MicroRNAs (miRNA) are small noncoding RNAs with gene
regulatory functions. Their expression is frequently dysregulated in almost all
human tumors and they can be found circulating within exosomes secreted by
cancer cells.
In addition to being promising cancer biomarkers with
diagnostic, prognostic, and theranostic implications, circulating miRNAs have
also important biologic functions: they can be engulfed by immune cells
surrounding cancer cells within the tumor microenvironment and bind to
toll-like receptors (TLR7 in mice and TLR8 in human) expressed by the
immune cells.
As a result, the binding miRNAs function as agonists of
these single-stranded RNA-binding TLRs, leading to NF-κB signaling
activation and secretion of interleukin (IL)-6 and TNF-α, which promote cancer
cell growth and metastasization.
This novel miRNA mechanism of action suggests that
these small noncoding RNAs can act as hormones (we call these miRNAs hormone
miRNAs or H-miRNAs).
The discovery that miRNAs released by cancer cells can
bind to a receptor in a surrounding immune cell is completely novel. Other
receptors (in addition to TLR7 and TLR8) are likely to be found, but
this is the first identified miRNA receptor and it is relevant to cancer. This
review discusses the meaning of this discovery and comments on the exciting
future implications of these findings in the context of tumor microenvironment
biology as well as of other human diseases.
Recall that NF-κB is a protein complex which has the ability
to control transcription. This means that activation of this protein and its
related pathways can result on growth and proliferation and if done in a
malignant cell can result in metastasis. Simply it senses from the kinase
receptors and then if activated sends out transcription factors to start the
process. We show this below.
Now the specifics are detailed below. We need an activator
and when the activator ligand is attached to a receptor the process begins,
allowing the Rel and p50 to move to the nucleus and start transcription.
Here is what the author argues happens. The Figure below
depicts it in some detail:
Specifically the steps are as follows:
1. Malignant cell releases miRNA from its nucleus which goes
out of cell to ECM
2. miRNA finds T cell and bind to Tcell receptor TLR, toll
like receptor
3. Binding causes T cell to release IL-6 and TNF-α
4. The IL-6 and TNF-α are attached to the malignant cell
receptors and promote growth and proliferation (metastasis)
Namely the malignant cell can by emitting miRNAs get the
surrounding cells to assist it in proliferating. This is an observation consistent
with some we commented on a few months ago, namely that cancer cells have the
ability to enlist the neighboring benign cells to assist it in spreading. The
difference here is the use of miRNAs to do that.
This is a positive feedback loop, an unstable process, one where the cancer cell has enlisted the benign cells which should be doing a different task to seed the malignant cell with metastatic strength. This is a wonderful example of how the small miRNAs can act in a multiple set of ways.
This is a positive feedback loop, an unstable process, one where the cancer cell has enlisted the benign cells which should be doing a different task to seed the malignant cell with metastatic strength. This is a wonderful example of how the small miRNAs can act in a multiple set of ways.
We find this most interesting not only from its prognostic
ability but also from its ability to target and suppress the miRNAs.
On the other hand our simple models just keep getting more
complex.
[1] Fabbri,
M., TLRs and miRNA Receptors, Cancer Research December 2012, http://cancerres.aacrjournals.org/content/72/24/6333.abstract
Posts
