Targeting microRNAs in cancer

Published on December 31, 2015   38 min
0:00
Hi, my name is Molly Taylor, I'm a Postdoctoral Scientist at AstraZeneca, and I'm going to be talking today about the role that microRNAs play in cancer, and how we might be able to target microRNAs for developing a cancer therapeutic.
0:19
So, cancer is a leading cause of death worldwide. For example, in 2012 there were approximately 14 million new cases of cancer diagnosed and 8.2 million cancer-related deaths. In 2000, Hanahan and Weinberg eloquently proposed this model through which cancer cells gain their proliferative and metastasic properties that make them really malignant. And these properties are sustaining proliferative signaling, evading growth suppression, activating invasion and metastasis, enabling replicative immortality, inducing angiogenesis, and resisting cell death. And the collective efforts of science and medicine have dramatically reduced the annual cancer death rate by about 20 percent over the last two decades by developing targeted inhibitors that hit each of these various different hallmarks of cancer. So today, I'm going to talk about how microRNAs function in these hallmarks of cancer and how we might be able to develop new therapeutics to target microRNAs and thus develop new therapies.
1:33
So the central dogma of molecular biology states that genetic information is transferred sequentially from DNA to RNA to protein. So we go from the blueprint of genetic information contained in DNA to a transient copy of that information contained in RNA to the protein that carries out a function in the cell. However, this model only accounts for about 1.5-2 percent of the human genome. So what is the rest of the genome doing?
2:06
A large proportion of the human genome is encoding non-coding RNAs. So RNAs that don't encode for a protein. There are several types of non-coding RNA, one of which is microRNA. MicroRNAs are small non-coding RNAs, about 22 nucleotides in length that mediate post-transcriptional gene silencing by controlling the translation of mRNA into protein. However, there's also lots of other types of non-coding RNA. For example, there are piRNAs, which are also small non-coding RNAs that bind to the PIWI subfamily of Argonaute proteins and are involved in maintaining genome stability in germline cells. There are also snoRNAs, which are intermediate in size, and they are responsible for sequence-specific modification to ribosomal RNA. In addition, there are many long non-coding RNAs which are over 200 nucleotides in length that are involved in numerous biological processes, such as modulation of chromatin remodeling, and transcriptional repression. In addition to these main types of non-coding RNAs, there are also many others such as promoter-associated small RNAs, transcription start site associated RNAs, promoter upstream transcript, and transcription initiation RNAs, as well as telomeric repeat-containing RNAs and circular RNAs.
3:43
But today we're going to focus on microRNA. So as I said, microRNAs are small non-coding RNAs, they are about 22 nucleotides long. They are highly conserved across species. They function to silence cellular target genes. And lin-4 and let-7 were the first microRNAs identified and were shown to be antisense translational repressors of mRNAs that encode protein of the heterochronic developmental timing pathway in C. Elegans.
4:16
So before we delve into what microRNAs do in the cell, we'll just go through some microRNA nomenclature so you can better understand how these microRNAs are named and what the different names mean. So the naming is sequential, so the lower the number of the microRNAs, the earlier it was discovered. The first three letters signify the organism that it comes from. So if it's from a human, it will have an 'hsa' in front of it. If it's from a mouse it will have an 'mmu' in front of it. The mature form of a microRNA is designated as 'miR' and then the number with a capital R, while the gene form of the microRNAs is designated as 'mir' and the number with a lower case r. Distinct precursor sequences that both lead to the production of the same mature form of the microRNAs have numbers at the end of them. So, for example, mir-121-1, and mir-121-2 would both encode for the same mature microRNA sequence but they come from two different locations in the genome. Many microRNAs also have lettered suffixes at the end of their name, which just denotes that they are closely related. So it means majority of the sequence is the same and there's perhaps just a few nucleotides that are different. And two microRNAs often originate from the same precursor hairpin, like miR-34 shown on the side of the slide. And when the relative abundancies are clear from the mature form, the predominantly expressed microRNA takes on the form of miR-56 or miR-34, and the less abundant miR from the opposite arm of the precursor takes the form of the miR*. When it's not known what the abundance of the mature form is, alternative names are given just based on which arm it comes from. So, for example, miR-142-5prime comes from the five prime arm and miR-142-3prime comes from the three prime arm. There are microRNA families, which denote a group of microRNAs that are closely related by sequence, and there are microRNAs clusters, which are when a group of microRNAs are transcribed from the same gene.
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Targeting microRNAs in cancer

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