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Constitutional abnormality of nuclear membrane proteins in small cell lung carcinoma

  • Jieying WangEmail author
  • Tetsuo Kondo
  • Tadao Nakazawa
  • Naoki Oishi
  • Kunio Mochizuki
  • Ryohei Katoh
Original Article
  • 21 Downloads

Abstract

Nuclear membrane proteins reportedly play important roles in maintaining nuclear structures and coordinating cell activities. Studying profiles of nuclear membrane proteins may help us evaluate the biological and/or clinical nature of malignant tumors. Using immunohistochemistry with antibodies for emerin, lamin A/C, lamin B, and LAP2, we examined 105 lung cancer tissues from 33 small cell lung carcinomas (SCLCs) and 72 non-SCLCs (34 adenocarcinomas, 30 squamous cell carcinomas, and 8 large cell carcinomas). Emerin had negative or local/weak positivity in 79% of SCLCs and 1% of non-SCLCs, and lamin A/C had similar positivity in 91% of SCLCs and 3% of non-SCLCs. LAP2’s expression was similar between SCLCs and non-SCLCs. RT-PCR analyses for these four nuclear membrane proteins over 7 cell lines showed that mRNA of emerin and lamin A/C were distinctly downregulated in the SCLC cell lines, supporting the immunohistochemical results. In conclusion, we suggest that downregulation of the nuclear membrane proteins emerin and lamin A/C is characteristic of SCLC cells, and this constitutional abnormality of the nuclear membrane may be related to the biological and/or clinical nature of SCLC. In addition, knowing the nuclear protein profile in SCLC cells may contribute to our understanding of nuclear fragility known as the crush artifact in pulmonary biopsy specimens.

Keywords

Nuclear membrane proteins Lung carcinoma Immunohistochemistry Polymerase chain reaction (PCR) 

Notes

Acknowledgments

The authors thank Ms. Mikiko Yoda, Ms. Miyuki Ito, Mr. Yoshihito Koshimizu, and Ms. Wakaba Iha for technical support and Ms. Kayoko Kono for executive assistance.

Contributions

Wang Jieying, Tetsuo Kondo, and Ryohei Katoh conceived and designed the study, and wrote, edited, and reviewed the manuscript. Wang Jieying and Tetsuo Kondo performed the experiment. Tadao Nakazawa, Naoki Oishi, and Kunio Mochizukia researched and analyzed data. All authors gave final approval for publication.

Funding

This study was funded by the Natural Science Foundation of Shaanxi Provincial Department of Education (grant number 18JK0666).

Compliance with ethical standards

The study protocols were approved by the Institutional Ethics Board of the University of Yamanashi, Yamanashi, Japan. The study complies with all ethical standards as stated in the Ethical Responsibilities of Authors on the Virchows Archiv webpage (https://www.springer.com/medicine/pathology/journal/428).

Conflict of interest

The authors declare that they have no conflicts of interest.

References

  1. 1.
    Berk JM, Tifft KE, Wilson KL (2013) The nuclear envelope LEM-domain protein emerin. Nucleus 4:298–314.  https://doi.org/10.4161/nucl.25751 CrossRefGoogle Scholar
  2. 2.
    Dittmer TA, Misteli T (2011) The lamin protein family. Genome Biol 12:222.  https://doi.org/10.1186/gb-2011-12-5-222 CrossRefGoogle Scholar
  3. 3.
    Foisner R (2003) Cell cycle dynamics of the nuclear envelope. Sci World J 3:1–20.  https://doi.org/10.1100/tsw.2003.06 CrossRefGoogle Scholar
  4. 4.
    Manilal S, Nguyen TM, Sewry CA, Morris GE (1996) The Emery-Dreifuss muscular dystrophy protein, emerin, is a nuclear membrane protein. Hum Mol Genet 5:801–808CrossRefGoogle Scholar
  5. 5.
    Paulin-Levasseur M, Blake DL, Julien M, Rouleau L (1996) The MAN antigens are non-lamin constituents of the nuclear lamina in vertebrate cells. Chromosoma 104:367–379CrossRefGoogle Scholar
  6. 6.
    Foisner R, Gerace L (1993) Integral membrane proteins of the nuclear envelope interact with lamins and chromosomes, and binding is modulated by mitotic phosphorylation. Cell 73:1267–1279CrossRefGoogle Scholar
  7. 7.
    Lin F, Blake DL, Callebaut I et al (2000) MAN1, an inner nuclear membrane protein that shares the LEM domain with lamina-associated polypeptide 2 and emerin. J Biol Chem 75:4840–4847CrossRefGoogle Scholar
  8. 8.
    Gerace L, Huber MD (2012) Nuclear lamina at the crossroads of the cytoplasm and nucleus. J Struct Biol 177:24–31.  https://doi.org/10.1016/j.jsb.2011.11.007 CrossRefGoogle Scholar
  9. 9.
    Burke B, Stewart CL (2013) The nuclear lamins: flexibility in function. Nat Rev Mol Cell Biol 14:13–24.  https://doi.org/10.1038/nrm3488 CrossRefGoogle Scholar
  10. 10.
    Andres V, Gonzalez JM (2009) Role of A-type lamins in signaling, transcription, and chromatin organization. J Cell Biol 187:945–957.  https://doi.org/10.1083/jcb.200904124 CrossRefGoogle Scholar
  11. 11.
    Gant TM, Harris CA, Wilson KL (1999) Roles of LAP2 proteins in nuclear assembly and DNA replication: truncated LAP2beta proteins alter lamina assembly, envelope formation, nuclear size, and DNA replication efficiency in Xenopus laevis extracts. J Cell Biol 144:1083–1096CrossRefGoogle Scholar
  12. 12.
    Ho CY, Jaalouk DE, Vartiainen MK, Lammerding J (2013) Lamin A/C and emerin regulate MKL1-SRF activity by modulating actin dynamics. Nature 497:507–511.  https://doi.org/10.1038/nature12105 CrossRefGoogle Scholar
  13. 13.
    Holaska JM, Wilson KL (2007) An emerin “proteome”: purification of distinct emerin-containing complexes from HeLa cells suggests molecular basis for diverse roles including gene regulation, mRNA splicing, signaling, mechanosensing, and nuclear architecture. Biochemistry 46:8897–8908.  https://doi.org/10.1021/bi602636m CrossRefGoogle Scholar
  14. 14.
    Segura TM, Kowalski AK, Craigie R et al (2002) Barrier-to-autointegration factor: major roles in chromatin decondensation and nuclear assembly. J Cell Biol 158:475–485CrossRefGoogle Scholar
  15. 15.
    Shtivelman E, Hensing TS, Dennis GR et al (2014) Molecular pathways and therapeutic targets in lung cancer. Oncotarget 5:1392–1433.  https://doi.org/10.18632/oncotarget.1891 Google Scholar
  16. 16.
    Idowu MO, Powers CN (2010) Lung cancer cytology: potential pitfalls and mimics. Int J Clin Exp Pathol 3:367–385Google Scholar
  17. 17.
    Davidson MR, Gazdar AF, Clarke BE (2013) The pivotal role of pathology in the management of lung cancer. J Thorac Dis 5:S463–S478.  https://doi.org/10.3978/j.issn.2072-1439.2013.08.43 Google Scholar
  18. 18.
    Travis WD, Muller-Hermelink HK et al (2004) Pathology and genetics of tumours of the lung, pleura, thymus and heart. WHO/IASLC classification of lung and pleural tumours. IARC Press, LyonGoogle Scholar
  19. 19.
    Ganti AK, West WW, Lackner RP, Kessinger A (2010) Current concepts in the diagnosis and management of small-cell lung cancer. Oncology 24:1034–1039Google Scholar
  20. 20.
    Cohen MH, Matthews MJ (1978) Small cell bronchogenic carcinoma: a distinct clinicopathologic entity. Semin Oncol 5:234–243Google Scholar
  21. 21.
    Ganti AK, West WW, Zhen W (2013) Current concepts in the management of small cell lung cancer. Indian J Med Res 137:1043–1051Google Scholar
  22. 22.
    Asioli S, Maletta F, Pacchioni D, Lupo R, Bussolati G (2010) Cytological detection of papillary thyroid carcinomas by nuclear membrane decoration with emerin staining. Virchows Arch 457:43–51.  https://doi.org/10.1007/s00428-010-0910-z CrossRefGoogle Scholar
  23. 23.
    Asioli S, Bussolati G (2009) Emerin immunohistochemistry reveals diagnostic features of nuclear membrane arrangement in thyroid lesions. Histopathology 54:571–579.  https://doi.org/10.1111/j.1365-2559.2009.03259.x CrossRefGoogle Scholar
  24. 24.
    Kinsella MD, Hinrichs B, Cohen C, Siddiqui MT (2013) Highlighting nuclear membrane staining in thyroid neoplasms with emerin: review and diagnostic utility. Diagn Cytopathol 41:97–504.  https://doi.org/10.1002/dc.22870 Google Scholar
  25. 25.
    Wang J, Kondo T, Yamane T, Nakazawa T, Oish N, Mochizuki K, Katoh R (2015) Expression of nuclear membrane proteins in normal, hyperplastic, and neoplastic thyroid epithelial cells. Virchows Arch 467:427–436.  https://doi.org/10.1007/s00428-015-1816-6 CrossRefGoogle Scholar
  26. 26.
    Coradeghini R, Barboro P, Rubagotti A, Boccardo F, Parodi S, Carmignani G, D’Arrigo C, Patrone E, Balbi C (2006) Differential expression of nuclear lamins in normal and cancerous prostate tissues. Oncol Rep 15:609–613Google Scholar
  27. 27.
    Sun S, Xu MZ, Poon RT, Day PJ, Luk JM (2010) Circulating Lamin B1 (LMNB1) biomarker detects early stages of liver cancer in patients. J Proteome Res 9:70–78.  https://doi.org/10.1021/pr9002118 CrossRefGoogle Scholar
  28. 28.
    Venables RS, McLean S, Luny D, Moteleb E, Morley S, Quinlan RA, Lane EB, Hutchison CJ (2001) Expression of individual lamins in basal cell carcinomas of the skin. Br J Cancer 84:512–519.  https://doi.org/10.1054/bjoc.2000.1632 CrossRefGoogle Scholar
  29. 29.
    Kim HJ, Hwang SH, Han ME, Baek S, Sim HE, Yoon S, Baek SY, Kim BS, Kim JH, Kim SY, Oh SO (2012) LAP2 is widely overexpressed in diverse digestive tract cancers and regulates motility of cancer cells. PLoS One 7:e39482.  https://doi.org/10.1371/journal.pone.0039482 CrossRefGoogle Scholar
  30. 30.
    Willis ND, Cox TR, Rahman-Casañs SF, Smits K, Przyborski SA, van den Brandt P, van Engeland M, Weijenberg M, Wilson RG, de Bruïne A, Hutchison CJ (2008) Lamin A/C is a risk biomarker in colorectal cancer. PLoS One 3:e2988.  https://doi.org/10.1371/journal.pone.0002988 CrossRefGoogle Scholar
  31. 31.
    Kaufmann SH, Mabry M, Jasti R, Shaper JH (1991) Differential expression of nuclear envelope lamins A and C in human lung cancer cell lines. Cancer Res 51:6Google Scholar
  32. 32.
    Broers JL, Raymond Y, Rot MK, Kuijpers H, Wagenaar SS, Ramaekers FC (1993) Nuclear A-type lamins are differentially expressed in human lung cancer subtypes. Am J Pathol 143:211–220Google Scholar
  33. 33.
    Machiels BM, Broers JL, Raymond Y, de Ley L, Kuijpers HJ, Caberg NE, Ramaekers FC (1995) Abnormal A-type lamin organization in a human lung carcinoma cell line. Eur J Cell Biol 67:328–335Google Scholar
  34. 34.
    Christopher DMF (2007) Diagnostic histopathology of tumors. In: Cesar AM, Saul S (eds) Tumor of the lung and pleura,3 edn. 189Google Scholar
  35. 35.
    Denais C, Lammerding J (2014) Nuclear mechanics in cancer. Adv Exp Med Biol 773:435–470.  https://doi.org/10.1007/978-1-4899-8032-8_20 CrossRefGoogle Scholar
  36. 36.
    Schreiber KH, Kennedy BK (2013) When lamins go bad: nuclear structure and disease. Cell 152:1365–1375.  https://doi.org/10.1016/j.cell.2013.02.015 CrossRefGoogle Scholar
  37. 37.
    Zwerger M, Ho CY, Lammerding J (2011) Nuclear mechanics in disease. Annu Rev Biomed Eng 13:397–428.  https://doi.org/10.1146/annurev-bioeng-071910-124736 CrossRefGoogle Scholar
  38. 38.
    Capo-chichi CD, Cai KQ, Testa JR et al (2006) Loss of GATA6 leads to nuclear deformation and aneuploidy in ovarian cancer. Mol Cell Biol 29:4766–4777.  https://doi.org/10.1128/MCB.00087-09 CrossRefGoogle Scholar
  39. 39.
    Broers JL, Ramaekers FC, Bonne G, Yaou RB et al (2006) Nuclear lamins: laminopathies and their role in premature ageing. Physiol Rev 86:967–1008.  https://doi.org/10.1152/physrev.00047.2005 CrossRefGoogle Scholar
  40. 40.
    Kontogianni K, Nicholson AG, Butcher D, Sheppard MN (2005) CD56: a useful tool for the diagnosis of small cell lung carcinomas on biopsies with extensive crush artefact. J Clin Pathol 58:978–980.  https://doi.org/10.1136/jcp.2004.023044 CrossRefGoogle Scholar
  41. 41.
    Kevin EK, Thomas US (2017) The nuclear pore complex as a flexible and dynamic gate. Cell 164(6):1162–1171.  https://doi.org/10.1016/j.cell.2016.01.034 Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pathology, Interdisciplinary Graduate School of Medicine and EngineeringUniversity of YamanashiYamanashiJapan
  2. 2.Department of Public HealthXi’an Medical UniversityXi’anChina

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