Shourya Mukhopadhyay
Outline the importance of the so called “high risk” human papillomavirus
types in cervical cancer
Human Papilloma Virus (HPV) consists of DNA and a protein coat. HPV strains are
classified into high and low- risk types. 85% of HPV strains are of low risk. Low risk strains
cause condylomas (genital warts) and laryngeal papilloma, most common types are 6 and
11. High risk HPV causes cervical, oral and anogenital cancer, the most common types
being 16 and 18.
High risk HPV strains are transmitted through skin contact although transmission through
sexual contact is more common. This can be prevented by using condoms. People with
weaker immune systems are more susceptible to infection. Smoking, age and multiple
sexual partners are other risk factors increasing persistent infection.
HPV cannot bind to squamous epithelial cells. It uses micro abrasion to destroy cell
membranes and interact with integrins to enter the cell through endocytosis. The viral
genome then replicates 20- 200 times. 1 Carcinogenesis involves viral oncogenes being
integrated into the host cells’ genome. The E2 protein prevents the transcription of the E6
and E7 oncoproteins. When the viral genome is integrated into the host genome the E2
protein is not transcribed, producing excess E6 and E7 oncoproteins. E6 binds to p53
forming a trimeric complex with enzyme EAP targeting it for proteolysis. The E7 protein
binds to the underphosphorylated form of pRb. As both proteins are degraded, their tumour
suppressor function is lost, and the cervical epithelial cells have no DNA regulation. The
binding of E7 to pRb displaces the E2 transcription factor (from the host cell) which is
normally bound to pRb. The binding of the E2F to RbF ensures that it is in inactive form.
When free from RbF, E2F is activated, allowing transcription of genes encoding proteins
which are important in the progression of the cell cycle and DNA replication. These include
cyclins and cyclin dependent kinases. 2
High risk E6 and E7 oncoproteins have a greater affinity for the tumour suppressor proteins
compared to low-risk HPV ; A study conducted by Roman A and Armstrong DJ in virology
19993 confirmed this by comparing the ability of HPV -6 and HPV -16 to transactivate the E2
promoter. This study was conducted upon baby rat kidney cells and human keratinocytes.
HPV type 16 has seen to cause 45 % of all cervical cancers. High- risk HPV strains integrate
their genome more efficiently into host’s cell genome. The E6 oncoprotein has functions that
promote carcinogenesis independent of its action on p53. These cellular targets include
proteins that are involved in immune evasion and in apoptosis such as BAK and TNF
receptor 1 (TNF R1), FADD and C-myc proteins. A recent study indicated that tumour cells
have an increased expression of BCL2 and a lower expression of BAK, supressing
apoptosis. 2
E7 has also been shown to interact and downregulate chaperone proteins, which may result
in structural differences between tumour cells and cells of the epithelial lining.
A study indicated that cells infected with HPV had higher rates of phosphorylation of serine
residues. These hyperphosphorylated proteins influence deregulating certain signalling
pathways.
, Shourya Mukhopadhyay
HPV E6 and E7 binding to P53, with Rb interfering with the normal
functions of the tumour suppressors
A micronuclei count can also be used as a marker of HPV infected cells. Micronuclei arise
when chromosomes are not accurately incorporated into daughter nuclei during mitosis.
Cells which were infected had a higher micro nuclei account compared to those that did not.
4
HPV infection causes cervical intraepithelial neoplasia. CIN is classified into three grades:
CIN 1 (mild), CIN 2 (moderate) and CIN3 (severe). Not all cases of CIN progress to cervical
cancer as most HPV infections are cleared by the immune system. CIN 1 and CIN 2 often
clear however can progress to CIN3 and then to cervical cancer. 5
Koilocytes are HPV infected cervical squamous cells and show a distinct clearing between
the nucleus and cytoplasm called the perinuclear halo, a greater nuclear to cytoplasmic ratio
and hyperchromatic nuclei.
Outline the importance of the so called “high risk” human papillomavirus
types in cervical cancer
Human Papilloma Virus (HPV) consists of DNA and a protein coat. HPV strains are
classified into high and low- risk types. 85% of HPV strains are of low risk. Low risk strains
cause condylomas (genital warts) and laryngeal papilloma, most common types are 6 and
11. High risk HPV causes cervical, oral and anogenital cancer, the most common types
being 16 and 18.
High risk HPV strains are transmitted through skin contact although transmission through
sexual contact is more common. This can be prevented by using condoms. People with
weaker immune systems are more susceptible to infection. Smoking, age and multiple
sexual partners are other risk factors increasing persistent infection.
HPV cannot bind to squamous epithelial cells. It uses micro abrasion to destroy cell
membranes and interact with integrins to enter the cell through endocytosis. The viral
genome then replicates 20- 200 times. 1 Carcinogenesis involves viral oncogenes being
integrated into the host cells’ genome. The E2 protein prevents the transcription of the E6
and E7 oncoproteins. When the viral genome is integrated into the host genome the E2
protein is not transcribed, producing excess E6 and E7 oncoproteins. E6 binds to p53
forming a trimeric complex with enzyme EAP targeting it for proteolysis. The E7 protein
binds to the underphosphorylated form of pRb. As both proteins are degraded, their tumour
suppressor function is lost, and the cervical epithelial cells have no DNA regulation. The
binding of E7 to pRb displaces the E2 transcription factor (from the host cell) which is
normally bound to pRb. The binding of the E2F to RbF ensures that it is in inactive form.
When free from RbF, E2F is activated, allowing transcription of genes encoding proteins
which are important in the progression of the cell cycle and DNA replication. These include
cyclins and cyclin dependent kinases. 2
High risk E6 and E7 oncoproteins have a greater affinity for the tumour suppressor proteins
compared to low-risk HPV ; A study conducted by Roman A and Armstrong DJ in virology
19993 confirmed this by comparing the ability of HPV -6 and HPV -16 to transactivate the E2
promoter. This study was conducted upon baby rat kidney cells and human keratinocytes.
HPV type 16 has seen to cause 45 % of all cervical cancers. High- risk HPV strains integrate
their genome more efficiently into host’s cell genome. The E6 oncoprotein has functions that
promote carcinogenesis independent of its action on p53. These cellular targets include
proteins that are involved in immune evasion and in apoptosis such as BAK and TNF
receptor 1 (TNF R1), FADD and C-myc proteins. A recent study indicated that tumour cells
have an increased expression of BCL2 and a lower expression of BAK, supressing
apoptosis. 2
E7 has also been shown to interact and downregulate chaperone proteins, which may result
in structural differences between tumour cells and cells of the epithelial lining.
A study indicated that cells infected with HPV had higher rates of phosphorylation of serine
residues. These hyperphosphorylated proteins influence deregulating certain signalling
pathways.
, Shourya Mukhopadhyay
HPV E6 and E7 binding to P53, with Rb interfering with the normal
functions of the tumour suppressors
A micronuclei count can also be used as a marker of HPV infected cells. Micronuclei arise
when chromosomes are not accurately incorporated into daughter nuclei during mitosis.
Cells which were infected had a higher micro nuclei account compared to those that did not.
4
HPV infection causes cervical intraepithelial neoplasia. CIN is classified into three grades:
CIN 1 (mild), CIN 2 (moderate) and CIN3 (severe). Not all cases of CIN progress to cervical
cancer as most HPV infections are cleared by the immune system. CIN 1 and CIN 2 often
clear however can progress to CIN3 and then to cervical cancer. 5
Koilocytes are HPV infected cervical squamous cells and show a distinct clearing between
the nucleus and cytoplasm called the perinuclear halo, a greater nuclear to cytoplasmic ratio
and hyperchromatic nuclei.
