Skip to main content

Advertisement

SpringerLink
Log in

Oncogenic potential of nucleoporins in non-hematological cancers: recent update beyond chromosome translocation and gene fusion

  • Review – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Introduction

The nuclear pore complex is comprised of approximately 30 proteins named nucleoporins (Nups) and tightly regulates nucleocytoplasmic transport of macromolecules across the nuclear membrane. Genetic alterations in many NUP genes are associated with many human maladies, such as neurological disease, autoimmune disorders and cancer.

Methods

We reviewed the status quo of recent advancement of the knowledge of oncogenic role of nucleoporins in human carcinogenesis, focusing on major non-hematological malignancies in the recent literature. Both clinical study-derived and experiment-based reports were critically reviewed. We have also discussed the potential of nucleoporins as novel cancer biomarkers and promising therapeutic target against human malignancies.

Results

Several Nups such as Nup53, Nup88, Nup98, Nup160 and Nup214 modulated a plethora of cellular and physiological pathways involved in tumorigenesis such as GSK3β-Snail, Wnt/β-Catenin and RanGap1/RanBP2 signaling axes, DNA damage response, resistance to apoptosis and chemotherapy.

Conclusion

Although classically, majority of studies have shown oncogenic roles of nucleoporins as genetic fusion partners in several types of leukemia, emerging evidence suggests that nucleoporins also modulate many cellular signaling pathways that are associated with several major non-hematological malignancies, such as carcinomas of skin, breast, lung, prostate and colon. Hence, nucleoporins are emerging as novel therapeutic targets in human tumors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

NE:

Nuclear membrane

NPC:

Nuclear pore complex

NUP:

Nucleoporin

AFM:

Atomic force microscopy

AML:

Acute myeloid leukemia

CML:

Chronic myeloid leukemia

ABL:

Acute biphenotypic leukemia

TNBC:

Triple negative breast cancer

PC:

Prostate cancer

CRPC:

Castration-resistant prostate cancer

SCC:

Squamous cell carcinoma

CIN:

Cervical intraepithelial neoplasia

IHC:

Immunohistochemistry

PDA:

Pancreatic ductal adenocarcinoma

References

  • Agudo D, Gomez-Esquer F, Martinez-Arribas F, Nunez-Villar MJ, Pollan M, Schneider J (2004) Nup88 mRNA overexpression is associated with high aggressiveness of breast cancer. Int J Cancer 109(5):717–720

    CAS  PubMed  Google Scholar 

  • Aitchison JD, Rout MP (2012) The yeast nuclear pore complex and transport through it. Genetics 190(3):855–883

    CAS  PubMed  PubMed Central  Google Scholar 

  • Akkafa F, Koyuncu I, Temiz E, Dagli H, Dilmec F, Akbas H (2018) miRNA-mediated apoptosis activation through TMEM 48 inhibition in A549 cell line. Biochem Biophys Res Commun 503(1):323–329

    CAS  PubMed  Google Scholar 

  • Alanee S, Delfino K, Wilber A, Robinson K, Brard L, Semaan A (2017) Single nucleotide variant in nucleoporin 107 may be predictive of sensitivity to chemotherapy in patients with ovarian cancer. Pharmacogenet Genom 27(7):264–269

    CAS  Google Scholar 

  • Basel-Vanagaite L, Muncher L, Straussberg R, Pasmanik-Chor M, Yahav M, Rainshtein L, Walsh CA, Magal N, Taub E, Drasinover V et al (2006) Mutated nup62 causes autosomal recessive infantile bilateral striatal necrosis. Ann Neurol 60(2):214–222

    CAS  PubMed  Google Scholar 

  • Bhattacharjya S, Roy KS, Ganguly A, Sarkar S, Panda CK, Bhattacharyya D, Bhattacharyya NP, Roychoudhury S (2015) Inhibition of nucleoporin member Nup214 expression by miR-133b perturbs mitotic timing and leads to cell death. Mol Cancer 14:42

    PubMed  PubMed Central  Google Scholar 

  • Bonnet A, Palancade B (2014) Regulation of mRNA trafficking by nuclear pore complexes. Genes 5(3):767–791

    PubMed  PubMed Central  Google Scholar 

  • Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA 68(6):394–424

    PubMed  Google Scholar 

  • Brustmann H, Hager M (2009) Nucleoporin 88 expression in normal and neoplastic squamous epithelia of the uterine cervix. Ann Diagn Pathol 13(5):303–307

    PubMed  Google Scholar 

  • Bui KH, von Appen A, DiGuilio AL, Ori A, Sparks L, Mackmull MT, Bock T, Hagen W, Andres-Pons A, Glavy JS et al (2013) Integrated structural analysis of the human nuclear pore complex scaffold. Cell 155(6):1233–1243

    CAS  PubMed  Google Scholar 

  • Choi YL, Lira ME, Hong M, Kim RN, Choi SJ, Song JY, Pandy K, Mann DL, Stahl JA, Peckham HE et al (2014) A novel fusion of TPR and ALK in lung adenocarcinoma. J Thorac Oncol 9(4):563–566

    CAS  PubMed  Google Scholar 

  • Closa A, Cordero D, Sanz-Pamplona R, Sole X, Crous-Bou M, Pare-Brunet L, Berenguer A, Guino E, Lopez-Doriga A, Guardiola J et al (2014) Identification of candidate susceptibility genes for colorectal cancer through eQTL analysis. Carcinogenesis 35(9):2039–2046

    CAS  PubMed  PubMed Central  Google Scholar 

  • Emig S, Schmalz D, Shakibaei M, Buchner K (1995) The nuclear pore complex protein p62 is one of several sialic acid-containing proteins of the nuclear envelope. J Biol Chem 270(23):13787–13793

    CAS  PubMed  Google Scholar 

  • Emterling A, Skoglund J, Arbman G, Schneider J, Evertsson S, Carstensen J, Zhang H, Sun XF (2003) Clinicopathological significance of Nup88 expression in patients with colorectal cancer. Oncology 64(4):361–369

    PubMed  Google Scholar 

  • Fradkin LG, Budnik V (2016) This bud’s for you: mechanisms of cellular nucleocytoplasmic trafficking via nuclear envelope budding. Curr Opin Cell Biol 41:125–131

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gasset-Rosa F, Chillon-Marinas C, Goginashvili A, Atwal RS, Artates JW, Tabet R, Wheeler VC, Bang AG, Cleveland DW, Lagier-Tourenne C (2017) Polyglutamine-expanded huntingtin exacerbates age-related disruption of nuclear integrity and nucleocytoplasmic transport. Neuron. 94(1):48–57

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gough SM, Slape CI, Aplan PD (2011) NUP98 gene fusions and hematopoietic malignancies: common themes and new biologic insights. Blood 118(24):6247–6257

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gould VE, Orucevic A, Zentgraf H, Gattuso P, Martinez N, Alonso A (2002) Nup88 (karyoporin) in human malignant neoplasms and dysplasias: correlations of immunostaining of tissue sections, cytologic smears, and immunoblot analysis. Hum Pathol 33(5):536–544

    CAS  PubMed  Google Scholar 

  • Greco A, Miranda C, Pagliardini S, Fusetti L, Bongarzone I, Pierotti MA (1997) Chromosome 1 rearrangements involving the genes TPR and NTRK1 produce structurally different thyroid-specific TRK oncogenes. Genes Chromosom Cancer 19(2):112–123

    CAS  PubMed  Google Scholar 

  • Grima JC, Daigle JG, Arbez N, Cunningham KC, Zhang K, Ochaba J, Geater C, Morozko E, Stocksdale J, Glatzer JC et al (2017) Mutant Huntingtin Disrupts the Nuclear Pore Complex. Neuron. 94(1):93–107

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hazawa M, Lin DC, Kobayashi A, Jiang YY, Xu L, Dewi FRP, Mohamed MS, Hartono Nakada M, Meguro-Horike M et al (2018) ROCK-dependent phosphorylation of NUP62 regulates p63 nuclear transport and squamous cell carcinoma proliferation. EMBO Rep 19(1):73–88

    CAS  PubMed  Google Scholar 

  • Juhlen R, Fahrenkrog B (2018) Moonlighting nuclear pore proteins: tissue-specific nucleoporin function in health and disease. Histochem Cell Biol 150(6):593–605

    CAS  PubMed  Google Scholar 

  • Kabachinski G, Schwartz TU (2015) The nuclear pore complex–structure and function at a glance. J Cell Sci 128(3):423–429

    CAS  PubMed  PubMed Central  Google Scholar 

  • Karacosta LG, Kuroski LA, Hofmann WA, Azabdaftari G, Mastri M, Gocher AM, Dai S, Hoste AJ, Edelman AM (2016) Nucleoporin 62 and Ca(2 +)/calmodulin dependent kinase kinase 2 regulate androgen receptor activity in castrate resistant prostate cancer cells. Prostate 76(3):294–306

    CAS  PubMed  Google Scholar 

  • Karakoula K, Suarez-Merino B, Ward S, Phipps KP, Harkness W, Hayward R, Thompson D, Jacques TS, Harding B, Beck J et al (2008) Real-time quantitative PCR analysis of pediatric ependymomas identifies novel candidate genes including TPR at 1q25 and CHIBBY at 22q12-q13. Genes Chromosom Cancer 47(11):1005–1022

    CAS  PubMed  Google Scholar 

  • Kikutake C, Yahara K (2016) Identification of epigenetic biomarkers of lung adenocarcinoma through multi-omics data analysis. PLoS One 11(4):e0152918

    PubMed  PubMed Central  Google Scholar 

  • Kim NH, Pham NB, Quinn RJ, Shim JS, Cho H, Cho SM, Park SW, Kim JH, Seok SH, Oh JW et al (2015) The small molecule R-(-)-beta-O-methylsynephrine binds to nucleoporin 153 kDa and inhibits angiogenesis. Int J Biol Sci 11(9):1088–1099

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kinoshita Y, Ito H, Hirano A, Fujita K, Wate R, Nakamura M, Kaneko S, Nakano S, Kusaka H (2009) Nuclear contour irregularity and abnormal transporter protein distribution in anterior horn cells in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 68(11):1184–1192

    CAS  PubMed  Google Scholar 

  • Kinoshita Y, Kalir T, Rahaman J, Dottino P, Kohtz DS (2012) Alterations in nuclear pore architecture allow cancer cell entry into or exit from drug-resistant dormancy. Am J Pathol 180(1):375–389

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kinoshita Y, Hunter RG, Gray JD, Mesias R, McEwen BS, Benson DL, Kohtz DS (2014) Role for NUP62 depletion and PYK2 redistribution in dendritic retraction resulting from chronic stress. Proc Natl Acad Sci USA 111(45):16130–16135

    CAS  PubMed  Google Scholar 

  • Knoess M, Kurz AK, Goreva O, Bektas N, Breuhahn K, Odenthal M, Schirmacher P, Dienes HP, Bock CT, Zentgraf H et al (2006) Nucleoporin 88 expression in hepatitis B and C virus-related liver diseases. World J Gastroenterol 12(36):5870–5874

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kraemer D, Wozniak RW, Blobel G, Radu A (1994) The human CAN protein, a putative oncogene product associated with myeloid leukemogenesis, is a nuclear pore complex protein that faces the cytoplasm. Proc Natl Acad Sci USA 91(4):1519–1523

    CAS  PubMed  Google Scholar 

  • Labade AS, Karmodiya K, Sengupta K (2016) HOXA repression is mediated by nucleoporin Nup93 assisted by its interactors Nup188 and Nup205. Epigenetics Chromatin 9:54

    PubMed  PubMed Central  Google Scholar 

  • Laurell E, Beck K, Krupina K, Theerthagiri G, Bodenmiller B, Horvath P, Aebersold R, Antonin W, Kutay U (2011) Phosphorylation of Nup98 by multiple kinases is crucial for NPC disassembly during mitotic entry. Cell 144(4):539–550

    CAS  PubMed  Google Scholar 

  • Li F, Zhai YP, Tang YM, Wang LP, Wan PJ (2012) Identification of a novel partner gene, TPR, fused to FGFR1 in 8p11 myeloproliferative syndrome. Genes Chromosom Cancer 51(9):890–897

    CAS  PubMed  Google Scholar 

  • Liashkovich I, Pasrednik D, Prystopiuk V, Rosso G, Oberleithner H, Shahin V (2015) Clathrin inhibitor Pitstop-2 disrupts the nuclear pore complex permeability barrier. Sci Rep 5:9994

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lim KS, Wong RW (2018) Targeting nucleoporin POM121-Importin beta axis in prostate cancer. Cell Chem Biol 25(9):1056–1058

    CAS  PubMed  Google Scholar 

  • Lu T, Bao Z, Wang Y, Yang L, Lu B, Yan K, Wang S, Wei H, Zhang Z, Cui G (2016) Karyopherinbeta1 regulates proliferation of human glioma cells via Wnt/beta-catenin pathway. Biochem Biophys Res Commun 478(3):1189–1197

    CAS  PubMed  Google Scholar 

  • Makise M, Nakamura H, Kuniyasu A (2018) The role of vimentin in the tumor marker Nup88-dependent multinucleated phenotype. BMC Cancer 18(1):519

    PubMed  PubMed Central  Google Scholar 

  • Makiyama K, Hamada J, Takada M, Murakawa K, Takahashi Y, Tada M, Tamoto E, Shindo G, Matsunaga A, Teramoto K et al (2005) Aberrant expression of HOX genes in human invasive breast carcinoma. Oncol Rep 13(4):673–679

    CAS  PubMed  Google Scholar 

  • Martinez N, Alonso A, Moragues MD, Ponton J, Schneider J (1999) The nuclear pore complex protein Nup88 is overexpressed in tumor cells. Cancer Res 59(21):5408–5411

    CAS  PubMed  Google Scholar 

  • Mohamed MS, Kobayashi A, Taoka A, Watanabe-Nakayama T, Kikuchi Y, Hazawa M, Minamoto T, Fukumori Y, Kodera N, Uchihashi T et al (2017) High-speed atomic force microscopy reveals loss of nuclear pore resilience as a dying code in colorectal cancer cells. ACS Nano 11(6):5567–5578

    CAS  PubMed  Google Scholar 

  • Mullan PB, Bingham V, Haddock P, Irwin GW, Kay E, McQuaid S, Buckley NE (2019) NUP98—a novel predictor of response to anthracycline-based chemotherapy in triple negative breast cancer. BMC Cancer 19(1):236

    PubMed  PubMed Central  Google Scholar 

  • Naylor RM, Jeganathan KB, Cao X, van Deursen JM (2016) Nuclear pore protein NUP88 activates anaphase-promoting complex to promote aneuploidy. J Clin Investig 126(2):543–559

    PubMed  Google Scholar 

  • Nofrini V, Di Giacomo D, Mecucci C (2016) Nucleoporin genes in human diseases. Eur J Hum Genet 24(10):1388–1395

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pante N, Fahrenkrog B (2014) Exploring nuclear pore complex molecular architecture by immuno-electron microscopy using Xenopus oocytes. Methods Cell Biol 122:81–98

    CAS  PubMed  Google Scholar 

  • Re A, Colussi C, Nanni S, Aiello A, Bacci L, Grassi C, Pontecorvi A, Farsetti A (2018) Nucleoporin 153 regulates estrogen-dependent nuclear translocation of endothelial nitric oxide synthase and estrogen receptor beta in prostate cancer. Oncotarget 9(46):27985–27997

    PubMed  PubMed Central  Google Scholar 

  • Rodriguez-Bravo V, Pippa R, Song WM, Carceles-Cordon M, Dominguez-Andres A, Fujiwara N, Woo J, Koh AP, Ertel A, Lokareddy RK et al (2018) Nuclear pores promote lethal prostate cancer by increasing POM121-driven E2F1, MYC, and AR nuclear import. Cell 174(5):1200–1215

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ryan KJ, White CC, Patel K, Xu J, Olah M, Replogle JM, Frangieh M, Cimpean M, Winn P, McHenry A et al (2017) A human microglia-like cellular model for assessing the effects of neurodegenerative disease gene variants. Sci Transl Med 9(421):eaai7635

    PubMed  PubMed Central  Google Scholar 

  • Sakuma S, D’Angelo MA (2017) The roles of the nuclear pore complex in cellular dysfunction, aging and disease. Semin Cell Dev Biol 68:72–84

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sheffield LG, Miskiewicz HB, Tannenbaum LB, Mirra SS (2006) Nuclear pore complex proteins in Alzheimer disease. J Neuropathol Exp Neurol 65(1):45–54

    CAS  PubMed  Google Scholar 

  • Shen Q, Yu M, Jia J-K, Li W-X, Tian Y-W, Xue H-Z (2018) Possible molecular markers for the diagnosis of pancreatic ductal adenocarcinoma. Med Sci Monit 24:2368–2376

    PubMed  PubMed Central  Google Scholar 

  • Shi J, Li C, Wang H, Xiao B, Qiu W (2019) NUP58 facilitates metastasis and epithelial-mesenchymal transition of lung adenocarcinoma via the GSK-3beta/Snail signaling pathway. Am J Transl Res 11(1):393–405

    PubMed  PubMed Central  Google Scholar 

  • Soman NR, Correa P, Ruiz BA, Wogan GN (1991) The TPR-MET oncogenic rearrangement is present and expressed in human gastric carcinoma and precursor lesions. Proc Natl Acad Sci USA 88(11):4892–4896

    CAS  PubMed  Google Scholar 

  • Takahashi N, van Kilsdonk JW, Ostendorf B, Smeets R, Bruggeman SW, Alonso A, van de Loo F, Schneider M, van den Berg WB, Swart GW (2008) Tumor marker nucleoporin 88 kDa regulates nucleocytoplasmic transport of NF-kappaB. Biochem Biophys Res Commun 374(3):424–430

    CAS  PubMed  Google Scholar 

  • Takeda A, Yaseen NR (2014) Nucleoporins and nucleocytoplasmic transport in hematologic malignancies. Semin Cancer Biol 27:3–10

    CAS  PubMed  Google Scholar 

  • Takeshima H, Wakabayashi M, Hattori N, Yamashita S, Ushijima T (2015) Identification of coexistence of DNA methylation and H3K27me3 specifically in cancer cells as a promising target for epigenetic therapy. Carcinogenesis 36(2):192–201

    CAS  PubMed  Google Scholar 

  • Tan X, Zhou L, Wang W, Wang B, Egami H, Baba H, Dai X (2010) Genomic analysis of invasion-metastasis-related factors in pancreatic cancer cells. Exp Ther Med 1(1):211–216

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tian C, Zhou S, Yi C (2018) High NUP43 expression might independently predict poor overall survival in luminal A and in HER2 + breast cancer. Future Oncol 14(15):1431–1442

    CAS  PubMed  Google Scholar 

  • von Lindern M, van Baal S, Wiegant J, Raap A, Hagemeijer A, Grosveld G (1992) Can, a putative oncogene associated with myeloid leukemogenesis, may be activated by fusion of its 3′ half to different genes: characterization of the set gene. Mol Cell Biol 12(8):3346–3355

    Google Scholar 

  • Wente SR, Rout MP (2010) The nuclear pore complex and nuclear transport. Cold Spring Harb Perspect Biol 2(10):a000562

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wu Y, Fang G, Wang X, Wang H, Chen W, Li L, Ye T, Gong L, Ke C, Cai Y (2019) NUP153 overexpression suppresses the proliferation of colorectal cancer by negatively regulating Wnt/beta-catenin signaling pathway and predicts good prognosis. Cancer Biomark 24(1):61–70

    CAS  PubMed  Google Scholar 

  • Zhang H, Schneider J, Rosdahl I (2002) Expression of p16, p27, p53, p73 and Nup88 proteins in matched primary and metastatic melanoma cells. Int J Oncol 21(1):43–48

    PubMed  Google Scholar 

  • Zhang ZY, Zhao ZR, Jiang L, Li JC, Gao YM, Cui DS, Wang CJ, Schneider J, Wang MW, Sun XF (2007) Nup88 expression in normal mucosa, adenoma, primary adenocarcinoma and lymph node metastasis in the colorectum. Tumour Biol 28(2):93–99

    PubMed  Google Scholar 

  • Zhao ZR, Zhang ZY, He XQ, Hu YM, Tian YF, Zhang LJ, Sun XF (2010) Nup88 mRNA overexpression in colorectal cancers and relationship with p53. Cancer Biomark 8(2):73–80

    CAS  PubMed  Google Scholar 

  • Zhao ZR, Zhang LJ, Wang YY, Li F, Wang MW, Sun XF (2012) Increased serum level of Nup88 protein is associated with the development of colorectal cancer. Med Oncol 29(3):1789–1795

    CAS  PubMed  Google Scholar 

  • Zhou MH, Yang QM (2014) NUP214 fusion genes in acute leukemia (Review). Oncol Lett 8(3):959–962

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the Ramalingaswami Re-entry fellowship Grant (BT/HRD/35/02/2006), Department of Biotechnology, Govt. of India to AR.

Author information

Authors and Affiliations

  1. Interdisciplinary School of Life Sciences, Institute of Science, Banaras Hindu University, Varanasi, 221005, India

    Adhiraj Roy

  2. Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, India

    Gopeshwar Narayan

Authors
  1. Adhiraj Roy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gopeshwar Narayan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Adhiraj Roy.

Ethics declarations

Conflict of interest

The authors declare that there is no conflict of interest to disclose.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Roy, A., Narayan, G. Oncogenic potential of nucleoporins in non-hematological cancers: recent update beyond chromosome translocation and gene fusion. J Cancer Res Clin Oncol 145, 2901–2910 (2019). https://doi.org/10.1007/s00432-019-03063-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-019-03063-2

Keywords

Search

Navigation