Epigenetic Control of Group V Phospholipase A2 Expression in Human Malignant Cells

Overview

Journal Tumour Biol

Publisher Sage Publications

Specialty Oncology

Date 2015 Dec 31

PMID 26715269

Citations 6

Authors

Mario Menschikowski

Albert Hagelgans

Brit Nacke

Carsten Jandeck

Olga A Mareninova

Liana Asatryan

Gabriele Siegert

Affiliations

Soon will be listed here.

Abstract

Secreted phospholipases A2 (sPLA2) are suggested to play an important role in inflammation and tumorigenesis. Different mechanisms of epigenetic regulation are involved in the control of group IIA, III and X sPLA2s expression in cancer cells, but group V sPLA2 (GV-PLA2) in this respect has not been studied. Here, we demonstrate the role of epigenetic mechanisms in regulation of GV-PLA2 expression in different cell lines originating from leukaemia and solid cancers. In blood leukocytes from leukaemic patients, levels of GV-PLA2 transcripts were significantly lower in comparison to those from healthy individuals. Similarly, in DU-145 and PC-3 prostate and CAL-51 and MCF-7 mammary cancer cell lines, levels of GV-PLA2 transcripts were significantly lower in relation to those found in normal epithelial cells of prostate or mammary. By sequencing and methylation-specific high-resolution melting (MS-HRM) analyses of bisulphite-modified DNA, distinct CpG sites in the GV-PLA2 promoter region were identified that were differentially methylated in cancer cells in comparison to normal epithelial and endothelial cells. Spearman rank order analysis revealed a significant negative correlation between the methylation degree and the cellular expression of GV-PLA2 (r = -0.697; p = 0.01). The effects of demethylating agent (5-aza-2'-deoxycytidine) and histone deacetylase inhibitor (trichostatin A) on GV-PLA2 transcription in the analysed cells confirmed the importance of DNA methylation and histone modification in the regulation of the GV-PLA2 gene expression in leukaemic, prostate and mammary cancer cell lines. The exposure of tumour cells to human recombinant GV-PLA2 resulted in a reduced colony forming activity of MCF-7, HepG2 and PC-3 cells, but not of DU-145 cells suggesting a cell-type-dependent effect of GV-PLA2 on cell growth. In conclusion, our results suggest that epigenetic mechanisms such as DNA methylation and histone modification play an important role in downregulation of GV-PLA2 expression in cancer cells.

Citing Articles

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Plasma phospholipase A2 activity may serve as a novel diagnostic biomarker for the diagnosis of breast cancer.

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References

Henderson Jr W, Ye X, Lai Y, Ni Z, Bollinger J, Tien Y . Key role of group v secreted phospholipase A2 in Th2 cytokine and dendritic cell-driven airway hyperresponsiveness and remodeling. PLoS One. 2013; 8(2):e56172. PMC: 3581544. DOI: 10.1371/journal.pone.0056172. View

Munoz N, Desai A, Meliton L, Meliton A, Zhou T, Leff A . Group V phospholipase A(2) increases pulmonary endothelial permeability through direct hydrolysis of the cell membrane. Pulm Circ. 2012; 2(2):182-92. PMC: 3401872. DOI: 10.4103/2045-8932.97604. View

Balestrieri B, Arm J . Group V sPLA2: classical and novel functions. Biochim Biophys Acta. 2006; 1761(11):1280-8. DOI: 10.1016/j.bbalip.2006.07.008. View

Brglez V, Lambeau G, Petan T . Secreted phospholipases A2 in cancer: diverse mechanisms of action. Biochimie. 2014; 107 Pt A:114-23. DOI: 10.1016/j.biochi.2014.09.023. View

Li L, Dahiya R . MethPrimer: designing primers for methylation PCRs. Bioinformatics. 2002; 18(11):1427-31. DOI: 10.1093/bioinformatics/18.11.1427. View

Brglez V, Pucer A, Pungercar J, Lambeau G, Petan T . Secreted phospholipases A₂are differentially expressed and epigenetically silenced in human breast cancer cells. Biochem Biophys Res Commun. 2014; 445(1):230-5. DOI: 10.1016/j.bbrc.2014.01.182. View

Menschikowski M, Hagelgans A, Kostka H, Eisenhofer G, Siegert G . Involvement of epigenetic mechanisms in the regulation of secreted phospholipase A2 expressions in Jurkat leukemia cells. Neoplasia. 2008; 10(11):1195-203. PMC: 2570595. DOI: 10.1593/neo.08640. View

Menschikowski M, Hagelgans A, Gussakovsky E, Kostka H, Paley E, Siegert G . Differential expression of secretory phospholipases A2 in normal and malignant prostate cell lines: regulation by cytokines, cell signaling pathways, and epigenetic mechanisms. Neoplasia. 2008; 10(3):279-86. PMC: 2259456. DOI: 10.1593/neo.07965. View

Menschikowski M, Platzbecker U, Hagelgans A, Vogel M, Thiede C, Schonefeldt C . Aberrant methylation of the M-type phospholipase A(2) receptor gene in leukemic cells. BMC Cancer. 2012; 12:576. PMC: 3561142. DOI: 10.1186/1471-2407-12-576. View

10.

Xue M, Shen K, McKelvey K, Li J, Chan Y, Hatzis V . Endothelial protein C receptor-associated invasiveness of rheumatoid synovial fibroblasts is likely driven by group V secretory phospholipase A2. Arthritis Res Ther. 2014; 16(1):R44. PMC: 3979138. DOI: 10.1186/ar4473. View

11.

Grivennikov S, Greten F, Karin M . Immunity, inflammation, and cancer. Cell. 2010; 140(6):883-99. PMC: 2866629. DOI: 10.1016/j.cell.2010.01.025. View

12.

Murakami M, Kambe T, Shimbara S, Higashino K, Hanasaki K, Arita H . Different functional aspects of the group II subfamily (Types IIA and V) and type X secretory phospholipase A(2)s in regulating arachidonic acid release and prostaglandin generation. Implications of cyclooxygenase-2 induction and phospholipid.... J Biol Chem. 1999; 274(44):31435-44. DOI: 10.1074/jbc.274.44.31435. View

13.

Martin R, Cordova C, Nieto M . Secreted phospholipase A2-IIA-induced a phenotype of activated microglia in BV-2 cells requires epidermal growth factor receptor transactivation and proHB-EGF shedding. J Neuroinflammation. 2012; 9:154. PMC: 3488565. DOI: 10.1186/1742-2094-9-154. View

14.

Ito M, Ishikawa Y, Kiguchi H, Komiyama K, Murakami M, Kudo I . Distribution of type V secretory phospholipase A2 expression in human hepatocytes damaged by liver disease. J Gastroenterol Hepatol. 2004; 19(10):1140-9. DOI: 10.1111/j.1440-1746.2004.03435.x. View

15.

Rhodes D, Kalyana-Sundaram S, Mahavisno V, Varambally R, Yu J, Briggs B . Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. Neoplasia. 2007; 9(2):166-80. PMC: 1813932. DOI: 10.1593/neo.07112. View

16.

Rubio J, Rodriguez J, Gil-de-Gomez L, Guijas C, Balboa M, Balsinde J . Group V secreted phospholipase A2 is upregulated by IL-4 in human macrophages and mediates phagocytosis via hydrolysis of ethanolamine phospholipids. J Immunol. 2015; 194(7):3327-39. DOI: 10.4049/jimmunol.1401026. View

17.

Mounier C, Wendum D, GREENSPAN E, Flejou J, Rosenberg D, Lambeau G . Distinct expression pattern of the full set of secreted phospholipases A2 in human colorectal adenocarcinomas: sPLA2-III as a biomarker candidate. Br J Cancer. 2008; 98(3):587-95. PMC: 2243149. DOI: 10.1038/sj.bjc.6604184. View

18.

Scott K, Sajinovic M, Hein J, Nixdorf S, Galettis P, Liauw W . Emerging roles for phospholipase A2 enzymes in cancer. Biochimie. 2010; 92(6):601-10. DOI: 10.1016/j.biochi.2010.03.019. View

19.

Zou B, Chim C, Zeng H, Leung S, Yang Y, Tu S . Correlation between the single-site CpG methylation and expression silencing of the XAF1 gene in human gastric and colon cancers. Gastroenterology. 2006; 131(6):1835-43. DOI: 10.1053/j.gastro.2006.09.050. View

20.

Boilard E, Lai Y, Larabee K, Balestrieri B, Ghomashchi F, Fujioka D . A novel anti-inflammatory role for secretory phospholipase A2 in immune complex-mediated arthritis. EMBO Mol Med. 2010; 2(5):172-87. PMC: 3058614. DOI: 10.1002/emmm.201000072. View