CNR - Institute of Neuroscience CNR
Institute of Neuroscience
 

Project

Retinoblastoma: pathogenesis and therapeutic perspectives

 

Retinoblastoma is the most common intra-ocular malignancy in children. Human retinoblastoma occurs in two forms: a non-heritable form, which is usually unilateral, and a heritable form, which is often bilateral with autosomal dominant expression. Both forms have been ascribed to biallelic mutation of the Rb1/p105 gene and the consequent loss of its tumor suppressive functions. In the familial form one mutated copy is inherited from an affected parent and a further mutation accumulates to determine the disease while in the sporadic form both mutations occurs spontaneously. Notwithstanding that mutation of pRb1/p105 is common to all retinoblastomas, much evidence indicates that loss of pRb1/p105 from a developing retinal cell is insufficient for malignancy. In a study performed in collaboration with the Institute of Pathological Anatomy of the University - Siena and with the Institute of Clinical Physiology CNR - Siena, we showed that, in some sporadic retinoblastoma, also the expression of pRb2/p130 is impaired and its loss of expression correlates with low apoptotic index suggesting that in sporadic retinoblastoma also Rb2/p130 gene could be mutated or functionally inactivated.

Mutational analysis of Rb2/p130 in primary tumors showed a tight correlation between Exon 1 mutations and pRb2/p130 expression level in sporadic retinoblastoma. These mutations are located within a CpG-enriched region prone to de novo methylation. Analysis of Rb2/p130 methylation status revealed that epigenetic events, most probably consequent to the Exon 1 mutations, determined the observed phenotype. Treatment of Weri-Rb1 cell line with 5-Aza-dC induced an increase in expression level of pRb2/p130, E2F1, p73 and p53. The overall of our results highlights a crucial role of epigenetic events in sporadic retinoblastoma and opens a perspective for new therapeutic approaches.

 

To identify epigenetically silenced genes and evaluate the possible use of demethylating agent as drug for retinoblastoma therapy, we recently performed cDNA microarray analysis on Weri-Rb1 cells treated with the demethylating agent 5-Aza-2-deoxycytidine (5-Aza-dC). We found that the exposition to the demethylating agent determines the re-expression of genes related to cell cycle arrest, DNA mismatch repair, p53 pathway, Fas- and TRAIL-mediated apoptotic signals. On the other hand, as consequence of 5-Aza-dC treatment, it is observed a down-regulation of key genes of NFκB and RAS/MAPK signaling pathways responsible of cell cycle progression and neoplastic transformation.

Publications

  • Tosi GM, Trimarchi C, Macaluso M, La Sala D, Ciccodicola A, Lazzi S, Massaro-Giordano M, Caporossi A, Giordano A, Cinti C (2005) Genetic and epigenetic alterations of RB2/p130 tumor suppressor gene in human sporadic retinoblastoma: implications for pathogenesis and therapeutic approach. Oncogene 24:5827-36.
  • Tosi GM, Trimarchi C, Macaluso M, La Sala D, Ciccodicola A, Lazzi S, Massaro-Giordano M, Caporossi A, Giordano A, Cinti C (2005) Genetic and epigenetic alterations of RB2/p130 tumor suppressor gene in human sporadic retinoblastoma: implications for pathogenesis and therapeutic approach. Oncogene 24:5827-36.
  • Marinelli F, La Sala D, Cicciotti G, Cattini L, Trimarchi C, Putti S, Zamparelli A, Giuliani L, Tomassetti G, Cinti C (2004) Exposure to 900 MHz electromagnetic field induces an unbalance between pro-apoptotic and pro-survival signals in T-lymphoblastoid leukemia CCRF-CEM cells. J. Cell. Physiol. 198:324-32.
  • Marinelli F, La Sala D, Cicciotti G, Cattini L, Trimarchi C, Putti S, Zamparelli A, Giuliani L, Tomassetti G, Cinti C (2004) Exposure to 900 MHz electromagnetic field induces an unbalance between pro-apoptotic and pro-survival signals in T-lymphoblastoid leukemia CCRF-CEM cells. J. Cell. Physiol. 198:324-32.
  • Zini N, Lisignoli G, Solimando L, Bavelloni A, Grassi F, Guidotti L, Trimarchi C, Facchini A, Maraldi NM (2003) IL1-beta and TNF-alpha induce changes in the nuclear polyphosphoinositide signalling system in osteoblasts similar to that occurring in patients with rheumatoid arthritis: an immunochemical and immunocytochemical study. Histochem. Cell Biol. 120:243-50.
  • Bellan C, De Falco G, Tosi GM, Lazzi S, Ferrari F, Morbini G, Bartolomei S, Toti P, Mangiavacchi P, Cevenini G, Trimarchi C, Cinti C, Giordano A, Leoncini L, Tosi P, Cottier H (2002) Missing expression of pRb2/p130 in human retinoblastomas is associated with reduced apoptosis and lesser differentiation. Invest. Ophthalmol. Vis. Sci. 43:3602-8.

Collaborations

  • Caterina Cinti, Istituto di Fisiologia Clinica CNR, Siena, Italy.

 

PI photo

Carmela Trimarchi

Contact information

email  E-mail

email  +39 050 315 3201

Participating staff
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