Molecular biology of oral cancer, ppt
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Transcript of Molecular biology of oral cancer, ppt
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Molecular biology of oral cancer
Presented by Raghda ragab Mohamed Hassan
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ContentOral cancer Risk factor for oral cancer Hallmarks of cancer Molecular basis of oral cancer. Proto – oncogenes, oncogenes. Common gene alteration identified in oral cancer. Cell cycle and dysregulation in oral cancer. Apoptosis and oral cancer. Tumor suppressor genes involved in oral cancer. DNA repair, defects and genome stability.
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Oral cancerOral cancer refers to a subgroup of head and neck
malignanciesthat develop at the lips, tongue, salivary glands, gingiva, floor of the mouth, oropharynx, buccal surfaces and other intra-oral locations.
There are several types of oral cancers.
The majority (>90%) of oral cancers are oral cancer squamous cell carcinoma (OSCC).
The incidence and mortality rates worldwide of OSCC are approximately 5.9 and 3.3 per 100,000 persons per year.
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Risk factors for oral cancer
Alcohol consumption
Smoking and tobacco consumption
Family history of cancer
Excessive sun
Exposure
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Figure 1: Hallmarks of cancer
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Cellular basis of cancer
Cancer charactarized by abnormal and uncontroled cell growth.
In normal tissues, the rate of new cell growth and old cell death are kept in balance.
In cancer cell, this balance is disturbed This disturbtion in cancer result from uncontrolled cell growth.Loss of a cell ability to undergo apoptosis.
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There are many differences between cancer cells and normal cells.
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Proto-oncogenes, oncogenes and oncoprotein
Protoncogenes are genes whose protein products have been found to be important for normal cell growth signaling and whose overexpression or mutation leads to unchecked cell growth and tumorigenesis.
Oncogenes represent a gain-of-function mutation
Oncogenes can effect a cellular change through mutation of only one of the two gene copies.
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Activation of oncogenes
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Table 1. Common gene alterations identified in oral cancer
Gene Frequency (%) FunctionProto-oncogenes EGFR c-myc/N-myc K-ras/N-ras Cyclin D1 STAT-3
>30% 20–40% 30–40% 30% 80%
Cell proliferation,
growth
Cell growth, apoptosis
Signaling, growth Cell-cycle
regulation Cytokine signaling,
cellproliferation
Tumor-suppressor genes Rb p53 p16
30– 50% 50–60% 80%
Cell cycle regulation Cell-cycle regulation Senescence, cell-cycleprogression
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Classification of oncogenes
1. Growth factors
2. Cell surface receptors (e.g EGFR)
3 .Intracellular signal transduction pathways (e.g RAS gene family).
4. DNA binding nuclear proteins transcription factors (MYC).
5. Cell cycle proteins (cyclins and cyclin dependent protein kinases).
6. Inhibitors of apoptosis (bcl2).
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Subcellular localization and functions of major classes of cancer-associated genes
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Stimulation of cell division induced by growth factor
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TGF-a Transforming growth factor alpha promotes cell
proliferation in oral tissues as well as in other cell types in the body.
TGF-a is overexpressed early and late in oral carcinogenesis.
TGF-a stimulates a target cell by binding to the epidermal growth factor receptor (EGFR) in an autocrine or paracrine fashion.
TGF-a likely serves a tumor-promoting role in epithelial carcinogenesis.
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2 .Cell surface receptors (EGFR )
Growth factor receptors are activated in human tumors by several mechanisms. These include mutations, gene rearrangements, and overexpression.
Mutations of genes encoding cell-surface receptors can result in an increased number of receptors or production of a ligand-independent mitogenic signal.
EGFR is frequently found to be overexpressed in human oral cancers.
.
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3 .Intracellular signal transduction pathways
Of all the members of the intracellular signaling pathway, only members of the ras gene family (H-ras, K-ras, N-ras) have been examined in human oral cancer.
Ras oncogenes encode for the related protein p21 that has been localized to the cytoplasmic side of the cellular membrane.
Ras proteins bind guanine nucleotides (GDP and GTP) with high affinity and specificity.
Ras proteins transmit mitogenic signals by binding GTP and hydrolysis of GTP to GDP ends the signal.
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Action of RAS gene
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Mutation in RAS gene
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4 .DNA binding nuclear proteins transcription factors
Transcription factors are proteins that regulate the expression of other genes.
E.g: c-myc which helps regulate cell proliferation
and differentiation,
C-myc is frequently overexpressed in oral cancers.
Amplification and over-expression of c-myc has been observed in 20–40% oral cancers.
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Tumor suppressor genes involved in oral cancer
1-p53
p53 gene is the most important TSG and has been called the ‘Guardian of the Genome’.
p53 has a role in maintaining genome stability, and an important role in cell cycle progression, cellular differentiation, DNA repair and apoptosis.
p53 is known to be mutated in approximately 70% of oral tumors. The loss of the heterozygosity of the p53 allele has been reported in 20% of oral cancer cases, as well as in 22% of premalignant oral leukoplakia lesions.
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Figure : p53 and cellular and genetic stability
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p53 gene can be inactivated by several mechanisms, including point mutations, deletion, and binding with cellular and viral proteins.
Point mutations result in a structurally altered protein.
Deletions lead to a reduction and loss of p53 expression and protein function.
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p16 gene and its role
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5 .Cell cycle proteinscell cycle phases
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Figure : Cell cycle checkpoints
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Retinoblastoma gene (Rb)
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Cyclins, cyclin dependent kinases (CDKs)
Cyclins are a group of proteins known as the cyclins (D= Departure; E= Exit through restriction point; A=Arrival at S Phase; B= Bi or two chromatids ) promote different phases of the cell cycle.
The cyclins and cyclin dependent kinases (CDKs) form the core of cell cycle regulation.
Expression of cyclins is cell cycle phase dependent .
The cyclin family members interact with CDKs, and these complexes are required to pass through specific phases of the cell cycle.
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Figure :Regulation of cell cycle processes by CDK– cyclin complexes.
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6. Inhibitors of apoptosis (bcl2)Apoptosis ( programmed cell death) Normal cells are either repaired or die (undergo apoptosis) when they are damaged or get old.
APOPTOSIs:
Extracellular:FAS Ligand acting on FASR, FAS receptor
releasingInitiating Intracellular Enzyme Caspases- cell death, thus called
“executioner”Intracellular: pores in mitochondrial inner,
outer membranes releasingInitiating Intracellular Enzyme Caspases- cell death, thus called
“executioner”
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DNA repair, Defects and Genomic instability
In normal cell, DNA damage can occur from environmental agents and the DNA of normal dividing cells is susceptible to alterations resulting from errors that occur during DNA replication.
Defects in three types of DNA repair systems, namely, mismatch repair, nucleotide excision repair, and recombination repair.
In oral cancer cells, Such mistakes, if not repaired ,it will push the cells in to neoplastic transformation.
Defects in repair mechanisms are present in human oral cancers and cause genomic instability.
Genomic instability occurs when both copies of these genes are lost as in tumor suppressor genes.
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Figure : DNA repair. & genomic stability.
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Figure : Mechanism of genome preservation and stability.
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