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01-01-2013 | Reseach Paper

Alternatively spliced lysyl oxidase-like 4 isoforms have a pro-metastatic role in cancer

Authors: Shulamit Sebban, Regina Golan-Gerstl, Rotem Karni, Olga Vaksman, Ben Davidson, Reuven Reich

Published in: Clinical & Experimental Metastasis | Issue 1/2013

Abstract

We previously found LOXL4 to be alternatively spliced in an anatomic site-specific manner in tumors involving the serosal cavities. LOXL4 splice variants were predominantly or exclusively expressed in effusion specimens from ovarian and breast carcinoma patients, and were absent in primary carcinomas. In the present study, LOXL4 full-length or splice variants were overexpressed in ES-2 and MDA-MB-231 cells and their invasive and metastatic potential and microRNA expression profile were evaluated. ES-2 cells were further injected into SCID mice ovaries and the extent of tumor progression and metastases formation were compared. We show that both splice variants have a positive effect on the metastatic potential of cells in vitro and on tumor progression in vivo. In contrast, full-length LOXL4 is not pro-metastatic, and may even be considered as a tumor suppressor. In addition, we show that LOXL4 is a possible splicing target of the oncogenic splicing factors SRSF1 and hnRNP A1. In conclusion, our results point to a significant role for LOXL4 alternative splicing in tumor progression.

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Kagan HM, Li W (2003) Lysyl oxidase: properties, specificity, and biological roles inside and outside of the cell. J Cell Biochem 88:660–672PubMedCrossRef

Holtmeier C, Görögh T, Beier U, Meyer J, Hoffmann M, Gottschlich S, Heidorn K, Ambrosch P, Maune S (2003) Overexpression of a novel lysyl oxidase-like gene in human head and neck squamous cell carcinomas. Anticancer Res 23:2585–2591PubMed

Giampuzzi M, Botti G, Cilli M, Gusmano R, Borel A, Sommer P, Di Donato A (2001) Down-regulation of lysyl oxidase-induced tumorigenic transformation in NRK-49F cells characterized by constitutive activation of ras proto-oncogene. J Biol Chem 276:29226–29232PubMedCrossRef

Contente S, Kenyon K, Sriraman P, Subramanyan S, Friedman RM (1999) Epigenetic inhibition of lysyl oxidase transcription after transformation by ras oncogene. Mol Cell Biochem 194:79–91PubMedCrossRef

Lazarus HM, Cruikshank WW, Narasimhan N, Kagan HM, Center DM (1995) Induction of human monocyte motility by lysyl oxidase. Matrix Biol 14:727–731PubMedCrossRef

Li W, Nellaiappan K, Strassmaier T, Graham L, Thomas KM, Kagan HM (1997) Localization and activity of lysyl oxidase within nuclei of fibrogenic cells. Proc Natl Acad Sci USA 94:12817–12822PubMedCrossRef

Molnar J, Fong KS, He QP, Hayashi K, Kim Y, Fong SF, Fogelgren B, Szauter KM, Mink M, Csiszar K (2003) Structural and functional diversity of lysyl oxidase and the LOX-like proteins. Biochim Biophys Acta 1647:220–224PubMedCrossRef

Liu X, Zhao Y, Gao J, Pawlyk B, Starcher B, Spencer JA, Yanagisawa H, Zuo J, Li T (2004) Elastic fiber homeostasis requires lysyl oxidase-like 1 protein. Nat Genet 36:178–182PubMedCrossRef

Kirschmann DA, Seftor EA, Fong SF, Nieva DR, Sullivan CM, Edwards EM, Sommer P, Csiszar K, Hendrix MJ (2002) A molecular role for lysyl oxidase in BC invasion. Cancer Res 62:4478–4483PubMed

10.

Akiri G, Sabo E, Dafni H, Vadasz Z, Kartvelishvily Y, Gan N, Kessler O, Cohen T, Resnick M, Neeman M, Neufeld G (2003) Lysyl oxidase-related protein-1 promotes tumor fibrosis and tumor progression in vivo. Cancer Res 63:1657–1666PubMed

11.

Fong SF, Dietzsch E, Fong KS, Hollosi P, Asuncion L, He Q, Parker MI, Csiszar K (2007) Lysyl oxidase-like 2 expression is increased in colon and esophageal tumors and associated with less differentiated colon tumors. Genes Chromosomes Cancer 46:644–655PubMedCrossRef

12.

Peinado H, Del Carmen Iglesias-de la Cruz M, Olmeda D, Csiszar K, Fong KS, Vega S, Nieto MA, Cano A, Portillo F (2005) A molecular role for lysyl oxidase-like 2 enzyme in snail regulation and tumor progression. EMBO J 24:3446–3458PubMedCrossRef

13.

Görögh T, Weise JB, Holtmeier C, Rudolph P, Hedderich J, Gottschlich S, Hoffmann M, Ambrosch P, Csiszar K (2007) Selective upregulation and amplification of the lysyl oxidase like-4 (LOXL4) gene in head and neck squamous cell carcinoma. J Pathol 212:74–82PubMedCrossRef

14.

Weise JB, Csiszar K, Gottschlich S, Hoffmann M, Schmidt A, Weingartz U, Adamzik I, Heiser A, Kabelitz D, Ambrosch P, Görögh T (2008) Vaccination strategy to target lysyl oxidase-like 4 in dendritic cell based immunotherapy for head and neck cancer. Int J Oncol 32:317–322PubMed

15.

Wu G, Guo Z, Chang X, Kim MS, Nagpal JK, Liu J, Maki JM, Kivirikko KI, Ethier SP, Trink B, Sidransky D (2007) LOXL1 and LOXL4 are epigenetically silenced and can inhibit ras/extracellular signal-regulated kinase signaling pathway in human bladder cancer. Cancer Res 67:4123–4129PubMedCrossRef

16.

Kim DJ, Lee DC, Yang SJ, Lee JJ, Bae EM, Kim DM, Min SH, Kim SJ, Kang DC, Sang BC, Myung PK, Park KC, Yeom YI (2008) Lysyl oxidase like 4, a novel target gene of TGF-beta1 signaling, can negatively regulate TGF-beta1-induced cell motility in PLC/PRF/5 hepatoma cells. Biochem Biophys Res Commun 373:521–527PubMedCrossRef

17.

Maki JM, Tikkanen H, Kivirikko KI (2001) Cloning and characterization of a fifth human lysyl oxidase isoenzyme: the third member of the lysyl oxidase-related subfamily with four scavenger receptor cysteine-rich domains. Matrix Biol 20:493–496PubMedCrossRef

18.

Asuncion L, Fogelgren B, Fong KS, Fong SF, Kim Y, Csiszar K (2001) A novel human lysyl oxidase-like gene (LOXL4) on chromosome 10q24 has an altered scavenger receptor cysteine rich domain. Matrix Biol 20:487–491PubMedCrossRef

19.

Cote GJ, Bruno IG, Jin W (2004) Abnormal regulation of RNA splicing in gliomas. In: Zhang W, Fuller GN (eds) Genomic and molecular neuro-oncology. Jones and Bartlett, Sudbury, pp 165–183

20.

Kalnina Z, Zayakin P, Silina K, Line A (2005) Alterations of pre-mRNA splicing in cancer. Genes Chromosomes Cancer 42:342–357PubMedCrossRef

21.

Roy M, Xu Q, Lee C (2005) Evidence that public database records for many cancer-associated genes reflect a splice form found in tumors and lack normal splice forms. Nucleic Acids Res 33:5026–5033PubMedCrossRef

22.

Song SW, Cote GJ, Wu C, Zhang W (2002) Alternative splicing: genetic complexity in cancer. In: Zhang W, Shmulevich I (eds) Computational and statistical approaches to genomics. Kluwer, Boston, pp 277–297

23.

Venables JP (2004) Aberrant and alternative splicing in cancer. Cancer Res 64:7647–7654PubMedCrossRef

24.

Cheng C, Sharp PA (2009) Regulation of CD44 alternative splicing by SRm160 and its potential role in tumor cell invasion. Mol Cell Biol 2:362–370

25.

Sebban S, Davidson B, Reich R (2009) Lysyl oxidase-like 4 is alternatively spliced in an anatomic site-specific manner in tumors involving the serosal cavities. Virchows Arch 454:71–79PubMedCrossRef

26.

Karni R, de Stanchina E, Lowe SW, Sinha R, Mu D, Krainer AR (2007) The gene encoding the splicing factor SF2/ASF is a proto-oncogene. Nat Struct Mol Biol 14:185–193PubMedCrossRef

27.

Reich R, Thompson EW, Iwamoto Y, Martin GR, Deason JR, Fuller GC, Miskin R (1988) Effects of inhibitors of plasminogen activator, serine proteinases, and collagenase IV on the invasion of basement membranes by metastatic cells. Cancer Res 48:3307–3312PubMed

28.

Brassart B, Randoux A, Hornebeck W, Emonard H (1998) Regulation of matrix metalloproteinase-2 (gelatinase A, MMP-2), membrane-type matrix metalloproteinase-1 (MT1-MMP) and tissue inhibitor of metalloproteinases-2 (TIMP-2) expression by elastin-derived peptides in human HT-1080 fibrosarcoma cell line. Clin Exp Metastasis 16:489–500PubMedCrossRef

29.

Rayhman O, Klipper E, Muller L, Davidson B, Reich R, Meidan R (2008) Small interfering RNA molecules targeting endothelin-converting enzyme-1 inhibit endothelin-1 synthesis and the invasive phenotype of ovarian carcinoma cells. Cancer Res 68:9265–9273PubMedCrossRef

30.

Elloul S, Silins I, Tropé CG, Benshushan A, Davidson B, Reich R (2006) Expression of E-cadherin transcriptional regulators in ovarian carcinoma. Virchows Arch 449:520–528PubMedCrossRef

31.

Kenny HA, Lengyel E (2009) MMP-2 functions as an early response protein in ovarian cancer metastasis. Cell Cycle 8:683–688PubMedCrossRef

32.

Noh S, Jung JJ, Jung M, Kim TS, Park CH, Lim SJ, Jeung HC, Cheol H, Chung HC, Rha SY (2011) MMP-2 as a putative biomarker for carcinomatosis in gastric cancer. Hepatogastroenterology 12:58

33.

Xiao LJ, Lin P, Lin F, Liu X, Qin W, Zou HF, Guo L, Liu W, Wang SJ, Yu XG (2011) ADAM17 targets MMP-2 and MMP-9 via EGFR-MEK-ERK pathway activation to promote prostate cancer cell invasion. Int J Oncol 23 [Epub ahead of print]. doi:10.3892/ijo.2011.1320

34.

Calin GA, Croce CM (2006) MicroRNA signatures in human cancers. Nat Rev Cancer 6:857–866PubMedCrossRef

35.

Iorio MV, Ferracin M, Liu CG, Veronese A, Spizzo R, Sabbioni S, Magri E, Pedriali M, Fabbri M, Campiglio M, Ménard S, Palazzo JP et al (2005) MicroRNA gene expression deregulation in human BC. Cancer Res 65:7065–7070PubMedCrossRef

36.

Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, Visone R, Iorio M, Roldo C, Ferracin M, Prueitt RL, Yanaihara N et al (2006) A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA 103:2257–2261PubMedCrossRef

37.

Zhang L, Huang J, Yang N, Greshock J, Megraw MS, Giannakakis A, Liang S, Naylor TL, Barchetti A, Ward MR, Yao G, Medina A et al (2006) microRNAs exhibit high frequency genomic alterations in human cancer. Proc Natl Acad Sci USA 103:9136–9141PubMedCrossRef

38.

Vaksman O, Stavnes HT, Kaern J, Trope CG, Davidson B, Reich R (2011) miRNA profiling along tumour progression in ovarian carcinoma. J Cell Mol Med 15:1593–1602PubMedCrossRef

39.

Cui J, Eldredge JB, Xu Y, Puett D (2011) MicroRNA expression and regulation in human ovarian carcinoma cells by luteinizing hormone. PLoS One 6:e21730PubMedCrossRef

40.

Black DL (2003) Mechanisms of alternative pre-messenger RNA splicing. Annu Rev Biochem 72:291–336PubMedCrossRef

41.

Huang Y, Steitz JA (2005) SRprises along a messenger’s journey. Mol Cell 17:613–615PubMedCrossRef

42.

Graveley BR (2000) Sorting out the complexity of SR protein functions. RNA 6:1197–1211PubMedCrossRef

43.

Dreyfuss G, Matunis MJ, Pinol-Roma S, Burd CG (1993) hnRNP proteins and the biogenesis of mRNA. Annu Rev Biochem 62:289–321PubMedCrossRef

44.

Hertel KJ, Graveley BR (2005) RS domains contact the pre-mRNA throughout spliceosome assembly. Trends Biochem Sci 30:115–118PubMedCrossRef

45.

Mayeda A, Krainer AR (1992) Regulation of alternative pre-mRNA splicing by hnRNPA1 and splicing factor SF2. Cell 68:365–375PubMedCrossRef

46.

Karni R, Hippo Y, Lowe SW, Krainer AR (2008) The splicing-factor oncoprotein SF2/ASF activates mTORC1. Proc Natl Acad Sci USA 105:15323–15327PubMedCrossRef

47.

Skotheim RI, Nees M (2007) Alternative splicing in cancer: noise, functional, or systematic? Int J Biochem Cell Biol 39:1432–1449PubMedCrossRef

48.

Kim Y, Roh S, Park JY, Kim Y, Cho DH, Kim JC (2009) Differential expression of the LOX family genes in human colorectal adenocarcinomas. Oncol Rep 22:799–804PubMed

49.

Ghigna C, Giordano S, Shen H, Benvenuto F, Castiglioni F, Comoglio PM, Green MR, Riva S, Biamonti G (2005) Cell motility is controlled by SF2/ASF through alternative splicing of the Ron protooncogene. Mol Cell 20:881–890PubMedCrossRef

50.

Umaa H, Nielsen PJ (1997) The splicing factor SRp20 modifies splicing of its own mRNA and ASF/SF2 antagonizes this regulation. EMBO J 16:5077–5085CrossRef

51.

Xu X, Yang D, Ding JH, Wang W, Chu PH, Dalton ND, Wang HY, Bermingham JR Jr, Ye Z, Liu F, Rosenfeld MG, Manley JL et al (2005) ASF/SF2-regulated CaMKIIdelta alternative splicing temporally reprograms excitation-contraction coupling in cardiac muscle. Cell 120:59–72PubMedCrossRef

Title: Alternatively spliced lysyl oxidase-like 4 isoforms have a pro-metastatic role in cancer
Authors: Shulamit Sebban
Regina Golan-Gerstl
Rotem Karni
Olga Vaksman
Ben Davidson
Reuven Reich
Publication date: 01-01-2013
Publisher: Springer Netherlands
Published in: Clinical & Experimental Metastasis / Issue 1/2013
Print ISSN: 0262-0898
Electronic ISSN: 1573-7276
DOI: https://doi.org/10.1007/s10585-012-9514-0

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