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Cancer Etiology 1. Introduction 2. Chemical Factors in Carcinogenesis 3. Physical Factors in Carcinogenesis 4. Viral Oncogenesis 5. Genetic Predisposition. Introduction. 肿瘤（ tumor ） 在致瘤因素作用下，细胞基因失去对细胞增殖、分化和死亡的正常调控，导致组织细胞不断增生而形成的新生物。 良性肿瘤（ benign tumor ） 恶性肿瘤（ malignant tumor ）.
Cancer Etiology1. Introduction 2. Chemical Factors in Carcinogenesis 3. Physical Factors in Carcinogenesis4. Viral Oncogenesis5. Genetic Predisposition
Figure 1. The Hallmarks of Cancer. This illustration encompasses the six hallmark capabilities originally proposed in our 2000 perspective. The past decade has witnessed remarkable progress toward understanding the mechanistic underpinnings of each hallmark. (Hanahan D, Weinberg RA. Hallmarks of Cancer: The Next Generation. Cell 2011, 144:646)
. (Hanahan D, Weinberg RA. Hallmarks of Cancer: The Next Generation. Cell 2011, 144:646)
Chemical Carcinogens (Direct and Indirect Carcinogens)
Promotion -------Epigenetic events
Progression ------Genetic and epigenetic events
A necessary, but insufficient prerequisite for tumor initiation
1. Based on mechanisms
methyl methanesulfonate (MMS),
N-ethyl-N-nitrosourea (ENU), nitrogen and sulfur mustards
require metabolic activation by cellular enzyme to form the DNA-reactive metabolite (members of the cytochrome P450 family)
benzo[a]pyrene, 2-acetylaminofluorene, benzidine, Aflatoxin B1, B2.
(1) Nitrosamines (NA)
MNNG, MMS (direct carcinogen)
(2) Polycyclic aromatic hydrocarbons (PAH)
Benzo(a)pyrene (indirect carcinogen)
(3) Aromatic amines (AA)
2-acetylaminofluorene, benzidine (indirect carcinogen)
(4) Aflatoxin (AF)
(5) Inorganic elements and their compounds: arsenic, chromium,
and nickel are also considered genotoxic agents
(1) DNA damages:
Pro-carcinogen metabolic activation (Phase I and II)
Ultimate carcinogen (electrophiles)
Interaction with macromolecules (nucleophiles)
DNA damage, mutations, chromosomal aberrations, or cell death
(2) Epigenetic changes
(3)Activation of oncogenes; inactivation of tumor suppressor genes
Numerous potential reaction sites for alkylation have been identified in all four bases of DNA (not all of them have equal reactivity:
BPDE intercalates into dsDNA non-covalently, leading to conformational abnormalities
Single Strand Break
Double Strand Break
Bulky aromatic-type adducts, Alkylation (small adducts),
Oxidation, Dimerization, Deamination
2.PCNA plays a central role in recruiting the TLS polymerases (translesion DNA synthesis) and effecting the polymerase switch from replicative to TLS polymerase (low stringency DNA polymerases).
3. TLS polymerases carry out TLS, either singly or in combination, past different types of DNA damage.
4.Such regulation must ensure that (1) the specialized polymerases act only when needed, and (2) that polymerases act only at the right location in DNA.
5.TLS evolved in mammals as a system that balances gain in survival with a tolerable mutational cost, and that disturbing this balance causes a potentially harmful increase in mutations, which might play a role in carcinogenesis.
Polκcan carry out TLS past DNA containing benzo[a] pyrene-guanine adducts.
Rev1 has a restricted DNA polymerase activity that is confined to the incorporation of one or two molecules of dCMP regardless of the nature of the template nucleotide.
5. Polζ is a heterodimer containing the Rev3 catalytic subunit and the Rev7 regulatory subunit.
genomic and mitochondrial DNA damage
malfunction of signaling molecules
endoplasmic reticulum stress
Genome of Human T-cell Leukemia virus (HTLV)
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
tax trans-acting x p40tax
rex repressive expression x p27rex,p21rex
Abelson murine leukemia virus (v-Abl)
Herpes virus: EB virus
Hepatitis B virus
1. HPV E6 interact with P53
E7 interact with RB
2. Adenovirus E1a interact with RB
3. Polyoma virus
SV40 Large T interact with RB
Py virus Large and Middle T
1. EB virus EBNA-2 and LMP
2. HBV p28 X protein
E1 Virus proliferation
E2 Regulation of transcription
E5、E6、E7 Cell transformation
L1、L2 Encoding capsid protein
E4 Encoding late cytosolic protein
E1A: Encoding intranuclear 26 and 30 kD phosphorylated proteins
E1B: Encoding a 19 kD protein located in nuclear and plasma membranes
SV40 virus: Large T Polyoma virus: Large and Middle T
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 MembraneProtein Activation of NF-κB
TP:Terminal Protein Function unknown
Transforming gene: X gene
X protein activates gene transcription via XRE
---Tumor susceptibility genes:
Cytochrome P450 family, DNA repair genes, Tumor suppressor genes
Cell cycle checkpoints, DNA repair, and Apoptosis