Serglycin Is Involved in TGF-β Induced Epithelial-Mesenchymal Transition and Is Highly Expressed by Immune Cells in Breast Cancer Tissue

Overview

Journal Front Oncol

Specialty Oncology

Date 2022 May 2

PMID 35494005

Authors

Marta Tellez-Gabriel

Xavier Tekpli

Trine M Reine

Beate Hegge

Stephanie R Nielsen

Meng Chen

Line Moi

Lisa Svartdal Normann

Lill-Tove R Busund

George A Calin

Gunhild M Maelandsmo

Maria Perander

Achilleas D Theocharis

Svein O Kolset

Erik Knutsen

Affiliations

Soon will be listed here.

Abstract

Serglycin is a proteoglycan highly expressed by immune cells, in which its functions are linked to storage, secretion, transport, and protection of chemokines, proteases, histamine, growth factors, and other bioactive molecules. In recent years, it has been demonstrated that serglycin is also expressed by several other cell types, such as endothelial cells, muscle cells, and multiple types of cancer cells. Here, we show that serglycin expression is upregulated in transforming growth factor beta (TGF-β) induced epithelial-mesenchymal transition (EMT). Functional studies provide evidence that serglycin plays an important role in the regulation of the transition between the epithelial and mesenchymal phenotypes, and it is a significant EMT marker gene. We further find that serglycin is more expressed by breast cancer cell lines with a mesenchymal phenotype as well as the basal-like subtype of breast cancers. By examining immune staining and single cell sequencing data of breast cancer tissue, we show that serglycin is highly expressed by infiltrating immune cells in breast tumor tissue.

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References

Chod J, Zavadova E, Halaska M, Strnad P, Fucikova T, Rob L . Preoperative transforming growth factor-beta 1 (TGF-beta 1) plasma levels in operable breast cancer patients. Eur J Gynaecol Oncol. 2009; 29(6):613-6. View

Mermel C, Schumacher S, Hill B, Meyerson M, Beroukhim R, Getz G . GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol. 2011; 12(4):R41. PMC: 3218867. DOI: 10.1186/gb-2011-12-4-r41. View

Theocharis A, Manou D, Karamanos N . The extracellular matrix as a multitasking player in disease. FEBS J. 2019; 286(15):2830-2869. DOI: 10.1111/febs.14818. View

Zhang Z, Deng Y, Zheng G, Jia X, Xiong Y, Luo K . SRGN-TGFβ2 regulatory loop confers invasion and metastasis in triple-negative breast cancer. Oncogenesis. 2017; 6(7):e360. PMC: 5541705. DOI: 10.1038/oncsis.2017.53. View

Shinde A, Hardy S, Kim D, Akhand S, Jolly M, Wang W . Spleen Tyrosine Kinase-Mediated Autophagy Is Required for Epithelial-Mesenchymal Plasticity and Metastasis in Breast Cancer. Cancer Res. 2019; 79(8):1831-1843. PMC: 6467765. DOI: 10.1158/0008-5472.CAN-18-2636. View

Guo J, Hsu H, Tyan S, Li F, Shew J, Lee W . Serglycin in tumor microenvironment promotes non-small cell lung cancer aggressiveness in a CD44-dependent manner. Oncogene. 2016; 36(17):2457-2471. PMC: 5415946. DOI: 10.1038/onc.2016.404. View

Ghandi M, Huang F, Jane-Valbuena J, Kryukov G, Lo C, McDonald 3rd E . Next-generation characterization of the Cancer Cell Line Encyclopedia. Nature. 2019; 569(7757):503-508. PMC: 6697103. DOI: 10.1038/s41586-019-1186-3. View

Watanabe K, Panchy N, Noguchi S, Suzuki H, Hong T . Combinatorial perturbation analysis reveals divergent regulations of mesenchymal genes during epithelial-to-mesenchymal transition. NPJ Syst Biol Appl. 2019; 5:21. PMC: 6570767. DOI: 10.1038/s41540-019-0097-0. View

Anders S, Pyl P, Huber W . HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics. 2014; 31(2):166-9. PMC: 4287950. DOI: 10.1093/bioinformatics/btu638. View

10.

Rosenlund I, Calin G, Dragomir M, Knutsen E . CRISPR/Cas9 to Silence Long Non-Coding RNAs. Methods Mol Biol. 2021; 2348:175-187. DOI: 10.1007/978-1-0716-1581-2_12. View

11.

Bertucci F, Finetti P, Cervera N, Esterni B, Hermitte F, Viens P . How basal are triple-negative breast cancers?. Int J Cancer. 2008; 123(1):236-40. DOI: 10.1002/ijc.23518. View

12.

Guo J, Chiu C, Wang M, Li F, Chen J . Proteoglycan serglycin promotes non-small cell lung cancer cell migration through the interaction of its glycosaminoglycans with CD44. J Biomed Sci. 2020; 27(1):2. PMC: 6939340. DOI: 10.1186/s12929-019-0600-3. View

13.

Du Q, Yuan Z, Huang X, Huang Y, Zhang J, Li R . miR-26b-5p suppresses chemoresistance in breast cancer by targeting serglycin. Anticancer Drugs. 2021; 33(3):308-319. PMC: 8812413. DOI: 10.1097/CAD.0000000000001268. View

14.

Ramadoss S, Chen X, Wang C . Histone demethylase KDM6B promotes epithelial-mesenchymal transition. J Biol Chem. 2012; 287(53):44508-17. PMC: 3531764. DOI: 10.1074/jbc.M112.424903. View

15.

Yang S, Burch M, Tannock L, Evanko S, Osman N, Little P . Transforming growth factor-β regulation of proteoglycan synthesis in vascular smooth muscle: contribution to lipid binding and accelerated atherosclerosis in diabetes. J Diabetes. 2010; 2(4):233-42. DOI: 10.1111/j.1753-0407.2010.00089.x. View

16.

Imamura T, Hikita A, Inoue Y . The roles of TGF-β signaling in carcinogenesis and breast cancer metastasis. Breast Cancer. 2011; 19(2):118-24. DOI: 10.1007/s12282-011-0321-2. View

17.

Lv Z, Kong B, Li J, Qu H, Wang X, Cao W . Transforming growth factor-β 1 enhances the invasiveness of breast cancer cells by inducing a Smad2-dependent epithelial-to-mesenchymal transition. Oncol Rep. 2012; 29(1):219-25. DOI: 10.3892/or.2012.2111. View

18.

Sarrio D, Rodriguez-Pinilla S, Hardisson D, Cano A, Moreno-Bueno G, Palacios J . Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype. Cancer Res. 2008; 68(4):989-97. DOI: 10.1158/0008-5472.CAN-07-2017. View

19.

Xia L, Huang W, Tian D, Zhang L, Qi X, Chen Z . Forkhead box Q1 promotes hepatocellular carcinoma metastasis by transactivating ZEB2 and VersicanV1 expression. Hepatology. 2013; 59(3):958-73. DOI: 10.1002/hep.26735. View

20.

Roy A, Attarha S, Weishaupt H, Edqvist P, Swartling F, Bergqvist M . Serglycin as a potential biomarker for glioma: association of serglycin expression, extent of mast cell recruitment and glioblastoma progression. Oncotarget. 2017; 8(15):24815-24827. PMC: 5421891. DOI: 10.18632/oncotarget.15820. View