Galectin-3 Promotes CXCR2 to Augment the Stem-like Property of Renal Cell Carcinoma

Overview

Journal J Cell Mol Med

Specialties Cell Biology
Molecular Biology

Date 2018 Sep 25

PMID 30246456

Citations 18

Authors

Chang-Shuo Huang

Shye-Jye Tang

Mei-Hsuan Lee

Chien-Chih Chang Wang

Guang-Huan Sun

Kuang-Hui Sun

Affiliations

Soon will be listed here.

Abstract

Although targeted therapy is usually the first-line treatment for advanced renal cell carcinoma (RCC), some patients can experience drug resistance. Cancer stem cells are tumour-initiating cells that play a vital role in drug resistance, metastasis and cancer relapse, while galectins (Gal) participate in tumour progression and drug resistance. However, the exact role of galectins in RCC stemness is yet unknown. In this study, we grew a subpopulation of RCC cells as tumour spheres with higher levels of stemness-related genes, such as Oct4, Sox2 and Nanog. Among the Gal family, Gal-3 in particular was highly expressed in RCC tumour spheres. To further investigate Gal-3's role in the stemness of RCC, lentivirus-mediated knockdown and overexpression of Gal-3 in RCC cells were used to examine both in vitro and in vivo tumorigenicity. We further assessed Gal-3 expression in RCC tissue microarray using immunohistochemistry. Upon suppressing Gal-3 in parental RCC cells, invasion, colony formation, sphere-forming ability, drug resistance and stemness-related gene expression were all significantly decreased. Furthermore, CXCL6, CXCL7 and CXCR2 were down-regulated in Gal-3-knockdown tumour spheres, while CXCR2 overexpression in Gal-3-knockdown RCC restored the ability of sphere formation. Gal-3 overexpression in RCC promoted both in vitro and in vivo tumorigenicity, and its expression was correlated with CXCR2 expression and tumour progression in clinical tissues. RCC patients with higher co-expressions of Gal-3 and CXCR2 demonstrated a worse survival rate. These results indicate that highly expressed Gal-3 may up-regulate CXCR2 to augment RCC stemness. Gal-3 may be a prognostic and innovative target of combined therapy for treating RCC.

Citing Articles

Cancer stem cells: advances in knowledge and implications for cancer therapy.

Chu X, Tian W, Ning J, Xiao G, Zhou Y, Wang Z Signal Transduct Target Ther. 2024; 9(1):170.

PMID: 38965243 PMC: 11224386. DOI: 10.1038/s41392-024-01851-y.

Galectin-3: action and clinical utility in chronic kidney disease.

Syn G, Lee Y, Lim Z, Chan G Int Urol Nephrol. 2024; 56(11):3535-3543.

PMID: 38861106 DOI: 10.1007/s11255-024-04107-4.

Targeting Galectin 3 illuminates its contributions to the pathology of uterine serous carcinoma.

Matoba Y, Zarrella D, Pooladanda V, Azimi Mohammadabadi M, Kim E, Kumar S Br J Cancer. 2024; 130(9):1463-1476.

PMID: 38438589 PMC: 11058234. DOI: 10.1038/s41416-024-02621-x.

Genetic and Epigenetic Characteristics in Isolated Pancreatic Metastases of Clear-Cell Renal Cell Carcinoma.

Sellner F, Comperat E, Klimpfinger M Int J Mol Sci. 2023; 24(22).

PMID: 38003482 PMC: 10671160. DOI: 10.3390/ijms242216292.

Galectin functions in cancer-associated inflammation and thrombosis.

Kruk L, Braun A, Cosset E, Gudermann T, Mammadova-Bach E Front Cardiovasc Med. 2023; 10:1052959.

PMID: 36873388 PMC: 9981828. DOI: 10.3389/fcvm.2023.1052959.

References

Wu K, Cui L, Yang Y, Zhao J, Zhu D, Liu D . Silencing of CXCR2 and CXCR7 protects against esophageal cancer. Am J Transl Res. 2016; 8(8):3398-408. PMC: 5009392. View

Murphy C, McGurk M, Pettigrew J, Santinelli A, Mazzucchelli R, Johnston P . Nonapical and cytoplasmic expression of interleukin-8, CXCR1, and CXCR2 correlates with cell proliferation and microvessel density in prostate cancer. Clin Cancer Res. 2005; 11(11):4117-27. DOI: 10.1158/1078-0432.CCR-04-1518. View

Fukumori T, Kanayama H, Raz A . The role of galectin-3 in cancer drug resistance. Drug Resist Updat. 2007; 10(3):101-8. PMC: 3626271. DOI: 10.1016/j.drup.2007.04.001. View

Oka N, Nakahara S, Takenaka Y, Fukumori T, Hogan V, Kanayama H . Galectin-3 inhibits tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by activating Akt in human bladder carcinoma cells. Cancer Res. 2005; 65(17):7546-53. DOI: 10.1158/0008-5472.CAN-05-1197. View

Chung L, Tang S, Sun G, Chou T, Yeh T, Yu S . Galectin-1 promotes lung cancer progression and chemoresistance by upregulating p38 MAPK, ERK, and cyclooxygenase-2. Clin Cancer Res. 2012; 18(15):4037-47. DOI: 10.1158/1078-0432.CCR-11-3348. View

Kise K, Kinugasa-Katayama Y, Takakura N . Tumor microenvironment for cancer stem cells. Adv Drug Deliv Rev. 2015; 99(Pt B):197-205. DOI: 10.1016/j.addr.2015.08.005. View

Nangia-Makker P, Honjo Y, Sarvis R, Akahani S, Hogan V, Pienta K . Galectin-3 induces endothelial cell morphogenesis and angiogenesis. Am J Pathol. 2000; 156(3):899-909. PMC: 1876842. DOI: 10.1016/S0002-9440(10)64959-0. View

Fukumori T, Oka N, Takenaka Y, Nangia-Makker P, Elsamman E, Kasai T . Galectin-3 regulates mitochondrial stability and antiapoptotic function in response to anticancer drug in prostate cancer. Cancer Res. 2006; 66(6):3114-9. DOI: 10.1158/0008-5472.CAN-05-3750. View

Acosta J, OLoghlen A, Banito A, Raguz S, Gil J . Control of senescence by CXCR2 and its ligands. Cell Cycle. 2008; 7(19):2956-9. DOI: 10.4161/cc.7.19.6780. View

10.

Newlaczyl A, Yu L . Galectin-3--a jack-of-all-trades in cancer. Cancer Lett. 2011; 313(2):123-8. DOI: 10.1016/j.canlet.2011.09.003. View

11.

Mestas J, Burdick M, Reckamp K, Pantuck A, Figlin R, Strieter R . The role of CXCR2/CXCR2 ligand biological axis in renal cell carcinoma. J Immunol. 2005; 175(8):5351-7. DOI: 10.4049/jimmunol.175.8.5351. View

12.

Yoshii T, Fukumori T, Honjo Y, Inohara H, Kim H, Raz A . Galectin-3 phosphorylation is required for its anti-apoptotic function and cell cycle arrest. J Biol Chem. 2001; 277(9):6852-7. DOI: 10.1074/jbc.M107668200. View

13.

Begley L, Kasina S, Mehra R, Adsule S, Admon A, Lonigro R . CXCL5 promotes prostate cancer progression. Neoplasia. 2008; 10(3):244-54. PMC: 2262133. DOI: 10.1593/neo.07976. View

14.

Steele C, Karim S, Leach J, Bailey P, Upstill-Goddard R, Rishi L . CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma. Cancer Cell. 2016; 29(6):832-845. PMC: 4912354. DOI: 10.1016/j.ccell.2016.04.014. View

15.

Arenberg D, Keane M, DiGiovine B, Kunkel S, Morris S, Xue Y . Epithelial-neutrophil activating peptide (ENA-78) is an important angiogenic factor in non-small cell lung cancer. J Clin Invest. 1998; 102(3):465-72. PMC: 508906. DOI: 10.1172/JCI3145. View

16.

Sakaki M, Fukumori T, Fukawa T, Elsamman E, Shiirevnyamba A, Nakatsuji H . Clinical significance of Galectin-3 in clear cell renal cell carcinoma. J Med Invest. 2010; 57(1-2):152-7. DOI: 10.2152/jmi.57.152. View

17.

Aman A, Piotrowski T . Wnt/beta-catenin and Fgf signaling control collective cell migration by restricting chemokine receptor expression. Dev Cell. 2008; 15(5):749-61. DOI: 10.1016/j.devcel.2008.10.002. View

18.

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

19.

Iurisci I, Tinari N, Natoli C, Angelucci D, Cianchetti E, Iacobelli S . Concentrations of galectin-3 in the sera of normal controls and cancer patients. Clin Cancer Res. 2000; 6(4):1389-93. View

20.

Giuliano S, Guyot M, Grepin R, Pages G . The ELRCXCL chemokines and their receptors CXCR1/CXCR2: A signaling axis and new target for the treatment of renal cell carcinoma. Oncoimmunology. 2014; 3:e28399. PMC: 4063157. DOI: 10.4161/onci.28399. View