Wednesday, May 22, 2013

GENES IN PENILE CANCER

One of the particularity of Penile cancer is that, at least in half of the patients, the trigger is infectious and Papilloma virus (HPV) primarily, and Herpes-2 secondarily.  And with the Viral cause comes the assumption that insertion of the viral genome in the Human genome will occur to take over the machinery of the human genome and use it to viral purposes!  First, not all types of HPV achieve this. Those with E6 and E7 will however lead to neoplastic transformation.  You would think that like any infection, stimulation of the immune system and awakening of NF-kB would be the predominant events.  The literature does not deny these roles, however, stray away to P14arf/MDM2/P53 and P16/INK4a /Cyclin D, and Retinoblastoma . These paths will lead to the activation of Ras, MYC, Telomerases, MMP, PGE and COX.  E-Cadherin is decreased. To come up to what is going on, let's review these factors in order to clarify these opportunities for targeting this cancer.

HPV ASSOCIATED CANCER:

In August 2012, the Medscape website released a slide presentation about HPV and cancer risk. The following table shows the incidence of HPV associated cancers in the period of 2004-2008 in the US.[14]
Cancer area Average Annual Number of cases HPV Attributable (Estimated) HPV 16/18 Attributable (Estimated)
Cervix 11,967 11,500 9,100
Vulva 3,136 1,600 1,400
Vagina 729 500 400
Penis 1,046 400 300
Anus (woman) 3,089 2,900 2,700
Anus (men) 1,678 1,600 1,500
Oropharynx (woman) 2,370 1,500 1,400
Oropharynx (men) 9,356 5,900 5,600
Total (women) 21,291 18,000 15,000
Total (men) 12,080 7,900 7,600
(wikipidia) 

HPV RELATED ONCOGENES"

E6 and E7, are known to act as oncogenes that promote tumor growth and malignant transformation. Oral infection with HPV increased the risk of HPV-positive oropharyngeal cancer independent of tobacco and alcohol use.[17] In the United States, HPV is expected to replace tobacco as the main causative agent for oral cancer.[18]
The p53 protein prevents cell growth and stimulates apoptosis in the presence of DNA damage. The p53 also upregulates the p21 protein, which blocks the formation of the Cyclin D/Cdk4 complex, thereby preventing the phosphorylation of RB and, in turn, halting cell cycle progression by preventing the activation of E2F. In short, p53 is a tumor suppressor gene that arrests the cell cycle when there is DNA damage.
E6 has a close relationship with the cellular protein E6-AP (E6-associated protein). E6-AP is involved in the ubiquitin ligase pathway, a system that acts to degrade proteins. E6-AP binds ubiquitin to the p53 protein, thereby flagging it for proteosomal degradation."

CONSEQUENTLY, P53 IS REMOVED FROM THE EQUATION, p21 IS DEPRESSED, CYCLIN D BOOSTED AND RB, A SUPPRESSION GENE, IS PHOSPHORYLATED WHILE APOPTOSIS IS BLOCKED EVEN IN THE PRESENCE OF A DERANGED HUMAN GENOME! TOLERANCE THAT IS NEEDED FOR NEOPLASIA TO PROSPER.

AND THIS IS HOW THE INTEGRATION GOES DOWN:

" E6/E7 proteins:
The two primary oncoproteins of high risk HPV types are E6 and E7. The “E” designation indicates that these two proteins are expressed early in the HPV life cycle, while the "L" designation indicates late expression.[15] The HPV genome is composed of six early (E1, E2, E4, E5, E6, and E7) ORFs, two late (L1 and L2) ORFs, and a non-coding long control region (LCR).[59] After the host cell is infected viral early promoter is activated and a polycistronic primary RNA containing all six early ORFs is transcribed. This polycistronic RNA then undergoes active RNA splicing to generate multiple isoforms of mRNAs.[60] One of the spliced isoform RNAs, E6*I, serves as an E7 mRNA to translate E7 protein.[61] However, viral early transcription subjects to viral E2 regulation and high E2 levels repress the transcription. HPV genomes integrate into host genome by disruption of E2 ORF, preventing E2 repression on E6 and E7. Thus, viral genome integration into host DNA genome increases E6 and E7 expression to promote cellular proliferation and the chance of malignancy. The degree to which E6 and E7 are expressed is correlated with the type of cervical lesion that can ultimately develop.[56]" WIKIPIDIA

HSU ET A
 " E6 proteins of both low-risk and high-risk human papillomavirus (HPV) interact with three coactivator HMTs, CARM1, PRMT1 and SET7, and downregulate their enzymatic activities in vitro"
THE E6 AND E7 OTHER ROLE IS EPISOMAL MAINTENANCE


(DICTIONARY)
TO BE CONTINUED
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