Cellular Oncology

, Volume 39, Issue 2, pp 161–174 | Cite as

Altered Lamin A/C splice variant expression as a possible diagnostic marker in breast cancer

  • Ahmad Aljada
  • Joseph Doria
  • Ayman M. Saleh
  • Shahad H. Al-Matar
  • Sarah AlGabbani
  • Heba Bani Shamsa
  • Ahmad Al-Bawab
  • Altayeb Abdalla Ahmed
Original Paper
First Online:
Accepted:

Abstract

Background

Lamin A/C alternative splice variants (Lamin A, Lamin C, Lamin AΔ10 and Lamin AΔ50) have been implicated in cell cycle regulation, DNA replication, transcription regulation, cellular differentiation, apoptosis and aging. In addition, loss of Lamin A/C expression has been observed in several cancers, including breast cancer, and it has been found that Lamin A/C suppression may lead to cancer-like aberrations in nuclear morphology and aneuploidy. Based on these observations, we hypothesized that Lamin A/C transcript variant quantification might be employed for the diagnosis of breast cancer.

Methods

Newly designed TaqMan qRT-PCR assays for the analysis of Lamin A/C splice variants were validated and their use as biomarkers for the diagnosis of breast cancer was assessed using 16 normal breast tissues and 128 breast adenocarcinomas. In addition, the expression levels of the Lamin A/C transcript variants were measured in samples derived from seven other types of cancer.

Results

We found that the expression level of Lamin C was significantly increased in the breast tumors tested, whereas the expression levels of Lamin A and Lamin AΔ50 were significantly decreased. No significant change in Lamin AΔ10 expression was observed. Our data also indicated that the Lamin C : Lamin A mRNA ratio was increased in all clinical stages of breast cancer. Additionally, we observed increased Lamin C : Lamin A mRNA ratios in liver, lung and thyroid carcinomas and in colon, ovary and prostate adenocarcinomas.

Conclusions

From our data we conclude that the Lamin C : Lamin A mRNA ratio is increased in breast cancer and that this mRNA ratio may be of diagnostic use in all clinical stages of breast cancer and, possibly, also in liver, lung, thyroid, colon, ovary and prostate cancers.

Keywords

Lamin A/C Progerin Breast cancer Metastasis Tumor marker 
This is a preview of subscription content, log in to check access.

Notes

Acknowledgments

This work was supported by the King Abdullah International Medical Research Center (KAIMRC) and National Guard Health Affairs, and conducted at the College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Kingdom of Saudi Arabia.

Author’s contributions

AA and AS conceived the experimental design. AJ and AS supervised the project. HS, JD, AB, SM and AG designed and performed the experiments and AJ, AA and JD analyzed the data and wrote the paper.

Compliance with ethical standards

Competing interests

The authors have no conflict of interest to declare.

References

  1. 1.
    J.L. Broers, B.M. Machiels, G.J. van Eys, H.J. Kuijpers, E.M. Manders, R. van Driel, F.C. Ramaekers, Dynamics of the nuclear lamina as monitored by GFP-tagged A-type lamins. J. Cell Sci. 112(Pt 20), 3463–3475 (1999)PubMedGoogle Scholar
  2. 2.
    A. Taddei, F. Hediger, F.R. Neumann, S.M. Gasser, The function of nuclear architecture: a genetic approach. Annu. Rev. Genet. 38, 305–345 (2004)CrossRefPubMedGoogle Scholar
  3. 3.
    T. Shimi, R.D. Goldman, Nuclear lamins and oxidative stress in cell proliferation and longevity. Adv. Exp. Med. Biol. 773, 415–430 (2014)CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    H. Cao, R.A. Hegele, LMNA is mutated in Hutchinson-Gilford progeria (MIM 176670) but not in Wiedemann-Rautenstrauch progeroid syndrome (MIM 264090). J. Hum. Genet. 48, 271–274 (2003)CrossRefPubMedGoogle Scholar
  5. 5.
    A. De Sandre-Giovannoli, R. Bernard, P. Cau, C. Navarro, J. Amiel, I. Boccaccio, S. Lyonnet, C.L. Stewart, A. Munnich, M. Le Merrer, N. Levy, Lamin a truncation in Hutchinson-Gilford progeria. Science 300, 2055 (2003)CrossRefPubMedGoogle Scholar
  6. 6.
    M. Eriksson, W.T. Brown, L.B. Gordon, M.W. Glynn, J. Singer, L. Scott, M.R. Erdos, C.M. Robbins, T.Y. Moses, P. Berglund, A. Dutra, E. Pak, S. Durkin, A.B. Csoka, M. Boehnke, T.W. Glover, F.S. Collins, Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 423, 293–298 (2003)CrossRefPubMedGoogle Scholar
  7. 7.
    B.M. Machiels, A.H. Zorenc, J.M. Endert, H.J. Kuijpers, G.J. van Eys, F.C. Ramaekers, J.L. Broers, An alternative splicing product of the lamin A/C gene lacks exon 10. J. Biol. Chem. 271, 9249–9253 (1996)CrossRefPubMedGoogle Scholar
  8. 8.
    L. Mounkes, S. Kozlov, B. Burke, C.L. Stewart, The laminopathies: nuclear structure meets disease. Curr. Opin. Genet. Dev. 13, 223–230 (2003)CrossRefPubMedGoogle Scholar
  9. 9.
    A. Muchir, H.J. Worman, The nuclear envelope and human disease. Physiology (Bethesda) 19, 309–314 (2004)CrossRefGoogle Scholar
  10. 10.
    D. McClintock, D. Ratner, M. Lokuge, D.M. Owens, L.B. Gordon, F.S. Collins, K. Djabali, The mutant form of lamin A that causes Hutchinson-Gilford progeria is a biomarker of cellular aging in human skin. PLoS One 2, e1269 (2007)CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    B.C. Capell, F.S. Collins, Human laminopathies: nuclei gone genetically awry. Nat. Rev. Genet. 7, 940–952 (2006)CrossRefPubMedGoogle Scholar
  12. 12.
    N. Sylvius, F. Tesson, Lamin A/C and cardiac diseases. Curr. Opin. Cardiol. 21, 159–165 (2006)CrossRefPubMedGoogle Scholar
  13. 13.
    C.D. Capo-chichi, K.Q. Cai, J. Smedberg, P. Ganjei-Azar, A.K. Godwin, X.X. Xu, Loss of A-type lamin expression compromises nuclear envelope integrity in breast cancer. Chin. J. Cancer 30, 415–425 (2011)CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    B.M. Machiels, J.L. Broers, Y. Raymond, L. de Ley, H.J. Kuijpers, N.E. Caberg, F.C. Ramaekers, Abnormal A-type lamin organization in a human lung carcinoma cell line. Eur. J. Cell Biol. 67, 328–335 (1995)PubMedGoogle Scholar
  15. 15.
    C.D. Capo-chichi, B. Aguida, N.W. Chabi, Q.K. Cai, G. Offrin, V.K. Agossou, A. Sanni, X.-X. Xu, Lamin A/C deficiency is an independent risk factor for cervical cancer. Cell. Oncol. (2015). doi: 10.1007/s13402-015-0252-6
  16. 16.
    B. Stadelmann, E. Khandjian, A. Hirt, A. Luthy, R. Weil, H.P. Wagner, Repression of nuclear lamin A and C gene expression in human acute lymphoblastic leukemia and non-Hodgkin’s lymphoma cells. Leuk. Res. 14, 815–821 (1990)CrossRefPubMedGoogle Scholar
  17. 17.
    R. Agrelo, F. Setien, J. Espada, M.J. Artiga, M. Rodriguez, A. Perez-Rosado, A. Sanchez-Aguilera, M.F. Fraga, M.A. Piris, M. Esteller, Inactivation of the lamin A/C gene by CpG island promoter hypermethylation in hematologic malignancies, and its association with poor survival in nodal diffuse large B-cell lymphoma. J. Clin. Oncol. 23, 3940–3947 (2005)CrossRefPubMedGoogle Scholar
  18. 18.
    J.D. Debes, T.J. Sebo, H.V. Heemers, B.R. Kipp, D.L. Haugen, C.M. Lohse, D.J. Tindall, p300 modulates nuclear morphology in prostate cancer. Cancer Res. 65, 708–712 (2005)CrossRefPubMedGoogle Scholar
  19. 19.
    L. Kong, G. Schafer, H. Bu, Y. Zhang, H. Klocker, Lamin A/C protein is overexpressed in tissue-invading prostate cancer and promotes prostate cancer cell growth, migration and invasion through the PI3K/AKT/PTEN pathway. Carcinogenesis 33, 751–759 (2012)CrossRefPubMedGoogle Scholar
  20. 20.
    N.D. Willis, T.R. Cox, S.F. Rahman-Casans, K. Smits, S.A. Przyborski, P. van den Brandt, M. van Engeland, M. Weijenberg, R.G. Wilson, A. de Bruine, C.J. Hutchison, Lamin A/C is a risk biomarker in colorectal cancer. PLoS One 3, e2988 (2008)CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    N.D. Willis, R.G. Wilson, C.J. Hutchison, Lamin A: a putative colonic epithelial stem cell biomarker which identifies colorectal tumours with a more aggressive phenotype. Biochem. Soc. Trans. 36, 1350–1353 (2008)CrossRefPubMedGoogle Scholar
  22. 22.
    E.J. Belt, R.J. Fijneman, E.G. van den Berg, H. Bril, P.M. Delis-van Diemen, M. Tijssen, H.F. van Essen, E.S. de Lange-de Klerk, J.A. Belien, H.B. Stockmann, S. Meijer, G.A. Meijer, Loss of lamin A/C expression in stage II and III colon cancer is associated with disease recurrence. Eur. J. Cancer 47, 1837–1845 (2011)CrossRefPubMedGoogle Scholar
  23. 23.
    P. Scaffidi, T. Misteli, Reversal of the cellular phenotype in the premature aging disease Hutchinson-Gilford progeria syndrome. Nat. Med. 11, 440–445 (2005)CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    S. Rodriguez, F. Coppede, H. Sagelius, M. Eriksson, Increased expression of the Hutchinson-Gilford progeria syndrome truncated lamin A transcript during cell aging. Eur. J. Hum. Genet. 17, 928–937 (2009)CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    J.I. Toth, S.H. Yang, X. Qiao, A.P. Beigneux, M.H. Gelb, C.L. Moulson, J.H. Miner, S.G. Young, L.G. Fong, Blocking protein farnesyltransferase improves nuclear shape in fibroblasts from humans with progeroid syndromes. Proc. Natl. Acad. Sci. U. S. A. 102, 12873–12878 (2005)CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    C.L. Moulson, L.G. Fong, J.M. Gardner, E.A. Farber, G. Go, A. Passariello, D.K. Grange, S.G. Young, J.H. Miner, Increased progerin expression associated with unusual LMNA mutations causes severe progeroid syndromes. Hum. Mutat. 28, 882–889 (2007)CrossRefPubMedGoogle Scholar
  27. 27.
    R. Al-Saaidi, P. Bross, Do lamin A and lamin C have unique roles? Chromosoma 124, 1–12 (2015)CrossRefPubMedGoogle Scholar
  28. 28.
    I.C. Lopez-Mejia, M. de Toledo, C. Chavey, L. Lapasset, P. Cavelier, C. Lopez-Herrera, K. Chebli, P. Fort, G. Beranger, L. Fajas, E.Z. Amri, F. Casas, J. Tazi, Antagonistic functions of LMNA isoforms in energy expenditure and lifespan. EMBO Rep. 15, 529–539 (2014)CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    J.L. Broers, B.M. Machiels, H.J. Kuijpers, F. Smedts, R. van den Kieboom, Y. Raymond, F.C. Ramaekers, A- and B-type lamins are differentially expressed in normal human tissues. Histochem. Cell Biol. 107, 505–517 (1997)CrossRefPubMedGoogle Scholar
  30. 30.
    M.A. Eckersley-Maslin, J.H. Bergmann, Z. Lazar, D.L. Spector, Lamin A/C is expressed in pluripotent mouse embryonic stem cells. Nucleus 4, 53–60 (2013)CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    R.A. Rober, K. Weber, M. Osborn, Differential timing of nuclear lamin A/C expression in the various organs of the mouse embryo and the young animal: a developmental study. Development 105, 365–378 (1989)PubMedGoogle Scholar
  32. 32.
    J. Swift, I.L. Ivanovska, A. Buxboim, T. Harada, P.C. Dingal, J. Pinter, J.D. Pajerowski, K.R. Spinler, J.W. Shin, M. Tewari, F. Rehfeldt, D.W. Speicher, D.E. Discher, Nuclear lamin-A scales with tissue stiffness and enhances matrix-directed differentiation. Science 341, 1240104 (2013)CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    H.J. Jung, J.M. Lee, S.H. Yang, S.G. Young, L.G. Fong, Nuclear lamins in the brain - new insights into function and regulation. Mol. Neurobiol. 47, 290–301 (2013)CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    T. Wakabayashi, T. Mori, Y. Hirahara, T. Koike, Y. Kubota, Y. Takamori, H. Yamada, Nuclear lamins are differentially expressed in retinal neurons of the adult rat retina. Histochem. Cell Biol. 136, 427–436 (2011)CrossRefPubMedGoogle Scholar
  35. 35.
    C.J. Hutchison, H.J. Worman, A-type lamins: guardians of the soma? Nat. Cell Biol. 6, 1062–1067 (2004)CrossRefPubMedGoogle Scholar
  36. 36.
    F. Lin, H.J. Worman, Expression of nuclear lamins in human tissues and cancer cell lines and transcription from the promoters of the lamin A/C and B1 genes. Exp. Cell Res. 236, 378–384 (1997)CrossRefPubMedGoogle Scholar
  37. 37.
    A. Matsumoto, M. Hieda, Y. Yokoyama, Y. Nishioka, K. Yoshidome, M. Tsujimoto, N. Matsuura, Global loss of a nuclear lamina component, lamin A/C, and LINC complex components SUN1, SUN2, and nesprin-2 in breast cancer. Canc. Med. 4, 1547–1557 (2015)CrossRefGoogle Scholar
  38. 38.
    U. Wazir, M.H. Ahmed, J.M. Bridger, A. Harvey, W.G. Jiang, A.K. Sharma, K. Mokbel, The clinicopathological significance of lamin A/C, lamin B1 and lamin B receptor mRNA expression in human breast cancer. Cell. Mol. Biol. Lett. 18, 595–611 (2013)CrossRefPubMedGoogle Scholar
  39. 39.
    W.S. Lee, J.J. Jung, H.C. Jeung, S.W. Noh, B.K. Oh, K.Y. Kim, T.S. Kim, H.C. Chung, J.K. Roh, S.Y. Rha, Methylation status of lamin A/C in gastric cancer cell lines. Hepatogastroenterology 59, 1313–1318 (2012)CrossRefPubMedGoogle Scholar
  40. 40.
    D. Constantinescu, H.L. Gray, P.J. Sammak, G.P. Schatten, A.B. Csoka, Lamin A/C expression is a marker of mouse and human embryonic stem cell differentiation. Stem Cells 24, 177–185 (2006)CrossRefPubMedGoogle Scholar
  41. 41.
    D. Lourim, J.J. Lin, Expression of nuclear lamin A and muscle-specific proteins in differentiating muscle cells in ovo and in vitro. J. Cell Biol. 109, 495–504 (1989)CrossRefPubMedGoogle Scholar
  42. 42.
    B. Liu, J. Wang, K.M. Chan, W.M. Tjia, W. Deng, X. Guan, J.D. Huang, K.M. Li, P.Y. Chau, D.J. Chen, D. Pei, A.M. Pendas, J. Cadinanos, C. Lopez-Otin, H.F. Tse, C. Hutchison, J. Chen, Y. Cao, K.S. Cheah, K. Tryggvason, Z. Zhou, Genomic instability in laminopathy-based premature aging. Nat. Med. 11, 780–785 (2005)CrossRefPubMedGoogle Scholar
  43. 43.
    A. Peter, R. Stick, Evolution of the lamin protein family: what introns can tell. Nucleus 3, 44–59 (2012)CrossRefPubMedGoogle Scholar
  44. 44.
    Y.S. Oh, D.G. Kim, G. Kim, E.C. Choi, B.K. Kennedy, Y. Suh, B.J. Park, S. Kim, Downregulation of lamin A by tumor suppressor AIMP3/p18 leads to a progeroid phenotype in mice. Aging Cell 9, 810–822 (2010)CrossRefPubMedGoogle Scholar

Copyright information

© International Society for Cellular Oncology 2016

Authors and Affiliations

  • Ahmad Aljada
    • 1
    • 2
  • Joseph Doria
    • 3
  • Ayman M. Saleh
    • 1
    • 2
  • Shahad H. Al-Matar
    • 1
  • Sarah AlGabbani
    • 1
  • Heba Bani Shamsa
    • 2
  • Ahmad Al-Bawab
    • 1
  • Altayeb Abdalla Ahmed
    • 1
  1. 1.Department of Basic Medical SciencesKing Saud bin Abdulaziz University for Health SciencesRiyadhKingdom of Saudi Arabia
  2. 2.King Abdullah International Medical Research Center (KAIMRC)National Guard Health AffairsRiyadhKingdom of Saudi Arabia
  3. 3.Department of NeurologyVirginia Commonwealth University Medical CenterRichmondUSA

Personalised recommendations