grape seed proanthocyanidins reactivate silenced tumor suppressor genes.pptx

7/29/2019 Grape seed proanthocyanidins reactivate silenced tumor suppressor genes.pptx

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Grape seed proanthocyanidinsreactivate silenced tumor

suppressor genes in human

skin cancer cells by targeting

epigenetic regulators


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Skin Cancer


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Skin Cancer

Long-term sun exposure can result in skin cancer.

Malignant melanoma is the deadliest form ofskin cancer.

Ultraviolet radiation (UVR) is a proven human

carcinogen.24

The sun emits three types of harmful rays

UVA

UVB UVC


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Types of Ultraviolet Rays

Copyright 2010 Pearson Education, Inc.


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Skin Cancer

The major factor in skin cancer formation is

sun exposure

Skin type is also important in dictating how

the skin reacts to the sun

Pale Celtic skin is most at risk

Dark afrocaribean skin is least at risk


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Stratosphere - Ozone Layer

UVC

100-280

UVB

280-315

UVA

315-400X-ray Visible Light

400-700

Dead Sea Level Sea Level


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Definition of Skin Cancer:

Cancer that forms in tissues of the skin.

Skin cancer begins in cells, the building blocksthat make up our skin. Normally, skin cells grow

and divide to form new cells. Every day skin cellsgrow old and die, and new cells take their place.

When this orderly process goes wrong new cellsform when the skin does not need them, and old

cells do not die when they should. They formgrowths or tumors which can be benign ormalignant.


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Skin Cancer

Not all races have an equal risk of developing skin cancer

Skin cancers overwhelmingly develop in white people

The following slide has the incidences of NMSC in differentraces in different parts of the world

The highest incidence found was in white Australian menliving in tropical Queensland

The incidence in coloured people was lower, even when they

lived in the tropics.


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Malignant skin tumors:

Genetic factors: Xeroderma pigmentosum, neurofibroma may change toneurofibrosarcoma.

Enviromental factors:

Ultraviolet light is the most important factor especially in those with fairskin.

Tar, arsenic, mineral oils.

X-ray: diagnostic or therapeutic.

Long standing scars, fistulas, sinuses.

Viruses: Burkuit lymphoma ----------- EBV

HPV may cause Ca cervix

Kaposi sarcoma is thought to be caused by herpessimplex virus- 8.

Drugs: long lasting use of immunosuppressant like azathioprime,cyclophosphamide, cyclosporine or even steroids.


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Skin cancer represents approximately two to four percent of all cancers in Asians.36

Skin cancer comprises one to two percent of all cancers in African Americans andAsian Indians. 36

Melanomas in African Americans, Asians, Filipinos, Indonesians, and native

Hawaiians most often occur on non-exposed skin with less pigment, with up to 60-75 percent of tumors arising on the palms, soles, mucous membranes and nailregions.36

Basal cell carcinoma (BCC) is the most common cancer in Caucasians, Hispanics,Chinese Asian and the Japanese.36

Squamous cell carcinoma (SCC) is the most common skin cancer among AfricanAmericans and Asian Indians.36

Squamous cell carcinomas in African Americans tend to be more aggressive andare associated with a 20-40 percent risk of metastasis (spreading).36


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Types of Skin Cancers

Copyright 2010 Pearson Education, Inc.


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Types of Skin Cancer

Melanoma-forms in melanocytes (skin cells

that make pigment).

Basal Cell Carcinoma-forms in basal cells

(small, round cells in the base of the outer

layer of skin).

Squamous cell carcinoma-forms in squamous

cells (cells that form the surface of the skin).


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Skin Cancer

The most common skin cancer is the Basal Cell Carcinoma(BCC)

The next most common is the Squamous Cell Carcinoma(SCC)

The least common is the Melanoma (MM)

BCC and SCC are often grouped together as non-melanomaskin cancer (NMSC)


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Basal Cell Carcinomas

Commonest skin cancer in Caucasian

populations

Major cause is sun exposure

Common sites on face and trunk

Not metastatic


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Squamous cell carcinoma

Second most common skin cancer in Caucasianpopulations

Caused by sun exposure - chronic sun exposure

Most at risk are those with pale skin who burn inthe sun

Commonest on sun exposed areas

Pre-cancerous lesion is the solar keratosis Metastatic potential - to regional lymph nodes,

then liver, lungs etc


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Melanoma

Third most common skin cancer

Caused by severe intermittent bouts of sun

exposure

Found on sun exposed and non-exposed sites

Second most common cancer to affect young

women

High metastatic potential - local, lymph nodes,

lung, liver and brain


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Melanoma

30% arise in a pre-existing mole

Features to look out for are asymmetry of the

mole, irregular shape and irregular colour

Most commonly arise in normal skin in renal

transplant patients


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Tumor Suppressor Genes


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Tumor suppressor genes Stop cell growth and division; prevent cancer

formation

May prevent expression of oncogenes

p53: codes for a regulatory protein that turns off

cell division when the cell is stressed or damaged

If mutated, runaway cell division

More than half of cancers has a mutated or missing p53gene

Cancer Usually Involves Several Genes


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Types of cancer genes

Types of proteinsMutated functionNormal functionType of gene

Enzymes for

mismatch or excision

repair

Fail to repair DNA

mutations

Repair DNA

mutations

DNA repair

gene mutation

Checkpoint

molecules

Fails to suppress

division

Suppresses cell

division

Tumor

suppressor

gene

Growth factorsPromotes division -

abnormal time or

cell type

Promotes divisionOncogene


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Epigenetics

Epigenetics - On or over the geneticinformation encoded in the DNA


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Skin cancer is the manifestation of a series of geneticand epigenetic events.

Epigenetic processes result in heritable phenotypical

changes in gene expression that do not involvealterations in the actual DNA sequence.

Involve variations in DNA methylation, chromatinstructure or microRNA profiles

The hallmarks of epigenetic gene regulation are DNAmethylation and histone modifications.

Reversible and can be manipulated pharmacologically,


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Epigenetic inactivation of genes by promoter

hypermethylation has been recognized as an

important mechanism by which tumor

suppressor genes are shut down duringdevelopment of cancers


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Epigenetics

The study of reversible heritable changes in

gene function that occur without a change in

the sequence of nuclear DNA

Gene-regulatory information that is not

expressed in DNA sequences is transmitted

from one generation (of cells or organisms) to

the next


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Epigenetics and

Different Aspects of Life Development of multicellular organism

Environment-organism interaction

For examples: Nutrition supplements and environmental toxins

Image: Randy Jirtle

Pathogenesis of diseases


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Molecular Mechanisms that Mediate

Epigenetic Phenomena

DNA methylation (CpG dinucleotides)

Histone modifications

Nucleosome


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Epigenetic Regulation of Gene Expression

Epigenetic information modulates gene

expression without modifying actual DNA

sequence

Histone modifications change the chromatin

structure and affect the accessibility of DNA to

regulatory proteins


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Histone

Methylated

DNA

Epigenetic Regulation of Gene Expression


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Histone Modification Status Correlates with

Transcriptional Activity

Gene activation correlated with H3-K9 acetylation

Gene silencing associated with H3-K9 methylation


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Epigenetic Inheritance

Transmission of non-DNA sequence informationthrough either meiosis or mitosis

When a methylated DNA sequence replicates, onlyone strand of the next-generation double helix has

all its methyl markers intact; the other strand needsto be remethylated

Maintenance methylase theory DNA methyltransferases (DNMTs): Enzymes that bind

methyl groups to cytosine nucleotides

DNMTs bind methyl groups to the naked cytosines basedon the methylation template provided by the other strand-


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Epigenetics and Cancer

Chromosomal infrastructure is essential for gene control,determining both active and repressed states

It is important not only to turn the right genes on but also toturn the right genes off

Histones and chromatin components have key roles in thisdecision making process

If as few as three inappropriate genes are turned off, a normalcell can be converted into a cancer cell

This epigenetic silencing of genes underlies a new approach tocancer therapy

Mistargeting of these enzymes leads to tumorigenesis, butinhibition of their activity presents a novel approach totherapy


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Grape seed proanthocyanidins


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grape seed proanthocyanidins reactivate silenced tumor suppressor genes.pptx

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