Differential alterations of the genes in the CDKN2A-CCND1-CDK4-RB1 pathway are associated with the development of head and neck squamous cell carcinoma in Indian patients. J Cancer Res Clin Oncol

Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Calcutta 700026, India.
Journal of Cancer Research and Clinical Oncology (Impact Factor: 3.08). 12/2003; 129(11):642-50. DOI: 10.1007/s00432-003-0485-z
Source: PubMed


The aim of this study was to analyse the alterations of the genes in the CDKN2A/CCND1/CDK4/RB1 pathway in the G1-S phase of the cell cycle during development of head and neck squamous cell carcinoma (HNSCC).
The alterations of these genes were analysed in 22 dysplastic lesions, 26 stage-I/II and 33 stage-III/IV HNSCC tumours of Indian patients.
The alterations [mutation, hypermethylation, homozygous deletion and loss of heterozygosity/microsatellite size alteration (LOH/MA)] in the CDKN2A were found to be highest in 57% of the samples, followed by CCND1 amplification and LOH/MA at the RB1 locus in 14% and 8.5% of the samples, respectively. No dominant CDK4 Arg24Cys mutation was seen in our samples. Comparatively high frequency of CDKN2A alterations (except homozygous deletion) was found in dysplastic head and neck lesions and remained almost constant or increased during progression of the tumour, whereas the homozygous deletion of CDKN2A and the alterations in CCND1 and RB1 genes were seen mainly in the later stages of the tumour.
Our study suggested that mutation/hypermethylation/allelic alterations (LOH/MA) of CDKN2A were associated with the development of dysplastic head and neck lesions. All the other alterations might provide some cumulative effect during progression of later stages of the tumour to have selective growth advantages.

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    • "As a matter of fact, several Hsp 90-inhibiting compounds are currently tested in preclinical or phase I–III clinical trials as single anti-cancer agents or in combination with conventional drugs and radiation [29]. One of the recent discovered Hsp 90 inhibitors is deguelin [15], [29], here we found that deguelin depleted Hsp 90 client proteins including Akt, survivin and Cdk4 by disrupting the their association with Hsp 90, all these proteins are proven to be important for cancer development for HNSCC [12], [45], [46]. "
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    ABSTRACT: Head and neck squamous cell carcinoma (HNSCC) represents more than 5% of all cancers diagnosed annually in United States and around the world. Despite advances in the management of patients with this disease, the survival has not been significantly improved, and the search for potential alternative therapies is encouraging. Here we demonstrate that deguelin administration causes a significant HNSCC cell death. Deguelin induces both cell apoptosis and autophagy by modulating multiple signaling pathways in cultured HNSCC cells. Deguelin inhibits Akt signaling, and down-regulates survivin and cyclin-dependent kinase 4 (Cdk4) expressions, by disrupting their association with heat shock protein-90 (Hsp-90). Deguelin induces ceramide production through de novo synthase pathway to promote HNSCC cell death. Importantly, increased ceramide level activates AMP-activated protein kinase (AMPK), which then directly phosphorylates Ulk1 and eventually leads to cell autophagy. We found that a low dose of deguelin sensitized HNSCC cells to 5-FU. Finally, using a nude mice Hep-2 xenograft model, we also showed a significant anti-tumor ability of deguelin in vivo. Together, we suggest that deguelin may represent a novel and effective chemo-agent against HNSCC.
    PLoS ONE 01/2013; 8(1):e54736. DOI:10.1371/journal.pone.0054736 · 3.23 Impact Factor
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    • "Present study revealed that there was no germline mutation in codon 24 and 22 of CDK4 and these results support the findings of previous studies [20,26,27]. The potentially dominant Arg24Cys mutation of CDK4 was not detected in Indian patients with squamous cell carcinoma of head and neck [8]. CDK4 mutations reported in the literature are rare and little is known about the functional implications of these changes [28]. "
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    ABSTRACT: Cyclin-dependent kinase 4 (CDK4) together with its regulatory subunit cyclin D1, governs cell cycle progression through G1 phase. Cyclin-dependent kinase inhibitors, including p16INK4A in turn regulate CDK4. In particular, deregulation of the p16/CDK4/cyclin D1 complex has been established in a variety of human tumors including gliomas, sarcomas, melanoma, breast and colorectal cancer. However, changes in CDK4 have rarely been observed. In this study we used a combination of PCR-SSCP and direct sequencing for mutational screening of CDK4. DNA was isolated from peripheral blood leukocyte of patients with squamous cell carcinoma of head and neck, for screening germline mutations in coding regions of CDK4. Variations observed in exon 2 and 5 were three missense mutations, g5051G > C (Ser52Thr), g5095G > C (Glu67Gln), g5906C > A, g5907C > G (Pro194Ser) and novel frame shift mutations g7321_23delTGA, g7121_7122insG, g7143delG in exon 7 and 3'UTR respectively. In conclusion, two novel mutations were found in N terminal domain which indicates that CDK4 mutation may play a major role in the development and progression of squamous cell carcinoma of head and neck.
    Hereditary Cancer in Clinical Practice 08/2012; 10(1):11. DOI:10.1186/1897-4287-10-11 · 1.47 Impact Factor
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    • "Compare to high LIMD1 alterations, RB1 deletion was very low (27%, 22/83) in the primary head and neck lesions (Fig 3B). Deletion frequency of RB1 was low in dysplastic lesions (8%, 2/25) and significantly (P = 0.045) increased to stage (I+II) tumors (32%, 6/19) consistence with our previous findings [13,14] (Fig 3B). No association between LIMD1 alterations and RB1 deletion was observed, however co-alteration of both genes was high (33%, 13/39) in the stage III+IV of head and neck lesions (Table 5). "
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    ABSTRACT: To understand the role of two interacting proteins LIMD1 and pRB in development of head and neck squamous cell carcinoma (HNSCC), alterations of these genes were analyzed in 25 dysplastic head and neck lesions, 58 primary HNSCC samples and two HNSCC cell lines. Deletions of LIMD1 and RB1 were analyzed along with mutation and promoter methylation analysis of LIMD1. The genotyping of LIMD1 linked microsatellite marker, hmlimD1, was done to find out any risk allele. The mRNA expression of LIMD1 and RB1 were analyzed by Q-PCR. Immunohistochemical analysis of RB1 was performed. Alterations of these genes were correlated with different clinicopathological parameters. High frequency [94% (78/83)] of LIMD1 alterations was observed in the samples studied. Compare to frequent deletion and methylation, mutation of LIMD1 was increased during tumor progression (P = 0.007). Six novel mutations in exon1 and one novel intron4/exon5 splice-junction mutation were detected in LIMD1 along with a susceptible hmlimD1 (CA)20 allele. Some of these mutations [42% (14/33)] produced non-functional proteins. RB1 deletion was infrequent (27%). Highly reduced mRNA expression of LIMD1 (25.1 +/- 19.04) was seen than RB1 (3.8 +/- 8.09), concordant to their molecular alterations. The pRB expression supported this data. Tumors with LIMD1 alterations in tobacco addicted patients without HPV infection showed poor prognosis. Co-alterations of these genes led the worse patients' outcome. Our study suggests LIMD1 inactivation as primary event than inactivation of RB1 in HNSCC development.
    Molecular Cancer 03/2010; 9(1):58. DOI:10.1186/1476-4598-9-58 · 4.26 Impact Factor
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