Micro RNAs and cancer

Micro RNAs are becoming important players in cancer research

Predicting the future is a tricky business, and spotting trends in the world of science is no exception. And because of the slow and careful nature of research, exciting new fields of interest take years to emerge, rather than springing up overnight.

One relatively new – and certainly exciting – area of cancer research is the study of molecules called micro RNAs. Previously thought to be intriguing but unimportant, these little strands of genetic material are now being thrust into the limelight as key players in cancer.

But what exactly are micro RNAs, and why are they so important?

DNA, RNA and micro RNA

To understand micro RNAs we need to track back a bit. Our story starts with DNA – the genetic ‘blueprint’ containing the information that tells our cells to grow, divide and specialise. Packed into the nucleus [link] of the cells, these DNA instructions (known as genes) are ‘read’ by the cell to produce molecules called messenger RNAs (mRNAs).

These mRNAs are then shuttled from the nucleus into the cytoplasm of the cell, where they’re used by microscopic protein ‘factories’ to produce a specific protein (diagram and explanation here)

If that all sounds a bit confusing, then imagine this: There is a cookery book (the DNA) in a reference library (the nucleus). You want to bake a cake from the book, but aren’t allowed to take it out of the library. So you make a copy of the recipe on a piece of paper (the messenger RNA), then take it home to your kitchen (the cytoplasm) and bake the cake (the protein).

So genes carry the instructions that tell cells to make proteins – this is the central dogma of biology. But only a small proportion of our DNA actually contains genes that describe how to make proteins. The rest of it – the so-called “non-coding DNA” is now coming into the limelight.

Same instructions – different cells

Virtually all our cells – from brain to bone, skin to stomach – contain the same genes. So how come we have so many different types of cells, if they all have the same set of instructions?

To steal a marketing catchphrase, the secret is in the blend. Our genome contains around 30,000 genes, but only a certain proportion of these will be active in any particular cell type. So skin cells will switch on the gene for keratin, the sturdy protein that gives our skin strength, while stomach cells will activate genes that produce digestive enzymes.

Ensuring that the correct pattern of genes is switched on or off in the right cells is a complex business, and one we’re only just starting to understand. And this is where the non-coding DNA comes in – it seems to play a vital role in ensuring that the right genes are switched on – or off – at the right time.

Perhaps most intriguingly, there are also stretches of DNA that are copied into RNA, but are never ‘read’ to make proteins. These non-coding RNAs pose an interesting puzzle – why do cells go to the effort of producing RNA for no apparent reason?

Shooting the messenger

The answer is that RNA is much more than just a copy of a protein recipe. In 2006 Andrew Fire and Craig Mello won a Nobel prize  for their discovery that complementary RNA molecules can pair up in cells, and that this paired (or ‘double-stranded’) RNA is then destroyed. So the messenger RNA cannot be read by the cell, and no protein is made. This is known as RNA interference.

What’s even more fascinating is that as well as shutting down protein production by “shooting the messenger”, RNA interference also leads to changes within the cell that switch off the relevant gene. This is important because it turns out that many different organisms from plants to animals use this method to control the activity of their genes, and switch them off when they’re not needed.

Micro RNAs

In recent years, scientists have made the amazing discovery that many cells also produce thousands of much smaller RNA molecules – micro RNAs – that can cause interference and shut down gene activity. More than 500 different micro RNAs have been found in human cells alone, and they’re thought to control just under a third of all our genes.

Implications for cancer

Back in 2004, researchers spotted that levels of micro RNAs are different in cancer cells, compared with healthy cells  – the first clue that these little molecules may play a role in the disease – with generally lower levels in tumours.

2005 was also a big year for small RNAs, as a number of research groups showed that human cancer cells produced a specific combination of micro RNAs. For example, researchers in the US found that the ‘signature’ of micro RNAs produced by a tumour was a better indicator of what type of cancer it was, genetically speaking, than its pattern of gene activity.

Last year, Cancer Research UK-funded scientists in London showed that it was possible to classify different sub-types of leukaemia by looking at patterns of micro RNA activity.  This could be an exciting way to diagnose cancer, and even help doctors to decide on the best treatment, in the future. It’s certainly technically possible, as micro RNAs are very stable in standard hospital tumour samples.

And recently Cancer Research UK’s Professor Adrian Harris and his colleagues showed that certain micro RNAs could be detected in the blood of people with a specific type of lymphoma.

Micro RNAs and cancer genes

Digging a bit deeper, it’s becoming increasingly clear that micro RNAs are involved in regulating some of the key players in cancer cells. As an example, US scientists have shown that an important gene called c-Myc switches on certain micro RNAs that, in turn, switch off another gene called E2F1.  This helps to keep a tight rein on cancer, as E2F1 helps to promote cell division but the micro RNAs “fine tune” the actions of the gene, preventing division from running out of control.

But in cancer cells, levels of these micro RNAs are lower, so the process runs out of control. In fact, some evidence suggests that measuring these levels could be used to predict survival in patients with bowel cancer.  Low levels of the micro RNAs mean that E2F1 is overactive, so cancer cells grow rapidly, leading to poor survival.

New cancer treatments?

Of course, this knowledge is only really beneficial to people with cancer if we can harness it to create new treatments for the disease. Researchers are currently testing whether specially adapted man-made RNAs, called “antagomirs” can block micro RNAs in the lab.  Other scientists are working on “micro RNA sponges” to mop up the little molecules.

Finally, researchers are harnessing the ability of micro RNAs to switch off cancer genes – potentially an extremely powerful approach for treating many different types of cancer. For example, scientists in Texas have used man-made micro RNAs to switch off HER2, a molecule that is overactive in around a fifth of all breast cancers and targeted by the drug Herceptin.

As with so many areas of science, it’s becoming clear that the more we find out about micro RNAs, the more we’re aware of the “known unknowns”  – the vast complexity that we’re only just starting to reveal. It’s still a fascinating and productive field of research, so who knows where it will lead us in the future?

Kat

Further reading

US science writer Charles Daney’s blog about micro RNA

A scientific article from Cancer Research UK scientists in Cambridge about micro RNAs and cancer

Click on the player below to listen to an interview with Cancer Research UK-funded scientists Eric Miska, an expert on micro RNAs:

Link to download (3 mins, 2.7Mb).

References:

Benjamin P. Lewis et al (2005). Conserved Seed Pairing, Often Flanked by Adenosines, Indicates that Thousands of Human Genes are MicroRNA Targets Cell, 120 (1), 15-20 DOI: 10.1016/j.cell.2004.12.035

G. A. Calin (2004). MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias Proceedings of the National Academy of Sciences, 101 (32), 11755-11760 DOI: 10.1073/pnas.0404432101

Jun Lu et al (2005). MicroRNA expression profiles classify human cancers Nature, 435 (7043), 834-838 DOI: 10.1038/nature03702

Amanda Dixon-McIver et al (2008). Distinctive Patterns of MicroRNA Expression Associated with Karyotype in Acute Myeloid Leukaemia PLoS ONE, 3 (5) DOI: 10.1371/journal.pone.0002141

Charles H. Lawrie et al (2008). Detection of elevated levels of tumour-associated microRNAs in serum of patients with diffuse large B-cell lymphoma British Journal of Haematology, 141 (5), 672-675 DOI: 10.1111/j.1365-2141.2008.07077.x

Kathryn A. O’Donnell et al (2005). c-Myc-regulated microRNAs modulate E2F1 expression Nature, 435 (7043), 839-843 DOI: 10.1038/nature03677

Raquel Díaz et al (2008). Deregulated expression of miR-106a predicts survival in human colon cancer patients Genes, Chromosomes and Cancer, 47 (9), 794-802 DOI: 10.1002/gcc.20580

Jan Krützfeldt et al (2005). Silencing of microRNAs in vivo with ‘antagomirs’ Nature, 438 (7068), 685-689 DOI: 10.1038/nature04303

Margaret S Ebert et al (2007). MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells Nature Methods, 4 (9), 721-726 DOI: 10.1038/nmeth1079