Virus and cancer

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Virus and cancer

• ??. ??????? ?????????

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Cancer

• Normal cell
• ????????????????????????? ???????
• ??????????????????????
• (transformation)
• Transformed cell
• carcinogenesis, oncogenesis
• Cancer cell

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????????

• ?????????? (benign tumor)
• ??????????????????????????????? ?????????????
• ??????????? (maligmant tumor), ??????
• ??????????????????????????????????
• ?????????????????????? ?????????
• ?????? - ??????????
• -???????????
• (?????, ???????, ??????????? oncogenic virus)

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Oncogene

• ????????????????????????????????????????????????
• ???????? 30 genes
• ???????? cellular oncogenes (c-oncs),
• proto-oncogene
• RNA virus ?? gene homologous ??? c-oncs
• ???????? viral oncogenes (v-oncs)
• DNA virus
• ????? homologous sequence ???????????

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????????????????/ ??????

• ?.?. 2451 Ellerman and Bang
• ????? leukemia ????????????????????????????????
• ?.?. 2454 Rous
• ????? sarcoma ????????????????????????????????
• ????????????????????????????
• - ???????????????????????
• - ????????????????????

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Oncoprotein

• Extracellular growth factor
• Membrane receptor
• Tyrosine kinases
• G protein ????????????? signal transduction
• Cytoplasmic protein kinases
• Transcriptional factor
• Nuclear hormone receptor

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?????????? Oncoprotein

• ?????????????????????????????????
• Oncogene
• - ????????????? signal transduction
• protein kinase ?????? membrane,
• ?? cytoplasm
• - ????????????? cell cycle
• protein ?????????????????????? G1 ???
• S phase

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(No Transcript)
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Cell transformation by retroviruses (RNA virus)

• Oncogene ???????????????????
• - ?????????? transform ???????????????????????
• ??????????? normal structure ??? gene
• ???????????????????????

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1. Acutely transforming (transducing)
retroviruses

• - ????????????? tumor ???? (???????)
• - ??????????????????? tumor ?????? 10
• v-onc ???????????? transduce ??? c-onc
• ???????????? sequence ??? v-onc
• Short deletion
• Insertion ?????? gag sequence
• ????????????????????????????
• overexpression
• inappropriate expression

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2. Chronic transforming (cis-activating)
retroviruses

• ????????????? tumor ??????? (?????)
• ??????????????????? tumor ???????
• ????? oncogene
• Provirus ??????? c-onc ??????? insertional
  activation
• Ex. ????? Avian Leukosis Virus (ALV) ???????
  myc gene

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3.Trans-activating retroviruses

• ????????????? tumor ??? (??)
• ??????????????????? tumor ??? (? 1 )
• ??????? cellular gene ??? transcriptional
  activator protein ??? ?????
• Ex. Human T-cell leukemia virus (HTLV)
• tax gene tax protein
• ?????????? transcription ????????
• ?????????? transcription ??? cellular gene

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Oncogenic DNA viruses

• ????? cellular oncogene
• Virus oncoprotein ???? nuclear protein
  ?????????????????????? DNA replication
• Virus oncoprotein ?????? cellular protein
  (negative regulatory ?? cell proliferation)
• Cellular protein (tumor suppressor protein)
• p53, Rb (Retinoblastoma)

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p53

• ?????? cell cycle
• Tumor suppressor protein (anti-oncogene)
• Mutation ??? p53 ?? tumor cell
• Tumor cell p53
• ?????????????????????????,
• ???????????????????????????????
• Virus oncoprotein ???????? p53

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Retinoblastoma (Rb)

• Tumor ??? optic nerve ?????????? Rb gene
• Tumor suppressor protein
• ?????? transcription factor (E2F)
• cell cycle ??????? G1 phase
• ?????? virus oncoprotein

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Viral oncoprotein

• 1. Adenovirus early protein
• E1A (trans-acting transcriptional regulator)
• - ?????? Rb
• - ????????????????????????????
• - ??????????????????????? cellular DNA
• - transform cell ??????????????? tumor ???????
• E1B ??? transform cell
• E1AE1B transform cell, ???? tumor ???????

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2. Polyomavirus

• SV 40 T-Ag (tumor antigen)
• T-Ag
• ????????????? genome replication
• T-Ag ?????? DNA polymerase ?
• ??????? viral genome replication

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• T-Ag ?????? tumor suppressor protein (p53,
  Rb)
• Inactivate tumor suppressor protein
• ????????????????????? G1 ??????? S Phase
• ??????????????????? transformation

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3. Hepatitis B virus

• ??????????? HBV ??????????? ?????????
• - ???????????????????????
• - ???????????? (??????????????????????)
• - ?? DNA ??? HBV ?????????? chromosome
• ??????????????????????????????????
• ???? insertional mutagenesis ???????

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???????????????????? (hepatocellular
carcinoma, HCC)

• 1. ??????? cellular oncogene ??????
• ???? HBV genome ??????? cellular genome
• insertion activation ??? c-onc gene

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• 2. Trans-activation ??? cellular oncogene ??? HBV
  gene
• ?????????????????????? hepatocyte
• ??????????????????????????
• malignant transformed hepatocyte

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Human papilloma virus (HPV)

• ?????????????????????
• ???????? 1 Low risk (HPV 6, 11)
• ???????? 2 High risk (HPV 16, 18, 31)
• ???????? 3 Medium risk
• (HPV 33,35,39,40,43,45,51-56,58)
• Premalignant lesion CINI, CINII, CINIII
• (Cervical Intraepithelial Neoplasia, CIN)
• Malignant lesion invasive carcinoma

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HPV

• HPV early protein cell transformation
• - Bovine papillomavirus (BPV) E5 protein
• - HPV E6, E7 protein
• E6 ?????? p53
• E7 ?????? Rb
• - HPV 16 cellular oncogene (ras)
• Transform phenotype

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Herpes simplex virus

• HSV-2 transforming gene HPV
• Hit and run mechanism
• ??????????????
• Hit and run mechanism
• HPV-immortalized cell
• transfect ???? HSV-2 transforming gene
• Transformed cell
• Subculture
• ??????? HSV-2 transforming gene

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Human herpes virus type 8

• HHV-8 ????????????????????????
• Kaposi sarcoma (KS)
• ???????????????????

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Epstein-Barr virus (EBV)

• ?? 1964 ???? lymphoblastoid cell line
• ???????????????????????????????????????????????
  (Burkitts lymphoma)
• EBV infection B-cell activation
• ?????????????????? B-cell
• EBV transformed human B-lymphocyte
• ???????????????????? tumor ????????? 4 ????

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EBV/Burkitts lymphoma (BL)

• ???????????? (translocation) ??? c-myc
  proto-oncogene ????????????????? 8 ??????????? 14
  ????????????? Immunoglobulin gene
• c-myc ???????????????????????????
• ??????????????????????? B-lymphocyte
• Lymph node ?????????? malignant B cell
• ????????????? ???????????????????????????

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Burkitts lymphoma

• Endemic or African BL
• Sporadic or Non-African BL
• EBV DNA - ?????? cellular DBA
• - ???????????? episome
• ?? EBV nuclear antigen (EBNA-1)

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Nasopharyngeal carcinoma (NPC)

• NPC ??????????????????????
• ????????????????
• ?? EBV DNA ?????????????
• ?? EBNA-1
• B-cell lymphoma
• ????????????????????????????