Frequent Alterations of the Candidate Genes hMLH1, ITGA9 and RBSP3 in early Dysplastic Lesions of Head and Neck: Clinical and Prognostic Significance
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
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Title |
Frequent Alterations of the Candidate Genes hMLH1,
ITGA9 and RBSP3 in early Dysplastic Lesions of Head
and Neck: Clinical and Prognostic Significance
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Creator |
Ghosh, Amlan
Ghosh, Susmita Maiti, Guru Prasad sabbir, Mohd.Golam Zabarovsky, Eugene R Roy, Anup Roychoudhury, Susanta Panda, Chinmay Kumar |
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Subject |
Molecular & Human Genetics
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Description |
To understand the association between candidate tumor suppressor
genes (TSGs) human mismatch repair protein homologue
1 (hMLH1), AP20 region gene 1 (APRG1), integrin a RLC (ITGA9),
RB1 serine phosphates from human chromosome 3 (RBSP3) at chromosomal
3p22.3 region and development of head and neck
squamous cell carcinoma (HNSCC), alterations (deletion ⁄ promoter
methylation ⁄ expression) of these genes were analyzed in 65 dysplastic
lesions and 84 HNSCC samples. Clinicopathological correlations
were made with alterations of the genes. In HNSCC, deletion
frequencies of hMLH1, ITGA9, and RBSP3 were comparatively
higher than APRG1. Overall alterations (deletion ⁄ methylation) of
hMLH1, ITGA9, and RBSP3 were high (45–55%) in mild dysplasia
and comparable in subsequent stages of tumor progression. Quantitative
RT-PCR analysis showed reduced expression of these genes
in tumors concordant to their molecular alterations. An in vitro
demethylation experiment by 5-aza-2¢-deoxycytidine confirmed
the promoter hypermethylation of RBSP3 in Hep2 and UPCI:SCC084
cell lines. Functionally less-active RBSP3A isoform was predominant
in tumor tissues contrary to the adjacent normal tissue of
tumors where more active RBSP3B isoform was prevalent. In
immunohistochemical analysis, intense nuclear staining of hMLH1
and pRB (phosphorylated RB, the substrate of RBSP3) proteins
were seen in the basal layer of normal epithelium. In tumors, concordance
was seen between (i) low ⁄ intermediate level of hMLH1
expression and its molecular alterations; and (ii) intense nuclear
staining of pRB and RBSP3 alterations. Poor patient outcome was
seen with hMLH1 and RBSP3 alterations. Moreover, in absence of
human papilloma virus (HPV) infection, tobacco-addicted patients
with hMLH1, RBSP3 alterations, and nodal invasions showed poor
prognosis. Thus our data suggests that dysregulation of hMLH1,
ITGA9, and RBSP3 associated multiple cellular pathways are
needed for the development of early dysplastic lesions of the head
and neck.
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Publisher |
Oxford University Press
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Date |
2010
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Type |
Article
PeerReviewed |
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Format |
application/pdf
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Identifier |
http://www.eprints.iicb.res.in/74/1/CANCER_SCIENCE_101(6)1511%2D1520_;2010[80].pdf
Ghosh, Amlan and Ghosh, Susmita and Maiti, Guru Prasad and sabbir, Mohd.Golam and Zabarovsky, Eugene R and Roy, Anup and Roychoudhury, Susanta and Panda, Chinmay Kumar (2010) Frequent Alterations of the Candidate Genes hMLH1, ITGA9 and RBSP3 in early Dysplastic Lesions of Head and Neck: Clinical and Prognostic Significance. Cancer Science, 101 (6). pp. 1511-1520. |
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Relation |
http:/dx.doi.org/10.1111/j.1349-7006.2010.01551.x
http://www.eprints.iicb.res.in/74/ |
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