Wednesday, 6 February 2013

Let-7 prevents an agressive shift towards EMT in breast cancer cells

I have written previously about examples of transcription factors (Twist) which can bind DNA to help the initiation of transcription, and chromatin re-remodelling factors (FOXA1) which can constrict or release tightly wound DNA. Transcription makes a copy of DNA called messenger RNA, this contains the gene tic information coding for the protein to be made, as well as regions before and after that gene DNA. When the human genome was sequenced a large proportion of our DNA was discovered to not code for specific genes and was termed “junk DNA”. The recent ENCODE project was a massive effort to study the human genome in more detail, interestingly they found that most of this “junk DNA” actually has a function. So what does this DNA do? Some of the DNA codes for microRNAs, these are small pieces of RNA which can negatively regulate the second major step of making protein, translation. These microRNAs contain a “seed” sequence which can share similarity with one or more messenger RNA sequences, microRNAs help guide cellular machinery to messenger RNA that prevents it from being translated into protein. The numbers of different microRNAs present in cells can therefore have a dramatic effect on the levels of many proteins in the cell, including those for processes such as cell growth and cell survival. Cancer cells exhibit changes in microRNA levels which allows them to alter protein expression to increase growth and avoid cell death.

Let-7 was discovered in a species of roundworm called Caenorhabditis elegans and is one of the first observed microRNAs; it is also expressed in mammalian cells such as humans and has been investigated in the context of cancer. Let-7, along with another microRNA miR-200, has been shown to control the epithelial to mesenchymal transition (EMT) in breast cancer cells, a process mentioned here in a previous blog post. A recent study by Guo and colleagues looked at a protein called oncostatin M, which is released by breast cancer cells and can cause them to undergo metastasis through EMT. They first show that oncostatin M is indeed present in breast cancer cells. Next, they take breast cancer cells that show low levels of oncostatin M that are less aggressive and treat them with oncostatin M, this makes them undergo EMT and become more motile and better at invading into a substance called Matrigel which mimics human tissue. When cells were treated with oncostatin M levels of the microRNAs Let-7 and miR-200 were reduced suggesting that they may negatively regulate oncostatin M induced EMT. To test this, the group artificially raised levels of both these microRNAs which as expected reduced the effect of oncostatin M to cause EMT. Additionally, preventing the action of Let-7, but interestingly not miRNA200, resulted in an increase in EMT.

Finally, the group probed the potential pathway of proteins involved in the Let-7  and miR200 dependent repression of oncostatin M induced EMT. They showed that a protein called HMGA2 is the “master regulator” of oncostatin M induced EMT, and is targeted by Let-7 microRNA. To increase HMGA2 protein levels in cancer cells and induce EMT, Let-7 levels are reduced by a protein called Lin28. Oncostatin M increases Lin28 levels through the transcription factor Stat3.This pathway is important for the initiation of EMT in breast cancer cells, whereas miR200 is directly inhibited by Stat3 allowing an increase in the levels of a miR200 target protein ZEB1. ZEB1 is a transcription factor important in initiation and maintenance of EMT. This study has therefore revealed that Let-7 and miR200 microRNAs act as brakes to prevent  cells undergoing EMT. By utilising a Stat3 signalling pathway, cancer cells can overcome this brake and become more aggressive by entering into EMT.

Mentioned Articles

Guo L, Chen C, Shi M, Wang F, Chen X, Diao D, Hu M, Yu M, Qian L, Guo N. (2013)
Stat3-coordinated Lin-28-let-7-HMGA2 and miR-200-ZEB1 circuits initiate and maintain oncostatin M-driven epithelial-mesenchymal transition.
Oncogene. 2013 Jan 14. doi: 10.1038/onc.2012.573. [Epub ahead of print]

Iorio MV, Croce CM.(2012)
Causes and consequences of microRNA dysregulation.
Cancer J. 2012 May-Jun;18(3):215-22. doi: 10.1097/PPO.0b013e318250c001.

Peter ME. (2009)
Let-7 and miR-200 microRNAs: guardians against pluripotency and cancer progression.
Cell Cycle. 2009 Mar 15;8(6):843-52. Epub 2009 Mar 22.

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