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The carcinogenic role of untranslated RNAs

Ever wondered what goes behind the uncontrolled cell division leading to cancer? So far, scientists believed that malfunctioned proteins are the real culprits. However, recent studies have now implicated a type of Ribonucleic acid (RNA), which does not code for proteins, to be responsible for this dreadful disease. In a recent study, researchers from the National Centre for Cell Science, Pune and Kalinga Institute of Industrial Technology (KIIT), Bhubaneswar, have identified a novel noncoding RNA that causes cancer in mice.

Ribonucleic acid, or RNA, is a critical molecule essential for life. In most living beings, the deoxyribonucleic acid or DNA has all the necessary recipes or codes to make the proteins required for survival. These codes are first converted into RNA, which then make the proteins. However, not all RNAs can do this! In fact, there are far too many RNAs—about 98% of what we have in our body—that can’t synthesise proteins at all! They are called ‘noncoding RNAs’. Depending on their size, they are called ‘long’ if they have more than 200 base pairs, or ‘short’ otherwise.

Once considered junk, non-coding RNAs are now associated with many vital biological functions like fine-tuning the process of cell development. They are also thought to have links to diseases like cancer, where they either cause or suppress it. In a previous study, published in the journal PLOS Biology, the researchers of this study have found how a specific long non-coding RNA causes genomic instabilities in the cell and disturbs the normal cellular growth balance. Such RNA is called genomic instability inducing RNA (Ginir). Its complementary nucleotide sequence is called Giniras.

The researchers of the current study found that the presence of Ginir RNA in the cells positively correlated with its metastatic state in mice. In the absence of Ginir, they observed a reduction in the tumour activity of the cells. The study reports that the RNA pair (Ginir and Giniras) is normally present during the development of the embryo, and is expressed more in brain cells. This finding indicates the possible role of this RNA in causing tumours in the central nervous system.

Most macromolecules in the body, including RNAs and proteins, do not work in isolation and involve an interacting partner to carry out their function. These cellular components are vital for maintaining the balanced function of the cell. Long non-coding RNAs are also known to carry out their activities by interacting with several intracellular targets. The researchers of the present study found that a centrosomal protein, called Cep112, interacts specifically with Ginir RNA and leads to the formation of tumours. The researchers show a specific interaction between Cep112 and another cancer-associated breast cancer type 1 susceptibility protein Brca1. In the presence of Ginir RNA, the interaction between Cep112 and Brca1 is impaired, which leads to abnormal cell division and malignancy- a condition that can lead to cancer.

“The levels of this noncoding RNA pair are well regulated under normal growth conditions, and the levels of the two transcripts—Ginir and Giniras—are perfectly balanced. Increase in levels of Ginir transcript pushes cells towards malignant growth conditions”, says Dr Anjali Shiras from NCCS, who is the lead author of the study.

However, we do not yet know why the level of Ginir rises and what are its triggers. “Hence, understanding key events that regulate cell growth is a complex phenomenon and we do not have answers to many such events”, she adds.

Although the current study deals with laboratory mice, the similarity between the genetic makeup of humans and mice makes the findings applicable to our cells as well. “In human cells too, increase in the levels of Ginir leads to increased cell division. However, we have not yet performed a detailed study on the role of this RNA in various types of human cancers. This is a question of prime interest to us as well, and a detailed understanding of the regulation of this noncoding RNA pair in mouse and human cells would be the focus area of our future research”, explains Dr Anjali.

The researchers also believe that Ginir RNA molecules can be used as a potential biomarker to detect cancer. The researchers are now trying to understand if Ginir RNA is secreted in body fluids like blood and if it could be a therapeutic target for cancers. The findings of these experiments may help cure cancer and alleviate the problem of many crippled by the disease.