Document

15/09/2014
Virus kanker
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Virus kanker
Virus terlibat dalam sekitar 15% kanker manusia:
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Kanker serviks
Kanker hati
Leukemia, limfoma
Kaposi’s sarcoma
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Retroviruses
Peyton Rous, 1966
The Retrovirus
Genome Encodes
Reverse Transcriptase
Rous Sarcoma Virus
Is a Retrovirus That
Cases Cancer and
Contains Oncogenes
In Its Genome
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Induksi kanker
Akibat infeksi virus :
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Transformasi sel oleh virus
• Infeksi Virus  “hit” untuk terjadinya kanker
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berperan sebagai “mutagen
kofaktor lain yang diperlukan untuk perkembangan kanker
• transformasi sel disertain dengan “persistence” semua
bagian/sebagian genome virus dan ekspresi yang terus menerus
dari sejumlah gen virus
• Oncogen virus yang diekspresikan mengubah ekspresi gen sel
inang dan sinyal transduksi
• Secara umum:
– RNA virus mengaktivasi onkogen
– DNA virus menginaktivasi tumor supressor gen
“There is no single mechanism by which viruses cause tumors”
TRANSFORMASI SEL OLEH VIRUS
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Human Viruses and Associated
Malignancies
• HPV 16, 18, 31, 33, 45
Cervical Carcinoma
• Hepatitis B&C viruses
Hepatocellular Carcinoma
• HTLV1
Adult T cell Leukemia
• Epstein-Barr virus (HHV-4)
Burkitt’s Lymphoma
Hodgkin’s Disease
PTLD
Nasopharyngeal Carcinoma
Gastric Carcinoma?
• Kaposi sarcoma-associated
herpesvirus (KSHV, HHV-8)
Kaposi’s Sarcoma
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RNA TUMOR
VIRUSES
Retrovirus Lifecycle
Simple retrovirus
•LTR-gag-pol-env-LTR
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Retroviruses
• Virus RNA membentuk onkogen dengan cara
memodifikasi protoonkogen sel inang
• V-onc tidak esensial untuk replikasi virus
• replikasi virus tidak bersifat sitosidal dan tidak
berkaitan dengan tumorigenesis
Mekanisme transformasi sel oleh
retrovirus
1) Transduksi onkogen oleh retrovirus
(transducing retrovirus)
2) Aktivasi onkogen dengan penyisipan
retrovirus (cis-acting / nontransducing
retrovirus)
3) Onkogenesis oleh protein esensial retrovirus
(trans-activating / nontransducing long-latency
retrovirus)
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Transducing retroviruses
• Adanya perubahan yang dilakukan virus terhadap
protoonkogen sel dengan sequence virus  onkogen
• Perubahan struktur + overekspresi  v-onc
mos vs src
• Replikasi sel berubah, adanya perubahan sequence dalam
sel inang  virus diperlukan untuk replikasi sel
v-ONC
Host DNA
c-ONC
cell
Possible mechanisms of oncogene capture by retroviruses
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Gen yang diperlukan untuk kaskade
sinyal
• Molekul sinyal eksternal atau faktor tumbuh (ligan reseptor)
(sis)
• Reseptor sel (erbB, fms, kit)
• Second messengers dalam kaskade sinyal (kinases: src, abl,
fgr, yes; mos raf)
• Faktor transkripsi (jun, fos, myc, myb, ets, rel)
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Perubahan struktural pada v-onc
c-Erb B (EGFR)
Epidermal growth factor
receptor
v-Erb B
Transduced retroviral
version
Ligand binding
domains
Viral gag
membrane
Kinase
domain
P
P
P
P
Regulatory
domain
P
P
P
P
Altered v-Erb B
functions as a
constitutively
activated EGFR
P
Efek transduksi retrovirus
• Karsinogenesis “Single hit”
• Polyclonal: tumor diinisiasi dalam setiap sel yang
terinfeksi
• Tumor dapat terbentuk dalam beberapa
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Cis-acting retroviruses
• tidak membawa onkogen
• semua gen virus dipertahankan
• Efek utama : replikasi
Mekanisme transformasi sel akibat cisacting retroviruses
• Integrasi retrovirus secara random ke dalam DNA
sel inang
• Insersi aktivasi atau inaktivasi
•
• Aktivasi Cis oleh promotor atau enhancer dekat
dengan proto-oncogen
LTR
Exon 1
Host
DNA
LTR
ALV
Exon 2
Exon 3
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Efek onkogen aktivasi oleh insersi
retrovirus
• Transformasi sel  jarang terjadi karena insersi di
dekat onkogen tidak sering terjadi
• Monoclonal tumors
• Pertumbuhan tumor lambat karena tumor dari 1
sel tunggal
Human T cell Leukemia Virus type I (HTLV-I)
•
2 penyakit manusia
• Adult T cell leukemia (ATL)
– clonal malignancy of infected mature CD4+ T cells
• Tropical spastic paraparesis/HTLV-1 associated myelopathy
– neurodegenerative disease
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Endemik di beberapa bagian Jepang, Amerika selatan, Afrika dan karibia
• Sekitar 10-20 juta orang terinfeksi
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Asimptomatik pada kebanyakan individu  2-5% merupakan HTLV-1
carrier  20-40 than berikutnya baru berkembang penyakitnya
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Terutama menginfeksi sel T CD4+
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Penyebaran HTLV 1
• Extended close contact (cell-associated virus)
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Sexual (60% male to female versus 1% female to male
transmission)
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Blood products (screening of blood supply since 1988)
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Mother to child (breast feeding: 20% children with
seropositive mothers acquire virus)
HTLV-I genome
• Genom RNA 9 kilobase RNA
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HTLV-I tidak membawa onkogen dari sel inang
• protein Tax and Rev
– replikasi virus
– ekspresi virus
Atypical flower
cells of ATL
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Matsuoka, 2003
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Mechanisms of cell transformation
by retroviruses
Virus category
Infecting viral
Genome
Transform
cultured
cells?
Tumor
latency
period
Efficiency of
tumor
formation
Oncogenic
effector
Transducing
retrovirus
Short (days)
High (can
reach 100% of
animals)
Cell-derived
oncogene carried in
viral genome
Viral-cellular
chimera,
replication
defective
Yes
Cis-acting/
nontransducing
Intermediate
(wk, mo)
High to
intermediate
Cellular oncogene
activated in situ by
provirus insertion
Intact,
replication
competent
No
Trans-activating/
nontransducing
long latency
Long
(mo, yr)
Very low
(<5%)
Virus-coded
Transcriptional
regulatory protein
Intact,
replication
competent
No
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Virus DNA oncogenik
• Terdapat berbagai kelompok virus dengan struktur,
organisasi genom dan strategi replikasi berbeda
• Beberapa virus yang menginduksi tumor pada
tubuh inang:
– Papilloma
– EBV, KSHV
– Hepatitis B
• Beberapa virus yang menginduksi tumor pada
eksperimen:
– Adenovirus
– Polyomaviruses , SV40
Virus DNA onkogenik
• Potensi onkogenik virus terkait pada strategi replikasi virus
• Onkogen  gen virus esensial tidak homolog dengan gen
sel inang
• Transformasi terjadi dalam siklus hidup virus yang abortive
– Frekuensi transformasi sel terinfeksi Adenovirus, SV40,
and polyomavirus : kurang dari 1 dalam 105
– For small DNA tumor viruses, integration of viral genome
may enable abortive viral lifecycle.
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Tumor supressor Target virus DNA
Virus
Adenovirus
SV40
Polyomavirus
Papillomavirus
Gene Product
E1A
E1B
Large T antigen Large T
antigen Middle T
antigen
E7
E6
E5
Cellular target
Rb
p53
Rb, p53
Rb
Src,
PI3K
Rb
p53
PDGF receptor
pRb the Master Controller:
The First Checkpoint
Robert A. Weinberg, How Cancer Arises, Scientific American 275(3):62-70,
September 1996.
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Phosphorylation of pRb by
cyclin/cyclin-kinase
complexes allows release
of pRb-bound transcription
factors such as E2F. Now
free, the transcription
factors can alter
expression of genes
necessary for cell growth
and DNA synthesis.
Rachel A. Freiberg, Susannah L. Green, Amato J. Giaccia
Hypoxia and Cell Cycle
In: Cell Cycle Checkpoints and Cancer
Mikhail V. Blagosklonny, Ed.
ISBN: 1-58706-067-1
Human Papilloma Virus, HPV, perturbs the pRb checkpoint allowing cells to enter S Phase
under conditions that may not be optimal or safe for DNA synthesis or cell replication.
Hoenil Jo, Jae Weon Kim, Implications of HPV infection in uterine cervical cancer,
Cancer Therapy 3: 419-434, 2005
Sequential phosporylation of Rb by cyclin/cdk complex inhibits the repressor activity of pRb. The HPV
E7 binds to the hypophosphorylated form of the pRb proteins. This binding disrupts the complex
between pRB & the cellular transcription factor E2F, resulting in the liberation of E2F, which allows the
cell to enter the S phase of the cell cycle.
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p53: the second major checkpoint
p53, p21 & The Second Checkpoint
Robert A. Weinberg, How Cancer Arises, Scientific American 275(3):62-70,
September 1996.
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Hoenil Jo, Jae Weon Kim,
Implications of HPV infection in uterine cervical cancer
Cancer Therapy 3: 419-434, 2005
HPV infection also perturbs the second,
p53, checkpoint preventing p53 from
diverting cells with damaged DNA
toward cell cycle arrest or cell death.
Damaged cells can then proliferate
unchecked.
DNA damage induces p53 activation, leading to either cell cycle
arrest or apoptosis. The HPV E6 binds to E6-AP & redirects it to
p53, which results in the E6-AP-mediated ubiquitination & rapid
proteasomal degradation of p53.
RB/p53 Interactions To Regulate Cell Cycle & Apoptosis
Cell cycle transition from G1-S phase is mediated by Rb interactions with the E2F transcription factor family, an
important regulator of the cell cycle. Growth factors lead to phosphorylation of Rb in late G1 phase by cdk/cyclin.
This is followed by release of E2F, allowing transcriptional activation of E2F target genes; this promotes S-phase
entry & cell proliferation. HPV E7 & Simian Virus 40 (SV40) promote release of E2F from Rb. In contrast HPV E6 & the
dominant negative, DN-p53 inhibit p53 activity leading to cell proliferation.
Shehata, Cancer Cell International 2005 5:10 doi:10.1186/1475-2867-5-10
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Transformasi aktivitas DNA Virus melalui
aktivitas yang homolog dengan aktivitas sel
• EBV LMP1 meniru CD40 (tumor necrosis factor receptor)
• E5 gene dari bovine papillomavirus meniru faktor tumbuh
growth factor (activates PDGF receptor signaling cascade)
• Polyomavirus middle T: src signaling pathway
• HHV 8: mengkode viral D cyclin, vIL-6
Epstein Barr Virus
Encodes several viral proteins implicated in immortalization.
EBNA1: maintenance of viral genome
EBNA2: Transcriptional coactivator upregulates
viral (LMP1) and cellular (c-myc) genes
EBNA3A&B: Interfere with Notch signalling
pathway
EBNA3C: Overcomes Rb cell cycle checkpoint
LMP1: constitutively active CD40=elevates bcl-2
and A20
LMP2: stimulates proliferation of epithelial cell
40
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Zheng et al., 2007
KSH-Virus
• KSHV Genome mengkode gen-gen yang homolog dengan
protein yang berperan untuk jalur transduksi dan protein
regulatory lainnya
• Penyebab Kaposi Sarcoma
• Dikenal sebagai Human Herpesvirus 8 (HHV8)
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Chemokines
Signaling molecules
Macrophage inflammatory
factors
v-G protein coupled
receptor
vIL-6
v-interferon regulatory
protein
Cell cycle
v-Bcl2
v cyclin D
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KSHV Proteins Interact with TumorSuppressor Pathways governed by Rb and p53
Papilloma E5 memimik PDGF ligand
Ligand binding
domain
Kinase
domain
PDGF mediated
receptor dimerization
BPV E5 ligand-independent
dimerization
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Papilloma dan Cervical Cancer
• Penyebab kematian utama pada wanita –
cervical cancer
• 100 tipe HPV  3 tipe: low, medium, dan high
risk types
• High risk: 16, 18, 31, 33, 35, 39, 45,51, 52, 56, and 86
• Low risk: 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, and 82
• HPV 16  > 50% cervical cancer
Papilloma Replication Scheme: replication in a
quiescent cell
•Virions penetrate epithelium thru microabrasions in skin
•Expression of E6 and E7 delays cell cycle arrest and differentiation
•Thickening of skin (wart)
•DNA replicates episomally
•Virus released from superficially epithelial cells to infect another individual
•Oncogenesis due to integration of virus. If integration disrupts E2 region (E2
represses txn of E6 and E7), overexpression of E6 and E7 ensues
•cells acquire extended lifespans, capacity to proliferate, and mutations
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Hepadnaviral (HBV) oncogenesis
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Infeksi transient 3-12 bln dan infeksi seumur hidup
– 0.1-25% infeksi jadi kronis
• Proliferasi hepatosit
• Peningkatan superoksida dan radikal bebas
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