Role of non-coding RNA in prostate cancer progression


View:745 Time:2018-05-29


Novel approach to combat prostate cancer

Dr. Arul Chinnaiyan, professor of urology and director of the Michigan Center for Translational Pathology, and his team have recently discovered that a non-coding RNA called ARLNC1 could play a role in the progression of prostate cancer. This discovery suggests ARLNC1 as a new potential drug target [1].

The Chinnaiyan lab is committed to dissecting cancer biology, using multiple methods such as genomic, proteomic, metabolomic and bioinformatics. Their research interests include prostate cancer.

Long noncoding RNAs (lncRNAs) are emerging as important regulators of tissue physiology and disease processes including cancer. But little is known about the underlying mechanisms. For this, lncRNAs are also referred to as the dark matter of the genome.

In 2015, Dr. Chinnaiyan's team delineated genome-wide lncRNA expression by using RNA sequencing libraries from tumors, normal tissues and cell lines comprising sequence information from many studies. They identified more than 46,000 lncRNAs that were previously unannotated[2].

Dr. Chinnaiyan's team continued their research to find that ARLNC1 (androgen receptor (AR)-regulated long noncoding RNA 1) is increased in prostate cancer compared with that in normal tissue. Additionally, this lncRNA is associated with AR signaling in prostate cancer progression. On one hand, the AR induces the expression of ARLNC1. On the other hand, ARLNC1 stabilizes the AR transcript via RNA-RNA interaction. Both in vitro and in vivo experiments revealed that blocking ARLNC1 could inhibit AR expression, global AR signaling, and prostate cancer growth. By contrast, increasing ARLNC1 could result in the formation of large tumors.

These data, collectively, suggest that the lncRNA ARLNC1 may play a role in prostate cancer progression and represent a new therapeutic target.

The AR is a nuclear receptor that functions as a transcription factor and regulates the normal development and growth of the prostate. It is activated by binding either of the androgenic hormones, testosterone, or dihydrotestosterone. However, the AR is also involved in the development of prostate cancer. Many studies have shown that the AR helps prostate cancer cells to survive. Thus, the AR has been suggested as a drug target. But inhibiting the AR has only proven to be effective in animal studies.

According to Dr. Chinnaiyan, it's important to better elucidate the AR. Their latest study reveals a mechanism involving ARLNC1 that potentiates AR signaling during prostate cancer progression and provides a novel approach to inhibit the AR.

Finally, Dr. Chinnaiyan pointed out that they'll further explore the dark matter of the genome. Except for ARLNC1, there are many other lncRNAs that remain poorly understood. A deeper understanding of these molecules would provide new insights into cancer, other diseases, as well as normal physiological processes.


Causative mechanisms in prostate cancer

Prostate cancer is the most common malignancy in men and the cause of 1-2% of deaths in men. The exact causes of prostate cancer remain unclear. Several risk factors for developing prostate cancer have been identified. However, which of these risk factors cause a prostate cell to become cancerous is not fully understood.

1. Age

Approximately 90% of patients with prostate cancer are over 50 years old. Old age is a major risk factor of prostate cancer.

2. Race

Epidemiology studies have suggested that prostate cancer occurs most frequently in African Americans while having lower rates in Asian males[3].

Fig. 1 Incidence of prostate cancer

3. A family history

Men who have a first-degree relative with prostate cancer have twice the risk of developing the disease compared to those in the general population. Genetic linkage studies in multiple-case families have identified the homeobox gene HOXB13 as a definite prostate cancer predisposition gene[4].

4. Obesity

Obesity is linked to aggressive prostate cancer. Avoiding obesity may prevent the risk of developing high-grade prostate cancer[5].

5. Nutrition and dietary factors

Accumulating evidence suggests that many dietary components may play a role in the pathogenesis of prostate cancer. For instance, excessive intake of animal fats appears to contribute to the onset of prostate cancer, and plant foods that provide a multitude of antioxidants and phytochemicals have a demonstrable beneficial effect on prostate cancer. However, the results of previous studies in this field have yielded inconsistent results, with individual antioxidants having been shown to have positive, negative, or no association with prostate cancer risk[6][7].

6. Environmental exposure disruptors

Several studies have suggested a link between exposure to certain chemicals and risk of prostate cancer. These chemicals include The bisphenol A (BPA), which is a synthetic estrogen, chlordecone, and Pesticides.


Screening of prostate cancer

Measurement of prostate specific antigen (PSA) is useful in screening of prostate cancer.

PSA is a protein produced by normal, as well as malignant, cells of the prostate gland. The PSA test measures the level of PSA in a man's blood. When a man has prostate cancer, his PSA level often increases. This is why the PSA test is usually the first step in any prostate cancer diagnosis.

However, the PSA screening by itself cannot tell you if cancer is present. It is often done along other examinations such as a digital rectal exam (DRE). In addition, PSA levels can be affected by many factors, such as age, race, certain medical procedures, certain medications, an enlarged prostate, and a prostate infection.

Many countries recommend offering the PSA test and DRE yearly to men 50 years or older who have a life expectancy of at least 10 years. But in some countries, the coverage of PSA test is relatively low, which is not good for early detection of prostate cancer.


Signs of prostate cancer

In its early stages, prostate cancer usually causes no symptoms. When it progresses to more advanced stages, it may cause signs and symptoms such as frequent urination, nocturia, difficulty starting and maintaining a steady stream of urine, blood in the urine, and painful urination. These symptoms can also occur in other diseases and conditions. If you have one or more of these symptoms, you’d better go to your doctor.


Prognosis of prostate cancer

The prognosis of prostate cancer is associated with disease stage. For men with localized prostate cancer, the prognosis is quite excellent that the 5-year survival rate is nearly 100%. Once prostate cancer has spread beyond the prostate, survival rates fall. In most cases, prostate cancer spreads to bones, such as the hip, spine, and pelvis bones. Patients with prostate cancer metastases have limited treatment options, prognosis, and outlook, compared with those with localized disease.


Reference:
[1] Yajia Zhang et al. Analysis of the androgen receptor-regulated lncRNA landscape identifies a role for ARLNC1 in prostate cancer progression. Nature Genetics (2018).
[2] Matthew K Iyer et al. The landscape of long noncoding RNAs in the human transcriptome. Nature Genetics (2015).
[3] Zeigler-Johnson M. Charnita et al, Evaluation of prostate cancer characteristics in four populations worldwide, The Canadian journal of urology (2008).
[4] Gerhardt Attard et al, Prostate cancer, The Lancet (2015).
[5] Adriana C. Vidal et al, Obesity Increases the Risk for High-Grade Prostate Cancer: Results from the REDUCE Study, Cancer Epidemiology, Biomarkers & Prevention (2014).
[6] Venita H Patel, Nutrition and prostate cancer: an overview, Expert Review of Anticancer Therapy (2014).
[7] Terrence M. Vance et al, Dietary Antioxidants and Prostate Cancer: A Review, Nutrition and Cancer (2013).
 
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