The mitotic spindle, assembled by microtubule organization center (MTOC), is a critical structure required for proper chromosome segregation during mitosis. Studies demonstrated that defects of mitotic spindle assembling would result in chromosome instability, associating with oncogenesis. In this study, we identified that heparanase (HPSE) was localized on MTOC in mitotic cells. Induced expression of HPSE in human airway epithelial cells promoted mitotic spindle formation, and silencing of HPSE expression disrupted the mitotic spindle formation, resulting in chromosome instability, including chromosome mis-segregation and increased micronuclei formation. In conclusion, HPSE is an important protein in regulation of mitotic spindle and loss of HPSE function on MTOC associates with chromosome instability, indicating that loss of HPSE on MTOC may play critical roles in oncogenesis.
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References
1.
AndreassenP.R., and MargolisR.L. (1994). Microtubule dependency of p34cdc2 inactivation and mitotic exit in mammalian cells. J Cell Biol, 127, 789–802.
2.
BergersG., BrekkenR., McMahonG., VuT.H., ItohT., TamakiK., et al. (2000). Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol, 2, 737–744.
3.
CassimerisL., and SkibbensR.V. (2003). Regulated assembly of the mitotic spindle: a perspective from two ends. Curr Issues Mol Biol, 5, 99–112.
4.
CohenE., AtzmonR., VlodavskyI., and IlanN. (2005). Heparanase processing by lysosomal/endosomal protein preparation. FEBS Lett, 579, 2334–2338.
5.
CohenE., DoweckI., NaroditskyI., Ben-IzhakO., KremerR., BestL.A., et al. (2008). Heparanase is overexpressed in lung cancer and correlates inversely with patient survival. Cancer, 113, 1004–1011.
6.
CrastaK., GanemN.J., DagherR., LantermannA.B., IvanovaE.V., PanY., et al. (2012). DNA breaks and chromosome pulverization from errors in mitosis. Nature, 482, 53–58.
7.
DemionM., ThireauJ., GueffierM., FinanA., KhoueiryZ., CassanC., et al. (2014). Trpm4 gene invalidation leads to cardiac hypertrophy and electrophysiological alterations. PLoS One, 9, e115256.
8.
DitchfieldC., JohnsonV.L., TigheA., EllstonR., HaworthC., JohnsonT., et al. (2003). Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores. J Cell Biol, 161, 267–280.
9.
ElkinM., IlanN., Ishai-MichaeliR., FriedmannY., PapoO., PeckerI., et al. (2001). Heparanase as mediator of angiogenesis: mode of action. FASEB J, 15, 1661–1663.
10.
FernandesD.S.T., GomesA.M., PaschoalM.E., StellingM.P., RumjanekV.M., JuniorA.R., et al. (2014). Heparanase expression and localization in different types of human lung cancer. Biochim Biophys Acta, 1840, 2599–2608.
11.
Gingis-VelitskiS., ZetserA., FlugelmanM.Y., VlodavskyI., and IlanN. (2004). Heparanase induces endothelial cell migration via protein kinase B/Akt activation. J Biol Chem, 279, 23536–23541.
12.
GoldshmidtO., NadavL., AingornH., IritC., FeinsteinN., IlanN., et al. (2002). Human heparanase is localized within lysosomes in a stable form. Exp Cell Res, 281, 50–62.
13.
GranicA., and PotterH. (2013). Mitotic spindle defects and chromosome mis-segregation induced by LDL/cholesterol-implications for Niemann-Pick C1, Alzheimer's disease, and atherosclerosis. PLoS One, 8, e60718.
14.
HarisiR., DudasJ., TimarF., PoganyG., TimarJ., KovalszkyI., et al. (2005). Invasive growth and topoisomerase-switch induced by tumorous extracellular matrix in osteosarcoma cell culture. Cell Biol Int, 29, 959–967.
15.
IzvolskyK.I., ShoykhetD., YangY., YuQ., NugentM.A., and CardosoW.V. (2003). Heparan sulfate-FGF10 interactions during lung morphogenesis. Dev Biol, 258, 185–200.
16.
JanssenA., van der BurgM., SzuhaiK., KopsG.J., and MedemaR.H. (2011). Chromosome segregation errors as a cause of DNA damage and structural chromosome aberrations. Science, 333, 1895–1898.
17.
Keller-PinterA., BottkaS., TimarJ., KulkaJ., KatonaR., DuxL., et al. (2010). Syndecan-4 promotes cytokinesis in a phosphorylation-dependent manner. Cell Mol Life Sci, 67, 1881–1894.
18.
KobayashiM., NaomotoY., NobuhisaT., OkawaT., TakaokaM., ShirakawaY., et al. (2006). Heparanase regulates esophageal keratinocyte differentiation through nuclear translocation and heparan sulfate cleavage. Differentiation, 74, 235–243.
19.
LinX. (2004). Functions of heparan sulfate proteoglycans in cell signaling during development. Development, 131, 6009–6021.
20.
McKenzieE.A. (2007). Heparanase: a target for drug discovery in cancer and inflammation. Br J Pharmacol, 151, 1–14.
21.
NadirY., and BrennerB. (2014). Heparanase multiple effects in cancer. Thromb Res, 133Suppl 2, S90–S94.
22.
NakajimaM., IrimuraT., and NicolsonG.L. (1988). Heparanases and tumor metastasis. J Cell Biochem, 36, 157–167.
23.
NobuhisaT., NaomotoY., OkawaT., TakaokaM., GunduzM., MotokiT., et al. (2007). Translocation of heparanase into nucleus results in cell differentiation. Cancer Sci, 98, 535–540.
24.
QiaoD., YangX., MeyerK., and FriedlA. (2008). Glypican-1 regulates anaphase promoting complex/cyclosome substrates and cell cycle progression in endothelial cells. Mol Biol Cell, 19, 2789–2801.
25.
RoshanL.S., NaokaT., AnnaF., NicolasL., JoannaC., and VijiM.D. (2014). TAO1 kinase maintains chromosomal stability by facilitating proper congression of chromosomes. Open Biol, 4, 130108.
26.
SchubertS.Y., IlanN., ShushyM., Ben-IzhakO., VlodavskyI., and GoldshmidtO. (2004). Human heparanase nuclear localization and enzymatic activity. Lab Invest, 84, 535–544.
27.
SchugerL., SkubitzA.P., GilbrideK., MandelR., and HeL. (1996). Laminin and heparan sulfate proteoglycan mediate epithelial cell polarization in organotypic cultures of embryonic lung cells: evidence implicating involvement of the inner globular region of laminin beta 1 chain and the heparan sulfate groups of heparan sulfate proteoglycan. Dev Biol, 179, 264–273.
28.
VarmarkH. (2004). Functional role of centrosomes in spindle assembly and organization. J Cell Biochem, 91, 904–914.
29.
VenkatesanS., NatarajanA.T., and HandeM.P. (2015). Chromosomal instability—mechanisms and consequences. Mutat Res Genet Toxicol Environ Mutagen, 793, 176–184.
30.
VijiM.D., FrankS., GrzegorzN., MathewE.S., ChenJ., AnthonyL., et al. (2007). A functional genomic screen identifies a role for TAO1 kinase in spindle-checkpoint signaling. Nat Cell Biol, 9, 556–564.
31.
VlodavskyI., MohsenM., LiderO., SvahnC.M., EkreH.P., VigodaM., et al. (1994). Inhibition of tumor metastasis by heparanase inhibiting species of heparin. Invasion Metastasis, 14, 290–302.
32.
WangF., LiuX., YangP., GuoL., LiuC., LiH., et al. (2014). Loss of TACSTD2 contributed to squamous cell carcinoma progression through attenuating TAp63-dependent apoptosis. Cell Death Dis, 5, e1133.
33.
WhitfieldM.L., SherlockG., SaldanhaA.J., MurrayJ.I., BallC.A., AlexanderK.E., et al. (2002). Identification of genes periodically expressed in the human cell cycle and their expression in tumors. Mol Biol Cell, 13, 1977–2000.
34.
ZhengH., RuanJ., ZhaoP., ChenS., PanL., and LiuJ. (2015). Heparanase is involved in proliferation and invasion of ovarian cancer cells. Cancer Biomark, 15, 525–534.
35.
ZongF., FthenouE., WolmerN., HollosiP., KovalszkyI., SzilakL., et al. (2009). Syndecan-1 and FGF-2, but not FGF receptor-1, share a common transport route and co-localize with heparanase in the nuclei of mesenchymal tumor cells. PLoS One, 4, e7346.
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