Reduced Expression of Limd1 in Ulcerative Oral Epithelium Associated with Tobacco and Areca Nut

  • Maiti, Guru Prasad (Department of Oncogene Regulation, Chittaranjan National Cancer Institute) ;
  • Ghosh, Amlan (Department of Oncogene Regulation, Chittaranjan National Cancer Institute) ;
  • Chatterjee, Ramdas (Oral Cancer Foundation) ;
  • Roy, Anup (North Bengal Medical College) ;
  • Sharp, Tyson V. (School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre) ;
  • Roychoudhury, Susanta (Molecular and Human Genetics and Genomic Division, Indian Institute of Chemical Biology) ;
  • Panda, Chinmay Kumar (Department of Oncogene Regulation, Chittaranjan National Cancer Institute)
  • Published : 2012.09.30


Purpose: The aim of this study was to cast light on initiating molecular events associated with the development of premalignant oral lesions induced by tobacco and/or areca nut. Method: Immunohistochemical analyses of cell cycle regulatory proteins (LIMD1, RBSP3, p16, RB, phosphorylated RB, p53), EGFR and SH3GL2 (EGFR associated protein) were performed with inflammatory/ulcerative epithelium and adjacent hyperplastic/mild dysplastic lesions. Results: No change in expression of the proteins was seen in inflammatory epithelium. Reduced nuclear expression of LIMD1 was evident in ulcerative epithelium. In hyperplastic lesions, reduced expression of RBSP3, p16, SH3GL2 and overexpression of p-RB and EGFR were apparent. Reduced nuclear expression of p53 was observed in mild dysplastic lesions. Conclusion: Our data suggest that inactivation of LIMD1 in ulcerative epithelium might predispose the tissues to alterations of other cell cycle regulatory and EGFR signaling proteins needed for the development of premalignant oral lesions.


  1. Califano J, van der Riet P, Westra W et al (1996). Genetic progression model for head and neck cancer: implications for field cancerization. Cancer Res, 56, 2488-92.
  2. Dikic I. Mechanisms controlling (2003). EGF receptor endocytosis and degradation. Biochem Soc Trans, 31, 1178-81.
  3. Foxler DE, James V, Shelton SJ, et al (2011). PU.1 is a major transcriptional activator of the tumour suppressor gene LIMD1. FEBS letters, 585, 1089-96.
  4. Ghosh A, Ghosh S, Maiti GP et al (2009). SH3GL2 and CDKN2A/2B loci are independently altered in early dysplastic lesions of head and neck: correlation with HPV infection and tobacco habit. J Pathol, 217, 408-19.
  5. Ghosh A, Ghosh S, Maiti GP et al (2010). Frequent alterations of the candidate genes hMLH1, ITGA9 and RBSP3 in early dysplastic lesions of head and neck: clinical and prognostic significance. Cancer Sci, 101, 1511-20.
  6. Ghosh S, Ghosh A, Maiti GP et al (2010). LIMD1 is more frequently altered than RB1 in head and neck squamous cell carcinoma: clinical and prognostic implications. Mol Cancer, 9, 58.
  7. Leemans CR, Braakhuis BJ, Brakenhoff RH (2010). The molecular biology of head and neck cancer. Nature reviews 2010, 11, 9-22.
  8. Munoz-Corcuera M, Esparza-Gomez G, Gonzalez-Moleset al (2009).Oral ulcers: clinical aspects. A tool for dermatologists. Part II.Chronic ulcers. Clinical and Experimental Dermatology, 34, 456-461.
  9. Mitsudomi T, Yatabe Y (2007). Mutations of the epidermal growth factor receptor gene and related genes as determinants of epidermal growth factor receptor tyrosine kinase inhibitors sensitivity in lung cancer. Cancer Sci, 98, 1817-24.
  10. Mitra S, Banerjee S, Misra C et al (2007). Interplay between human papilloma virus infection and p53 gene alterations in head and neck squamous cell carcinoma of an Indian patient population. Journal of clinical pathology, 60, 1040-7.
  11. Pandya S, Chaudhary AK, Singh M, Singh M, Mehrotra R (2009). Correlation of histopathological diagnosis with habits and clinical findings in oral submucous fibrosis. Head & Neck Oncology, 1, 10.
  12. Perez-Ordonez B, Beauchemin M, Jordan RC (2006). Molecular biology of squamous cell carcinoma of the head and neck. J Clin Pathol, 59, 445-53.
  13. Perrone F, Suardi S, Pastore E et al (2006). Molecular and cytogenetic subgroups of oropharyngeal squamous cell carcinoma. Clin Cancer Res, 12, 6643-51.
  14. Ren Y, Xu HW, Davey F et al (2008). Endophilin I expression is increased in the brains of Alzheimer disease patients. J Biol Chem, 283, 5685-91.
  15. Sengupta S, Chakrabarti S, Roy A et al (2007). Inactivation of human mutL homolog 1 and mutS homolog 2 genes in head and neck squamous cell carcinoma tumors and leukoplakia samples by promoter hypermethylation and its relation with microsatellite instability phenotype. Cancer, 109, 703-12.
  16. Sharp TV, Al-Attar A, Foxler DE et al (2008). The chromosome 3p21.3-encoded gene, LIMD1, is a critical tumor suppressor involved in human lung cancer development. Proc Natl Acad Sci U S A , 105, 19932-7.
  17. Sinha S, Singh RK, Alam N et al (2008). Frequent alterations of hMLH1 and RBSP3/HYA22 at chromosomal 3p22.3 region in early and late-onset breast carcinoma: clinical and prognostic significance. Cancer Sci, 99, 1984-91.
  18. Sinha S, Chunder N, Mukherjee N et al (2008). Frequent deletion and methylation in SH3GL2 and CDKN2A loci are associated with early- and late-onset breast carcinoma. Ann Surg Oncol, 1, 1070-80.
  19. Spendlove I, Al-Attar A, Watherstone O et al (2008). Differential subcellular localisation of the tumour suppressor protein LIMD1 in breast cancer correlates with patient survival. Int J Cancer, 123, 2247-53.
  20. Wu Y, Evers BM, Zhou BP (2009). Small C-terminal domain phosphatase enhances snail activity through dephosphorylation. The Journal of biological chemistry, 284, 640-8.
  21. Yeo M, Lin PS, Dahmus ME, Gill GN (2003). A novel RNA polymerase II C-terminal domain phosphatase that preferentially dephosphorylates serine 5. J Biol Chem, 278, 26078-85.
  22. Zhang L, Michelsen C, Cheng X et al (1997). Molecular analysis of oral lichen planus. A premalignant lesion? Am J Pathol, 151, 323-7.

Cited by

  1. Reduction of Proliferation and Induction of Apoptosis are Associated with Shrinkage of Head and Neck Squamous Cell Carcinoma due to Neoadjuvant Chemotherapy vol.14, pp.11, 2013,
  2. in oral squamous cell carcinoma vol.230, pp.3, 2013,
  3. Molecular progression of head and neck squamous cell carcinoma vol.60, pp.2, 2017,
  4. Deregulation of LIMD1–VHL–HIF-1α–VEGF pathway is associated with different stages of cervical cancer vol.475, pp.10, 2018,