples. Immunostaining and Western blotting were used to analyze the expression of galectin-3 in vitro and in the clinical samples. Short hairpin RNA and overexpression of galectin-3 were used to study loss- and gain-of-function in a wound-healing assay and a Transwell migration assay, and Western blotting was used to study the Ras-Raf signaling pathway.

Results: Galectin-3 was expressed at lower levels in DLD-1 than in Caco2 cells. The lower galectin-3 level in DLD-1 cells was associated with decreased cell migration, in comparison with that of Caco2 cells. Overexpression of galectin-3 increased the migration rate of DLD-1, while knockdown of galectin-3 decreased the migration. Overexpression of galectin-3 was correlated with increased lamellipodia formation and distal lung localization in a mouse model. The galectin-3 enhancement of DLD-1 cell migration was mediated by K-Ras, Raf and Erk1/2 pathway activation, but not the H-Ras, p38, or JNK activation.

Conclusions: Galectin-3 plays an important role in regulating colon cancer cell migration and potential distal localization. The galectin-3 enhancement of cell migration is mediated through the K-Ras-Raf-Erk1/2 pathway. Specific targeting of the K-Ras-Raf-Erk1/2 pathway may be useful for treating colon cancers associated with increased galectin-3 expression.

Citing Articles

Galectins in epithelial-mesenchymal transition: roles and mechanisms contributing to tissue repair, fibrosis and cancer metastasis.

Perez-Moreno E, Oyanadel C, de la Pena A, Hernandez R, Perez-Molina F, Metz C Biol Res. 2024; 57(1):14.

PMID: 38570874 PMC: 10993482. DOI: 10.1186/s40659-024-00490-5.

Selectively Modified Lactose and -Acetyllactosamine Analogs at Three Key Positions to Afford Effective Galectin-3 Ligands.

Abdullayev S, Kadav P, Bandyopadhyay P, Medrano F, Rabinovich G, Dam T Int J Mol Sci. 2023; 24(4).

PMID: 36835132 PMC: 9962200. DOI: 10.3390/ijms24043718.

Targeting galectin-driven regulatory circuits in cancer and fibrosis.

Marino K, Cagnoni A, Croci D, Rabinovich G Nat Rev Drug Discov. 2023; 22(4):295-316.

PMID: 36759557 DOI: 10.1038/s41573-023-00636-2.

Highlights on the Role of Galectin-3 in Colorectal Cancer and the Preventive/Therapeutic Potential of Food-Derived Inhibitors.

Aureli A, Del Corno M, Marziani B, Gessani S, Conti L Cancers (Basel). 2023; 15(1).

PMID: 36612048 PMC: 9817985. DOI: 10.3390/cancers15010052.

Decoding Strategies to Evade Immunoregulators Galectin-1, -3, and -9 and Their Ligands as Novel Therapeutics in Cancer Immunotherapy.

Lau L, Mohammed N, Dimitroff C Int J Mol Sci. 2022; 23(24).

PMID: 36555198 PMC: 9778980. DOI: 10.3390/ijms232415554.

References

Hsu D, Chernyavsky A, Chen H, Yu L, Grando S, Liu F . Endogenous galectin-3 is localized in membrane lipid rafts and regulates migration of dendritic cells. J Invest Dermatol. 2008; 129(3):573-83. PMC: 2645233. DOI: 10.1038/jid.2008.276. View

Hittelet A, Legendre H, Nagy N, Bronckart Y, Pector J, Salmon I . Upregulation of galectins-1 and -3 in human colon cancer and their role in regulating cell migration. Int J Cancer. 2002; 103(3):370-9. DOI: 10.1002/ijc.10843. View

Kim S, Takahashi H, Lin W, Descargues P, Grivennikov S, Kim Y . Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature. 2009; 457(7225):102-6. PMC: 2746432. DOI: 10.1038/nature07623. View

Inder K, Lau C, Loo D, Chaudhary N, Goodall A, Martin S . Nucleophosmin and nucleolin regulate K-Ras plasma membrane interactions and MAPK signal transduction. J Biol Chem. 2009; 284(41):28410-28419. PMC: 2788890. DOI: 10.1074/jbc.M109.001537. View

Su W, Chen H, Jen C . Polymorphonuclear leukocyte transverse migration induces rapid alterations in endothelial focal contacts. J Leukoc Biol. 2007; 82(3):542-50. DOI: 10.1189/jlb.0207080. View

Saravanan C, Liu F, Gipson I, Panjwani N . Galectin-3 promotes lamellipodia formation in epithelial cells by interacting with complex N-glycans on alpha3beta1 integrin. J Cell Sci. 2009; 122(Pt 20):3684-93. PMC: 2758802. DOI: 10.1242/jcs.045674. View

Dreissigacker U, Mueller M, Unger M, Siegert P, Genze F, Gierschik P . Oncogenic K-Ras down-regulates Rac1 and RhoA activity and enhances migration and invasion of pancreatic carcinoma cells through activation of p38. Cell Signal. 2005; 18(8):1156-68. DOI: 10.1016/j.cellsig.2005.09.004. View

Endo K, Kohnoe S, Tsujita E, Watanabe A, Nakashima H, Baba H . Galectin-3 expression is a potent prognostic marker in colorectal cancer. Anticancer Res. 2005; 25(4):3117-21. View

Schoeppner H, Raz A, Ho S, Bresalier R . Expression of an endogenous galactose-binding lectin correlates with neoplastic progression in the colon. Cancer. 1995; 75(12):2818-26. DOI: 10.1002/1097-0142(19950615)75:12<2818::aid-cncr2820751206>3.0.co;2-#. View

10.

Sanjuan X, Fernandez P, Castells A, Castronovo V, Van den Brule F, Liu F . Differential expression of galectin 3 and galectin 1 in colorectal cancer progression. Gastroenterology. 1997; 113(6):1906-15. DOI: 10.1016/s0016-5085(97)70010-6. View

11.

Dudas S, Yunker C, Sternberg L, Byrd J, Bresalier R . Expression of human intestinal mucin is modulated by the beta-galactoside binding protein galectin-3 in colon cancer. Gastroenterology. 2002; 123(3):817-26. DOI: 10.1053/gast.2002.35395. View

12.

van den Brule F, Califice S, Garnier F, Fernandez P, Berchuck A, Castronovo V . Galectin-1 accumulation in the ovary carcinoma peritumoral stroma is induced by ovary carcinoma cells and affects both cancer cell proliferation and adhesion to laminin-1 and fibronectin. Lab Invest. 2003; 83(3):377-86. DOI: 10.1097/01.lab.0000059949.01480.40. View

13.

Raz A, Lotan R . Endogenous galactoside-binding lectins: a new class of functional tumor cell surface molecules related to metastasis. Cancer Metastasis Rev. 1987; 6(3):433-52. DOI: 10.1007/BF00144274. View

14.

Shalom-Feuerstein R, Plowman S, Rotblat B, Ariotti N, Tian T, Hancock J . K-ras nanoclustering is subverted by overexpression of the scaffold protein galectin-3. Cancer Res. 2008; 68(16):6608-16. PMC: 2587079. DOI: 10.1158/0008-5472.CAN-08-1117. View

15.

Nagy N, Legendre H, Engels O, Andre S, Kaltner H, Wasano K . Refined prognostic evaluation in colon carcinoma using immunohistochemical galectin fingerprinting. Cancer. 2003; 97(8):1849-58. DOI: 10.1002/cncr.11268. View

16.

Wang Y, Nangia-Makker P, Tait L, Balan V, Hogan V, Pienta K . Regulation of prostate cancer progression by galectin-3. Am J Pathol. 2009; 174(4):1515-23. PMC: 2671381. DOI: 10.2353/ajpath.2009.080816. View

17.

Bresalier R, Mazurek N, Sternberg L, Byrd J, Yunker C, Nangia-Makker P . Metastasis of human colon cancer is altered by modifying expression of the beta-galactoside-binding protein galectin 3. Gastroenterology. 1998; 115(2):287-96. DOI: 10.1016/s0016-5085(98)70195-7. View

18.

Hoogwater F, Nijkamp M, Smakman N, Steller E, Emmink B, Westendorp B . Oncogenic K-Ras turns death receptors into metastasis-promoting receptors in human and mouse colorectal cancer cells. Gastroenterology. 2010; 138(7):2357-67. DOI: 10.1053/j.gastro.2010.02.046. View

19.

Ellerhorst J, Nguyen T, Cooper D, Lotan D, Lotan R . Differential expression of endogenous galectin-1 and galectin-3 in human prostate cancer cell lines and effects of overexpressing galectin-1 on cell phenotype. Int J Oncol. 1999; 14(2):217-24. View

20.

Glinsky V, Glinsky G, Glinskii O, Huxley V, Turk J, Mossine V . Intravascular metastatic cancer cell homotypic aggregation at the sites of primary attachment to the endothelium. Cancer Res. 2003; 63(13):3805-11. View