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Functional Characterization of MicroRNAs in Prostate Cancer
Prostate Cancer
Prostate cancer is the name given to the cancer that starts in the prostate gland. The prostate is a part of the mans reproductive system and is as big as a walnut. It is wrapped around the urethra, the urine carrying tube (Mason and Moffat 2003).The most common cancer to be diagnosed is that of prostate cancer (CaP). The malignant tumor is responsible for the cause of death of the majority of the American men. Overall prostate cancer is known to be the third commonest cause of death of men which have crossed the age of 75. Men less than 40 years of age are rarely found to have developed prostate cancer.
Those who have been found more vulnerable to this type of cancer are the African American men, men over the age of sixty and those that have history of prostate in the family. Those who take animal enriched fat diet, farmers, Painters, tire plant workers, alcoholics, men exposed to cadium and orange exposure are also at a greater risk of developing prostate cancer( Meyer and Nash 1994).
Most often the men with prostate cancer complain of the symptoms like leakage or dribbing of urine, blood in urine or semen, pain in the lower back and pelvic bones, delayed or slow urinary stream. For prostate screening the PSA (Prostate Specific Antigen) blood test is conducted. The diagnosis is confirmed the prostate biopsy. In this the tissue is taken from the prostate and is examined under the microscope. The results of the biopsy are based on the Gleason Grade and the Gleason Score. The Gleason grade is the determinant of the severity of the prostate cancer. The scale of the Gleason Grade is from 1-5.
This grading is done according to the shape of the cells. The more they differ from the normal cells the higher the grade value. Sometimes one tissue sample may have multiple Gleason grades. Hence for this purpose a Gleason score is created. In this the two most dominant grades of the tissue sample are added together using a scale of 2-10. The more higher the Gleason score the more it is probable that the cancer has spread beyond the prostate gland (Amin 2004). The cancer is graded as follows:
Score 2-4: Low grade cancer
Score 5-7: Intermediate grade cancer. It has been noted that the majority of the prostate cancer fall into this category.
Score 8-10: High grade cancer. The cells of this type of cancer are poorly differentiated.
Tests and Therapies available
The Prostate biopsy is needed when the PSA blood test is high. However even a rectal examination that shows a large prostate or hard irregular surface may also point to the prostate biopsy. PSA blood test is useful and done after the treatment of the cancer as well. For the spread of cancer CT scan and Bone Scan tests are performed (Mason and Moffat 2003).
The treatment for the prostate cancer depends and varies from person to person. The doctor usually advises the treatment according to the type of the cancer and the risks concerned with the patient. Usually a combination of 2-3 treatments is suggested.
Surgery is another option and is looked into after thorough discussion of the risks involved. This type of the surgery is called prostatectomy. Today it can be done with robotic surgery. The risks of the surgery are that patients often complain of uncontrolled urine, bowel movements and problems of errection.
Radiation Therapy
Other therapies include the radiation therapy and hormone therapy. In the radiation therapy powered x rays or radioactive seeds are used to kill the cancer cells. The radiation therapy is good when the doctor thinks that the cancer has not spread beyond the prostate gland and it is also useful in nullifying the pain when the cancer has reached the bone. The side effects of this type of therapy are bladder urgency, blood in urine, incontinence and impotency. Prostate brachytherapy is the name given to the treatment in which the radioactive seeds are placed inside the prostate to kill the cancer cells. The side effects of this treatment are swelling, bruising of the scrotum or penis, diarrhea, incontinence, red brown semen or urine and impotence.
Hormone Therapy
The hormone therapy is used mainly in patients in whom the cancer has spread. It is used to help alleviate the symptoms. Testosterone is the main hormone in the males. In case of prostate tumors the testosterone makes the cancer cells grow. So the hormonal therapy is provided to negate the effect of testosterone. The drugs that are used in the hormone therapy are two. These are the Luteinizing hormone releasing hormones (LH-RH) agonist and the androgen-blocking drugs (Masson and Moffat, 2003).
Drastic Treatments
More drastic treatments that can be used are the Orchiectomy which is the removal of the testes, as most of the testosterone is produced by them. Immunotherapy and chemotherapy is used when the cancer shows no effect after being treated by the hormone therapy. Single or combination of drugs is usually advised after the treatment. Routine checkups and PSA blood tests are recommended for a year.
Introduction to MICRO RNA
MICRO RNAs are found in all the eukaryotic cells and are considered to be the ancient part of the genetic regulation. They are short ribonucleic acid (RNAs) molecules. They have an average of 22 nucleotides and are post-transcriptional regulators that attach themselves to the complementary sequences on the target messenger RNA. This results in the gene silencing and translational repression.
Plants and metazoans, miRNAs, show entirely different characteristics. The plant miRNA complementarity to its mRNA is almost perfect. This is quite the opposite in the metazoans. There is also a difference of the location of the target sites on the mRNAs. The miRNA target sites of the metazoans are at the three prime untranslated regions. (3UTR) of the mRNA. In plants the targets are present at the coding regions as well as the 3UTR.
MiRNA are responsible for a lot of the developmental processes. They are thought to have some role in the gene expression and the fine tuning in the cells. Keeping in view of the targets of the miRNAS that might as well be thousands, they could be thought to be the formation of a layer of circulatory mechanism in the cell. By this it can be concluded that in case of mis regulation of these miRNAs the regulatory system of the cells could be affected as well. Hence the regulatory disruptions of the cell might be responsible for production of the tumors.
Characteristics of miRNA Action
There are many similarities of miRNA and the Transcription factors (TFs). Like them the miRNA has the ability to bind with the discrete cis-regulatory elements. Thereby they can control the targeted genes (Gaur and Ross 2009).Moreover miRNA use the binding site accessibility for the genes regulatory control. It jointly works to read out the combined expression patterns. The unique character of the miRNA is that they have the capability of spatially compartmentalization within a cell for the local alteration of the gene expression. They have more specified and pronounced regulatory control because of the speed and reversibility (Strooper Bart D and Christen Yves 2010, 104-129).
MiRNA and the non coding RNAs
The mapping of the first chromosome in 1999 revealed that human genome would probably consist of 100,000 protein coding genes. Yet the identification could only be made of some 20,000 proteins. After many studies it is revealed that majority of the transcripts are non coding RNA and also snoRNAs and miRNAs.
MiRNA and the nervous system
The miRNA have been found to be the regulators of the nervous system. These are the neural miRNA which function at the different stages of the synaptic development, synaptic maturation and formation. In patients with schizophrenia there have been found to be alteration of this miRNA.
MiRNA and heart disease
The involvement of the miRNA in the heart has been established by the inhibition of the miRNA maturation in the murine heart. It has been found that the expression levels of the diseased hearts have altered miRNAs (Appasani 2008).
MiRNA function in Cancer
Many types of the miRNAs have been linked with the cancer. According to a study conducted on mice which altered the production of c-Myc protein with multiple mutations It showed that miRNAs had an effect on the cancer. The mice died within two weeks of time that produced the miRNA in abundance. The mice without the surplus amount of miRNA lived twice as long. It is also now known that leukemia can occur with injecting the viral genome next to 17-92 array of the miRNAs. E2F1 is a protein that is responsible for the regulatory mechanism of the cell and already two types of the miRNA are found which inhibit the function of this protein. This occurs because of the miRNA binding to the messenger RNA before being translated to the proteins making them switch off and on (Wang 2009, 20-21).
Taking the measurement of the 217 genes that encode the miRNA, we can obtain the patterns of the gene activity and this knowledge will help in the evaluation of the different types of the cancer. Hence this signature of the miRNA will in future provide the knowledge for the classification of the different types of the cancer. Moreover with this in place the doctors would find it very easy to pinpoint the tissue which formed the cancer. With this the specific tissue targeting treatments could be achieved. Proven and in practice is already the profiling of the miRNA with which the doctors are able to identify the slow to fast progressive cancer in patients with chronic lymphocytic leukemia (Majumder 2009, 74).
MiRNA function in prostate cancer
MiR 17-92 has been found to suppress the working of the anti angi genic factors. There are many members of this cluster. One specific member of the cluster miR 17-92 is miR-20a is known for the oncogenic properties in the prostate cancer (Jain 2010).
Loss of p27 as the predictor for the recurring prostate cancer
The expression of p27 in the prostatectomy specimen is found to be in accordance to the biochemical recurrence. When this p27 is absent it clearly defines for the reoccurrence of the prostate cancer.
MiRNA Biomarkers of prostate cancer
A high throughput and optimized miRNA expression profiling provides exclusive identification from the prostate cancer biopsies. This enables for the differentiation of the pooled normal prostatic samples to those of the metastatic prostate cancers and non malignant precursor lesions (Jain 2010, 313).
Today the miRNAs expressions have been found to be a much authenticated diagnostic as well as prognostic tool for the prostate cancer. With the hierarchical samples of the prostate tumor in reference to their miRNAs expression it is now possible to separate and distinguish the benign prostate hypertrophy from the carcinomas. Further classification of the carcinomas is also possible for which the androgen dependence needs to be looked for.
Today in humans the serum levels of the miRNA can identify the person with prostate cancer to that of healthy person. Until now the some of the known different expressions of miRNAs that are related to the prostate cancer are the let 7-c,miR 19-b,miR20-a, miR29-b, miR-100, miR- 25b, miR-126*,miR- 128b, miR- 146a, miR- 146b, miR- 184, , miR- 221, miR-222, miR-361, miR- 424, miR- 663. However of these the specifications of only five are known.
Three of them have characteristics of oncogenes and two work as tumor suppressors. These are the miR- 20a, miR- 125b, miR-126*, miR- 146a and miR-221/222 respectively. The Oncogenic miRNAs are responsible for the down regulation of the apoptosis genes, whereas the tumor suppressors are taken as the new biomarkers. These are the future therapeutic targets for the prostate cancer treatment (Maulik Bandyopadhyay Wang 2010, 99-100).
It is the discovery of the miRNAs for the prostate cancer and the sites where they attach that has made possible the advancement in the cure of the disease. For the development of advanced and multiple therapies use of new computational methods is of inherent importance. Through direct biochemical cloning the miRNA genes are classified extensively. These are then gathered in the databases as miRBase and Micro RNA db.
References
Amin Mahul B. 2004. Gleason Grading of prostate cancer: a contemporary approach. Philadelphia: Lippincott Williams and Wilkins.
Appasani Krishnarao. 2008. Micro RNAs: from basic science to disease biology. United Kingdom: Cambridge University Press.
Gaur Rajesh k and Ross John J. 2009. Regulation of gene expression by small RNAs. USA: CRC Press.
Jain, kewal k. 2010. The handbook of biomarkers. USA: Springer.
Majumder Sadhan. 2009. Stem Cells and Cancer. USA: Springer.
Mason Malcolm and Moffat Leslie. 2003. Prostate Cancer: The Facts. New York: Oxford University Press.
Maulik, Ujjwal. Bandyopadhyay, Sanghamitra and Wang, Jason, T. 2010. Computational analysis and pattern analysis in Biology informatics. USA: John Wiley and sons.
Meyer Sylvan and Nash Seymour c. 1994. Prostate Cancer: Making Survival Decisions. USA: University of Chicago Press.
Strooper Bart D and Christen Yves. 2010. Macro Roles of Micro RNAs in the life and death of neurons. USA: Springer.
Wang Zhiguo. 2009. Micro RNA Interference Technology. USA: Springer.
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