Viruses and human cancer lecture 5

Question 1

Name the cancer causing viruses

Answer 1

Epstein-Barr virus (EBV)

Hepatitis B (HBV)

Human T cell lymphotrophic virus type 1 (HTLV1)

High-risk human papilloma virus (HPV16, 18, 45)

Hepatitis C (HCV)

Kaposi’s sarcoma herpes virus (KSHV)

Merkel cell polyomavirus (MPV)

Question 2

Describe Epstein Barr virus and cancer

Answer 2

• Lifelong silent infection
• Patients have malaria
• 100% cause of Endemic Burkitt Lymphoma
• Raises Hodgkin Lymphoma incidences by 80%
• Causes B cell infection which moves to the germinal centre and undergoes somatic hypermutation
• Because of DSBs C-myc translocation to Ig heavy/light promoter occurs
• Because patients also have malaria division and tumour growth happens quickly

EBV

• Transforms resting B cells into continuously proliferating lymphoblastoid cell lines
• Associated with malignancies of:

B cells (hodgkin lymphoma

NK/T cells (T-cell lymphoma)

Epithelial cells (Gastric carcinoma)

Viruses associated with 16% of cancers

Question 3

Describe the causes of Burkitt lymphoma

Answer 3

EBV Malaria

C-myc translocation to the Ig heavy or light chain

Question 4

Describe the causes of Kaposi’s sarcoma

Answer 4

KSHV -tumour from mesenchymal tissue -highly vascular tumour

• classical- v rare - iatrogenic (immunosuppression)
• HIV/AIDS patients

Question 5

Describe the causes of skin cancer in EV

Answer 5

HPV5, HPV8

UV light

Epidermodysplasia verruciformis gene mutation due to UV light

Question 6

Describe the causes of hepatocellular carcinoma

Answer 6

HBV and Aflatoxin

Question 7

What are the common characteristics viruses that cause cancer have?

Answer 7

• Common persistent infections in general population (EBV)
• Incidence increased in immunocompromised (HIV, EBV)
• Viral genes that control cell proliferation/survival
• Clonal integration of viral DNA into host (HPV)

Question 8

How do viruses act as carcinogens?

Answer 8

Direct- introduction of a vital oncogene into host cell, activates an endogenous oncogene, inhibits a tumour suppressor gene

Indirect- causes chronic inflammation, prevention of apoptosis, virus induced immunosuppression (HIV) They prolong cell cycling allowing the cell to live longer and squire more genetic mutations and promote cell survival making cancer more likely

Question 9

Name some protein targets of HPV virus that cause cancer

Answer 9

HPV encodes E7 which binds RB so it releases E2F-1 that activates transcription of S phase genes.

Rb provides G1/S phase checkpoint by binding E2F TFs when hypophosphorylated. E7 binds hypophosphorylated Rb and displaces it so the TFs are free. This means stimulation of CyclinD and Cdk4 is not required to move into S phase

p53 is normally stimulated in non-regulated movement of cells into S-phase and goes on to cause cell cycle arrest

• Encoded E6 binds to p53, attracting E6Ap which ubiquitylates p53; sending it to the proteasome for degradation. p21 can not be initated by putting cell in apoptosis.
• This results in the cell cycling continuously and the accumulation of chromosomal mutations occurs

Question 10

Describe the function of the retinoblastoma protein

Answer 10

Tumour suppressor

Unless hyperphosphorylated, prevents progression through the restrictions point in G1 to S phase

When hypophosphorylated, bound to E2F, DP, GDAC and p300

Phosphorylation of pRB by cycD and cdk4/6 removes HDAC

Phosphorylation by cycD and cdk2 removes RB from the complex activating transcription p16(ink4a) is a cdk inhibitor and promotes cell senescence

Question 11

Describe the role of p53

Answer 11

Guardian of genome

Activated by ATM, CHK2 as apart of the DNA damage response

Regulated by mdm2 a E3 ubiquitin kinase

Activated by CBP, TRAF, PCAF P300 ASPP1

Promotes anti-angiogenesis (tsp1), growth arrest (p21), DNA repair (p48) and apoptosis (DRS, Fas)

Question 12

Describe HPV vaccination and how it works

Answer 12

HPV16 and 18 most prevalent HPV type in cancers Cervical cancer arises at the “squamocolumnar” junction of the cervix

Vaccine is the proteins that make up the virus particle that assemble into the native 3D structure when in cells and so initiates a good antibody response

HPV gets into basal cells (replicating cells) and binds to receptors which allows entry into epithelial cell. THe vaccine binds to virus particles to stop virus prtticles from interacting with receptors. It also causes destriction by neutrophils.