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Mutation Analysis of the Dimer Forming Domain of the Caspase 8 Gene in Oral Submucous Fibrosis and Squamous Cell Carcinomas

  • Menon, Uthara (Department of Oral Medicine and Radiology, Faculty of Dentistry, SRM University) ;
  • Poongodi, V (Department of Oral Medicine and Radiology, Faculty of Dentistry, SRM University) ;
  • Raghuram, Pitty Hari (Department of Oral Medicine and Radiology, Faculty of Dentistry, SRM University) ;
  • Ashokan, Kannan (Department of Oral Medicine and Radiology, Faculty of Dentistry, SRM University) ;
  • Govindarajan, Giri Valanthan Veda (Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Sri Ramachandra University) ;
  • Ramanathan, Arvind (Enable Biolabs, Madurai Meenakshipuram Extension)
  • Published : 2015.06.26

Abstract

Background: Missense and frame-shift mutations within the dimer forming domain of the caspase 8 gene have been identified in several cancers. However, the genetic status of this region in precancerous lesions, like oral submucous fibrosis (OSMF), and well differentiated oral squamous cell carcinomas (OSCCs) in patients from southern region of India is not known, and hence the present study was designed to address this issue. Materials and Methods: Genomic DNA isolated from biopsy tissues of thirty one oral submucous fibrosis and twenty five OSCC samples were subjected to PCR amplification with intronic primers flanking exon 7 of the caspase 8 gene. The PCR amplicons were subsequently subjected to direct sequencing to elucidate the status of mutation. Results: Sequence analysis identified a frame-shift and a novel missense mutation in two out of twenty five OSCC samples. The frame-shift mutation was due to a two base pair deletion (c.1225_1226delTG), while the missense mutation was due to substitution of wild type cysteine residue with phenylalanine at codon 426 (C426F). The missense mutation, however, was found to be heterozygous as the wild type C426C codon was also present. None of the OSMF samples carried mutations. Conclusions: The identification of mutations in OSCC lesions but not OSMF suggests that dimer forming domain mutations in caspase 8 may be limited to malignant lesions. The absence of mutations in OSMF also suggests that the samples analyzed in the present study may not have acquired transforming potential. To the best of our knowledge this is the first study to have explored and identified frame-shift and novel missense mutations in OSCC tissue samples.

Keywords

Caspase 8 mutation in oral carcinoma;loss of function of caspase 8;caspase 8 mutation in cancer

References

  1. Alenzi FQ, Lotfy M, Wyse R (2010). Swords of cell death: caspase activation and regulation. Asian Pac J Cancer Prev, 2, 271-80.
  2. Andon FT and Fadeel B (2013). Programmed cell death: molecular mechanisms and implications for safety assessment of nanomaterials. Acc Chem Res, 46, 733-42. https://doi.org/10.1021/ar300020b
  3. Barca O, Seoane M, Senaris RM and Arce VM (2013). Fas/CD95 ligation induces proliferation of primary fetal astrocytes through a mechanism involving caspase 8-mediated ERK activation. Cell Physiol Biochem, 32, 111-20.
  4. Chandrasekharan D, Ramanathan A (2014). Identification of a novel heterozygous truncation mutation in exon 1 of ARHGAP29 in an Indian subject with nonsyndromic cleft lip with cleft palate. Eur J Dentistry, 8, 528-532. https://doi.org/10.4103/1305-7456.143637
  5. Crawford ED, Wells JA (2011). Caspase substrates and cellular remodelling. Annu Rev Biochem, 80, 1055-87. https://doi.org/10.1146/annurev-biochem-061809-121639
  6. Hsue SS, Wang WC, Chen CH, Lin CC, Chen YK, Lin LM (2007). Malignant transformation in 1458 patients with potentially malignant oral mucosal disorders: a follow-up study based in a Taiwanese hospital. J Oral Pathol Med, 36, 25-9.
  7. Keller N, Grutter MG and Zerbe O (2010). Studies of the molecular mechanism of caspase-8 activation by solution NMR. Cell Death Differ, 17, 710-8. https://doi.org/10.1038/cdd.2009.155
  8. India Project Team of the International Cancer Genome Consortium (IPT-ICGC) (2013). Mutational landscape of gingivo-buccal oral squamous cell carcinoma reveals new recurrently-mutated genes and molecular subgroups. Nat Commun, 4, 2873.
  9. Indian Genome Variation Consortium (IGVC) (2008). Genetic landscape of the people of India: a canvas for disease gene exploration. J Genet, 87, 3-20. https://doi.org/10.1007/s12041-008-0002-x
  10. Jayaraman B, Valiathan GM, Jayakumar K, et al (2012). Lack of mutation in p53 and H-ras genes in phenytoin induced gingival overgrowth suggests its non cancerous nature. Asian Pac J Cancer Prev, 13, 5535-8. https://doi.org/10.7314/APJCP.2012.13.11.5535
  11. Kaneda Y, Shimamoto H, Matsumura K, et al (2006). Role of caspase 8 as a determinant in chemosensitivity of p53-mutated head and neck squamous cell carcinoma cell lines. J Med Dent Sci, 53, 57-66.
  12. Kuranaga E (2012). Beyond apoptosis: caspase regulatory mechanisms and functions in vivo. Genes Cells, 17, 83-97. https://doi.org/10.1111/j.1365-2443.2011.01579.x
  13. Li K, Wu D, Chen X, et al (2014). Current and emerging biomarkers of cell death in human disease. Biomed Res Int, 2014, 690103.
  14. McIlwain DR, Berger T and Mak TW (2013). Caspase functions in cell death and disease. Cold Spring Harb Perspect Biol, 5, 8656. https://doi.org/10.1101/cshperspect.a008656
  15. Parrish AB, Freel CD, Kornbluth S (2013). Cellular mechanisms controlling caspase activation and function. Cold Spring Harb Perspect Biol, 5, 8672. https://doi.org/10.1101/cshperspect.a008672
  16. Pingoud-Meier C, Lang D, Janss AJ, et al (2003). Loss of caspase-8 protein expression correlates with unfavorable survival outcome in childhood medulloblastoma. Clin Cancer Res, 9, 6401-9.
  17. Podgorski I, Sloane BF (2006). Loss of caspase-8 in tumor cells: mechanism to overcome integrin-mediated death? Mol Interv, 6, 132-6. https://doi.org/10.1124/mi.6.3.3
  18. Prinos P, Lacoste MC, Wong J, Bonneau AM, Georges E (2011). Mutation of cysteine 21 inhibits nucleophosmin/B23 oligomerization and chaperone activity. Int J Biochem Mol Biol, 2, 24-30.
  19. Ryoo HD, Bergmann A (2012). The role of apoptosis-induced proliferation for regeneration and cancer. Cold Spring Harb Perspect Biol, 4, 8797. https://doi.org/10.1101/cshperspect.a008797
  20. Sankari SL, Masthan KM, Babu NA, Bhattacharjee T, Elumalai M (2012). Apoptosis in cancer-an update. Asian Pac J Cancer Prev, 10, 4873-8.
  21. Soung YH, Lee JW, Kim SY, et al (2005). Caspase-8 gene is frequently inactivated by the frameshift somatic mutation 1225_1226delTG in hepatocellular carcinomas. Oncogene, 24, 141-7. https://doi.org/10.1038/sj.onc.1208244
  22. Walczak H (2013). Death receptor-ligand systems in cancer, cell death, and inflammation. Cold Spring Harb Perspect Biol, 5, 8698. https://doi.org/10.1101/cshperspect.a008698
  23. Wallach D, Kang TB, Rajput A, et al (2010). Anti-inflammatory functions of the "apoptotic" caspases. Ann N Y Acad Sci, 1209, 17-22. https://doi.org/10.1111/j.1749-6632.2010.05742.x
  24. Weinlich R, Oberst A, Dillon CP, et al (2013). Protective roles for caspase-8 and cFLIP in adult homeostasis. Cell Rep, 5, 340-8. https://doi.org/10.1016/j.celrep.2013.08.045
  25. Zhang CD, Li HT, Liu K, et al (2014). Impact of caspase-8 (CASP8) -652 6N del and D302H polymorphisms on prostate cancer in different ethnic groups. Asian Pac J Cancer Prev, 18, 7713-8.

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