09 September 2014

Oncogenic RNA was found in the "genetic garbage"

Ovarian cancer oncogene found among "junk DNA"

NanoNewsNet based on Medical Xpress materials: Researchers find ovarian cancer oncogene in 'junk DNA'

In recent years, scientists have made a huge step forward in understanding and treating cancer, using genome analysis in their research to find links between genetic changes and the disease. Most of these studies have focused on the part of the human genome that encodes proteins. In general, this part makes up only 2 percent of human DNA. However, the vast majority of cancer-related changes in the genome are outside the protein-coding genes, in the part of it that has traditionally been called "junk DNA".

Today, scientists know that "junk DNA" performs quite specific functions – most of it, for example, is transcribed into RNA – but determining the specific functions of these sequences remains a problem.

A group of scientists from the Perelman School of Medicine of the University of Pennsylvania (UPenn), led by research Professor of the Department of Obstetrics and Gynecology Lin Zhang, PhD, obtained such sequences and identified one of the non-protein-coding RNAs (non-protein-coding RNA), the expression of which is associated with ovarian cancer. The results of this study are published in the online edition of the journal Cancer Cell (Hu et al., A Functional genomic approach identifies FAL1 as an oncogenic long non-coding RNA that associates with BMI1 and represses p21 expression in human cancer).

With the support of the Basser BRCA Research Center (Basser Research Center for BRCA) At the Abramson Cancer Center UPenn, Dr. Zhang and his group built DNA copy count profiles of almost 14,000 long non-coding RNAs (lncRNAs) in cells of 12 types of cancer, including ovarian and breast cancer. They found that in 12 different types of cancer, the number of copies of lncRNA genes on the first chromosome is steadily altered and lncRNA genes are widely expressed in cancer cells.

What these non-coding RNA proteins do is still relatively unknown. However, given their huge number in the human genome, researchers believe that they probably play an important role in normal human development and in the body's response to disease.

Using clinical and genetic data, as well as gene expression data, as filters to distinguish genes whose copy count change causes cancer from genes whose copy count change is random, the researchers reduced their list from 14,000 to a more acceptable number. Each of the remaining genes was systematically tested in genetic experiments on animals.

Of the 37 fully tested lncRNAs, one, which they named FAL1 (focally amplified lncRNA on chromosome 1), had all the signs of an RNA oncogene. To date, FAL1 is one of the few lncRNAs associated with cancer. This information may well be used for clinical purposes. For example, the expression of FAL1 may be a biomarker for the prognosis of BRCA-associated cancer and the basis for the creation of new anti-cancer drugs. As proof of the potential effectiveness of targeting this RNA, Zhang's group grew human ovarian tumors in immunocompromised mice, and then injected animals with short interfering RNAs against FAL1 to block tumor growth using RNA interference. As a result, the tumors in these mice decreased, while in the control animals their growth continued.

FAL1 RNA is overexpressed in ovarian and breast cancer tissue samples. Blocking the activity of this gene by RNA interference suppresses the growth of cancer cells, while overexpression of FAL1 in normal cells enhances their growth. After evaluating the expression of FAL1 in human ovarian cancer samples, the researchers concluded that a high level of FAL1 expression is usually correlated with a poor clinical prognosis.

"This is the first genome-wide study using bioinformatics and clinical information to systematically identify one lncRNA, which, as we have established, is oncogenic," Dr. Zhang comments on the results of his work.

Finally, the researchers studied the function of FAL1. They searched for proteins associated with FAL1 and identified a protein called Bmi1, which is a member of the PRC1 gene regulatory complex. In the absence of FAL1, the Bmi1 protein is unstable. FAL1 RNA stabilizes Bmi1, which in turn suppresses the expression of several hundred other genes. One of the genes suppressed in this case is the gene encoding the tumor suppressor p21.

These findings, Dr. Zhang explains, suggest the existence of a molecular mechanism in which the amplification of the FAL1 gene in ovarian cancer causes an excess of FAL1 RNA. This leads to increased stability of the Bmi1 protein, suppression of the oncosuppressor p21 and, ultimately, unrestrained cell growth.

Oncogenic lncRNA FAL1 (dragon), disrupting gene transcription and promoting tumorogenesis. FAL1 RNA stabilizes the Bmi1 protein (stone) by binding to it (the dragon wrapped around the stone), which as a result enhances the activity of the PRC1 gene-regulatory complex (pile of stones). The growth of normal cells requires a constant flow of information from DNA to matrix RNA (water flow). Suppression of transcription (water congestion) from tumor suppressor genes, such as p21, leads to cellular transformation (growth due to drought of cactus-like desert plants instead of normal plants). (Fig. Lili Guo)The expression of FAL1 can serve as a prognostic biomarker of BRCA-associated cancer if these data are confirmed in other populations.

In addition, it is possible to develop new anti-cancer drugs, whether they are drugs specifically targeting FAL1 RNA, or small molecules blocking the interaction between FAL1 and Bmi1.

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