| Abstract |
The polyoma virus such as the BK Virus (BKV), the JC Virus and the Simian Virus
40 (SV40), as well as the Human Papilloma Virus (HPV) are present in human
population. The family of the polyoma viruses cause persistent subclinical infections
and promote oncogenesis in both human and non human cell lines. In order to check
the involvement of these viruses in ocogenesis, in prostate and pancreas, the frecuency
of occurrence of the BKV, JCV and HPV were studied in a series of human
malignancies of prostate and pancreas. Also studied was the RAS proto-oncogenes (HRas,
K-Ras and N-RAS), which are part of the intracellular signaling pathways that
play an important role in cell growth regulation, as well as in the formation of
malignancies. The significant difference between the normal human gene RAS, the
gene for bladder cancer, and the gene of the sarcoma virus in rodents is a single
change in one codon, the codon XII, and therefore in a single amino acid change.
Human cells can turn into cancer cells under the influence of all factors mentioned
above.
The family of polyoma viruses, including human virus BK (BKV), virus JC (JCV)
and Simian virus (SV40), and the papillomaviruses (HPV) are common pathogens of
the urinary system. These pathogens are linked to the pathogenesis of urinary tract
malignancies such as prostate cancer and malignancies such as pancreatic cancer. The
genetic material of polyoma virus consists of a circular double-molecule DNA, of
about 5 kb. The genome contains a small region that encodes the T-antigen (T large
and small t), which is divided into an early and a late region coding for the expression
of proteins (AGNO + capsid proteins), and a non-coding regulatory region. Based on
the structure of non-coding regulatory region, Polyoma viruses can be classified into
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two forms: the archetype and the mutant variation. The archetypal form of polyoma
contains a single copy of the promoter and enhancer. The BKV and JCV share
approximately 72% of nucleotide homology between them and 70% of nucleotide
homology with SV40.
The BKV was first identified in 1971 in a urine sample after a kidney transplant.
The BK virus has been detected in various human tissues, including brain, pancreatic
islets and the prostate. Among other cases, the detection of this virus family polyoma
was possible in cases of immunocompromised patients, either parallel or due to
immunosuppressive therapy or AIDS infection, and in some patients, especially
children, who had undergone transplant or had immunodeficiency. The types of the
disease where the polyoma viruses were found to be present vary greatly. Examples of
such cases are renal transplantation, transplantation of bone marrow, AIDS (HIV-1),
sarcoma Kaposi, brain tumors, the pancreatic islets, kidney, bladder and prostate
cancers as well as in hemorrhagic cystitis in kidney and liver dysfunction. Human cells
can turn into cancer cells under the influence and other factors beyond the viral.
The discovery of RAS genes occurred after the restoration of DNA from malignant
cells, and thus human DNA sequences that may have oncogenic properties were
isolated from most of the genome of mice. The first gene family of RAS, which was
isolated from tumours of the bladder was almost identical to the normal human gene
and nearly identical to the tumor gene bearing viruses, which occur in malignancies.
The significant difference between the normal human gene, the gene of bladder cancer
and the gene of the virus of rodents was a single change in one codon, which showed
the codon XII, and therefore there was only one change of amino acids, which turned
out able to cause changes in normal cell growth.
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Forty-two (42) samples that were diagnosed with prostate malignancies were tested
by protocol polymerase chain reaction (PCR). The differentiation of viruses BKV and
JCV, between polyoma virus-positive samples was reached after analysis of
sequencing products of the investigation of samples with PCR. The overall prevalence
of polyoma virus was 19% while that of HPV was detected in 4.8% of samples.
Analysis of the sequencing of the polyoma virus, which was detected in positive
samples, revealed the exclusive presence of BKV in all samples. To check the
involvement of the family of polyoma viruses in tumorigenic properties of pancreatic
cancer, we investigated the prevalence of BKV in a range of human malignancies of
the pancreas. Fifty-seven (57) samples of pancreatic tumors diagnosed were similarly
tested with PCR protocols. Further, in the present study we investigated the presence
of mutations in codon 12 of H-, K- and N-Ras oncogenes in the series of fifty-seven
pancreatic tumors, using the technique of PCR-RFLP. Beta-2 microglobulin (α2m)
was used as positive control for all PCR experiments conducted.
Reconstitution of virus (Viral Reconstitution) BK by BKV-positive samples of
prostate cells in culture was achieved successfully, as has also been growing and
producing a progeny of viral particles, thus confirming the presence of virus in the
samples of our study. Also genotyping for HPV was performed, using primers specific
for subtypes of HPV -11, -16, -18 and -33. However, none of these subtypes was
found. There was also no detection of the presence of polyoma virus in the samples of
pancreatic cancer under investigation. The overall rate of Ras mutation was 33.33% of
all samples (or 53.3% of total samples with clinical data, TSWCD). Specifically, HRas
mutations were detected in 3 of 57 (5.3%) samples. In addition, N-Ras mutations
were detected in only 2 of 57 (3.5%) malignancies. By contrast, K-Ras mutations were
detected in 17 of the 57 or 29,8% (43,3% TSWCD) of tumor samples.
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There were no simultaneous BKV infections and HPV in any of the patients. We
also found no correlation between the presence of BK virus DNA and
clinicopathological parameters of patients. In conclusion, BKV had a strong presence
in the prostate samples checked and could therefore be an important factor in the
development and progression of human prostate cancer, while HPV virus does not
appear to be involved in this kind of human neoplasia, in accordance with these
findings. Contrasting and always based on the results of this investigation suggest that
the Ras and especially K-Ras mutations are not rare in tumors of the pancreas, which
reinforces the theory that this proto-oncogene plays an important role in pancreatic
carcinogenesis.
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