Transcript RNA Oncovirus

Cancer Etiology
1. Introduction
2. Chemical Factors in Carcinogenesis
3. Physical Factors in Carcinogenesis
4. Viral Oncogenesis
5. Genetic Predisposition
Jimin Shao
[email protected]
Cancer-associated Infectious Agents
Persistent infection with one of several
pathogens is an important cause of about 20
percent of cancers worldwide.
This knowledge has enabled the development
of new cancer prevention strategies that use
medicines and vaccines to eliminate or prevent
infection with these agents.
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Viral Oncogenesis
• RNA Oncovirus (Retrovirus)
• DNA Oncovirus
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RNA Oncovirus
Retroviruses:
ssRNA viruses
Reverse transcriptase
Oncogenes
Rous sarcoma in chickens (RSV): in 1911
Human T-cell lymphotropic virus (HTLV-I,II)
Human immunodeficiency virus (HIV)
Structure of RNA Oncovirus
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Genome of RNA Oncovirus and
Gene Products
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Life cycle
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Receptor binding and membrane fusion
Internalization and uncoating
Reverse transcription of the RNA genome to form double-stranded
linear DNA
Nuclear entry of the DNA
Integration of the linear DNA into host chromosomal DNA to form the
provirus
Transcription of the provirus to form viral RNAs
Splicing and nuclear export of the RNAs
Translation of the RNAs to form precursor proteins
Assembly of the virion and packaging of the viral RNA genome
Budding and release of the virions
Proteolytic processing of the precursors and maturation of the
virions
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Replication of RNA Oncovirus
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Mechanisms of Oncogenesis
Induced by RNA Oncovirus
• Transducing Retrovirus
v-onc
• cis-Activating Retrovirus
c-onc
• trans-Activating Retrovirus
tax trans-acting x p40tax
rex repressive expression x p27rex, p21rex
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• Oncogene transduction
– Acutely transforming in vivo and in vitro
– Transform cells by the delivery (transduction) of an
oncogene from the host cell (v-onc) to a target cell
– Cause the formation of polyclonal tumors
– Most of this group of viruses are replication defective
(the requirement of a helper virus)
– Examples:
RSV (v-src);
Abelson murine leukemia virus (v-Abl)
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•Insertional activation
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Long latent periods, Less efficient
Do not induce transformation of cells in vitro
Usually are replication competent
No oncogenes
Tumors are usually monoclonal
Provirus (LTR) is found within the vincity of a protooncogene (c-myc)
– Examples: lymphoid leukosis virus;
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•Grow stimulation and two-step oncogenesis
– The defective spleen focus-forming virus (SFFV) and its helper,
the Friend murine leukemia virus (Fr-MuLV)
– Induce a polyclonal erythrocytosis in mice
– Require the continued viral replication
– A mutant env protein gp55 of SFFV binds and stimulated the
erythropoietin receptor, thus inducing erythroid hyperplasia
– Fr-MuLV or SFFV integration inactivates p53
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• Transactivation
– HTLV-1 and 2
– Like cis-activation group: replication competent, carries no oncogene,
induces monoclonal leukemia, and latent
– Like transducing group: can immortalize cells in vitro, has no specific
integration site
– Unique 3’ genomic structure: the X region; Encodes at least three proteins:
Tax (p40), Rex (p27, p21)
– Tax is the focus
– Transactivate the viral LTR, results in a 100- to 200-fold increase in the
rate of proviral transcription
– Transactivate cellular enhancers and promoters, including genes for IL-2,
granulocyte-macrophage colony-stimulating factor (GM-CSF), c-fos, and
others.
Genome of HTLV
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•Immunodeficiency
• AIDS patients have an extraordinary increased rate of developing
high-grade lymphomas and Kaposi’s sarcoma (KS)
• Probably secondary
• However, Tat protein of HIV (the transactivating protein) may
induce KS-like lesions in mice.
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Endogenous retroviruses
• Exo or endo: somatic vs germline
• 0.5-1% mammalian genome is composed of retroviral
proviruses
• Some properties:
– Most are defective
– Great variations between species or within
– Variable level of expression
– Generally not pathogenic
– The potential to induce disease is notable
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DNA Oncovirus
Papilloma virus: HPV
Polyoma virus
Herpes virus: EBV
Hepatitis B virus
Hepatitis C virus
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Mechanism of Oncogenesis
Induced by DNA Oncovirus
Transforming proteins
1. HPV
E6 interact with P53
E7 interact with RB
2. Adenovirus
E1a interact with RB
E1b
3. Polyoma virus
SV40
Large T interact with RB
Py virus Large and Middle T
Transcription activators
1. EB virus
EBNA-2 and LMP
2. HBV
p28 X protein
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Gene Map and Function of HPV
ORF
E1
E2
E5、E6、E7
L1、L2
E4
E3、E8
Function
Virus proliferation
Regulation of transcription
Cell transformation
Encoding capsid protein
Encoding late cytosolic protein
Unkown
E5: activates growth factor receptor
E6: ubiquitin-mediated degradation of p53
E7: binds and inactivates unphosphorylated pRb
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Genome of EB Virus
EBNA (EB virus Nuclear Antigen)
EBNA-1 Immortalization of cell
EBNA-2 trans-acting transcription activator
EBNA-3 Function unknown
LP: Leader Protein RNA Processing
LMP: Latent Membrane Protein Activation of NF-κB
TP: Terminal Protein Function unknown
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Genome and Products of HBV
Transforming gene: X gene
X protein activates gene transcription via XRE
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Genetic Predisposition
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Hereditary Cancer
Tumor Genetic Susceptibility
Immunity
Metabolism
Hormones
Psychological factors
others
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Tumor Genetic Susceptibility
Some individuals are at increased risk of certain cancers because
they inherited a cancer-predisposing genetic mutation.
Tumor susceptibility genes (DNA repair genes, Tumor suppressor
genes, Cytochrome P450 family, etc).
Not all potentially inheritable causes of cancer have been
identified, but if an individual suspects that a relative has a cancer
caused by one of the 17 known cancer-predisposing genetic
mutations, he or she should consult a physician and consider genetic
testing for verification.
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Beyond inherited cancers, some medical conditions with
higher risk for certain types of cancer
Inflammation and Cancer：for example, ulcerative colitis and Crohn disease increase an
individual’s risk for colorectal cancer six fold.
Obesity and Cancer: Obesity increases risk for a growing number of cancers, most
prominently the adenocarcinoma subtype of esophageal cancer, and colorectal, endometrial,
kidney, pancreatic, and postmenopausal breast cancers. It also negatively impacts tumor
recurrence, metastasis, and patient survival for several types of cancers.
Type 2 Diabetes Mellitus and Cancer:
Those with type 2 diabetes are most at risk for developing liver, pancreatic, and
endometrial cancers, but also have an increased risk for developing biliary tract, bladder,
breast, colorectal, esophageal, and kidney cancers, as well as certain forms of lymphoma.
it is not well established how type 2 diabetes increases cancer risk.
Similar to obesity, type 2 diabetes increases levels of insulin and causes persistent
inflammation.
Energy balance is a complex dynamic that is not only influenced by calorie consumption
and physical activity, but also by other factors such as genetics, diet composition, body
weight or body composition, and sleep. How changes in energy balance promote cancer is an
area of intense research investigation.
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Hormones and cancer
• Major carcinogenic consequence of hormone exposure:
cell proliferation
• How to get exposure: contraceptives, hormone replacement
therapy, or during prevention of miscarriage
• The emergence of a malignant phenotype depends on a series of
somatic mutation; Germline mutations may also occur
• Epidemiological studies
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Hormone-related cancer
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Breast cancer and estrogen
Endometrial cancer: Estrogen replacement therapy
Ovarian cancer: follicle stimulating hormone
Vaginal adenocarcinoma: in utero diethylstilbestrol (DES)
exposure
• Prostate cancer and androgen
• Cervical cancer
• Thyroid cancer: the pituitary hormone thyroid stimulating
hormone (TSH)
• Osteosarcoma: incidence associates with the pattern of
childhood skeleton growth; and hormonal activity is a primary
stimulus for skeleton growth
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