Science and Reason: MicroRNA and cancer II

We haven't recently discussed the role of microRNA in cancer. Last time (February 2008) is here. There have been some relatively recent research announcements, so let's have a look.

If you want a refresher on the subject, here's a good introductory overview from Cancer Research UK: Micro RNAs and cancer. Although this piece is fairly elementary, it does have many good links to actual research papers.

Now let's jump into a few summaries of recent research.

What's Feeding Cancer Cells? (2/17/09): Cancer cells grow and multiply rapidly, so they need lots of nutrients. Much is already known about how cancer cells use blood sugar, but other nutrients are also needed. One of these is the amino acid glutamine. This research found that the transcription factor Myc is able to enhance the expression of the enzyme glutaminase (GLS) in cellular mitochondria. GLS is the first enzyme that processes glutamine to produce energy in mitochondria. (Overexpression of Myc is frequently found in cancer – see here.)

The research found that depriving cancer cells of GLS slowed their growth significantly. It was suspected that Myc could directly up-regulate the GLS gene, but it was not that simple. Instead, it appears that Myc down-regulates genes for two types of microRNA: mi-R23a and mi-R23b. Since these mircoRNAs interfere with the GLS messenger RNA, the net effect of Myc is to enhance GLS production.

Research abstract: c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism
A new discovered mutation can hold the key to treat a large number of different cancers (2/17/09): Since microRNA normally inhibits production of certain proteins, if the proteins affected promote cancer, the inhibitory miRNA will counteract this. This research examined cells of twelve different cancer types.

The basic finding was that mutations of the gene TARBP2 disrupts a pathway that produces anti-oncogenic microRNAs. Mutated TARBP2 diminishes TRBP protein expression, resulting in a defect in the processing of miRNAs. Specifically, the DICER1 protein, which is necessary for miRNA production, is adversely affected.

Research abstract: A TARBP2 mutation in human cancer impairs microRNA processing and DICER1 function
Micro RNA Plays A Key Role In Melanoma Metastasis (2/15/09): Metastasis is the main process by which cancer becomes deadly, and it is especially problematic in melanoma. In order for cancer cells to metastasize (spread to another body location) they must become able to migrate and establish themselves in the new location. This research finds that the microRNA miR-182 assists in this process.

MiR-182 is frequently up-regulated in human melanoma, usually because melanoma cellular DNA contains extra copies of the miR-182 gene. This up-regulation was shown to assist metastasis. Conversely, down-regulation impedes invasion and triggers apoptosis. Over-expressed miR-182 is shown to repress the expression of two tumor suppressors, FOXO3 and MITF, which are both transcription factors. (For more on FOXO3, see here.)

Research abstract: Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor
New Genes Involved In Acute Lymphoblastic Leukemia Play Fundamental Role In Prognosis Of The Disease (2/6/09): This investigation found that 13 microRNAs were epigenetically regulated in an abnormal way in many patients with acute lymphoblastic leukaemia (ALL). This means that instead of having actual gene mutations, certain parts of the DNA were methylated in an unusual way, so that the underlying genes, which coded for microRNAs, were down-regulated. More precisely, certain histones of the cell's chromatin were methylated, so that genes located on the DNA wrapped around those histones would not be expressed. The genes involved coded for microRNAs that, evidently, are important for suppressing cancer. When approriate steps were taken to reverse abnormal epigenetic regulation of the affected genes, expression levels rose, confirming that the abnormal methylation patterns were responsible for down-regulation.

65% of 352 ALL patients had one or more methylation abnormalities affecting microRNA under investigation. There was a highly significant positive correlation between patient survival at 14 years after diagnosis and absence of such abnormalities. Consequently, tests for methylation problems with the appropriate microRNA genes should be good predictors of survival prospects.

Research abstract: Epigenetic regulation of microRNAs in acute lymphoblastic leukemia
Researchers Identify Another Potential Biomarker For Lung Cancer (1/13/09): The research showed that smoking impacts bronchial airway gene expression. Various miRNAs were found that were differently expressed in bronchial airway epithelial cells, mostly down-regulated. Messenger RNAs were also identified, whose expression was inversely correlated to the miRNA expression (so that the corresponding genes appear to be down-regulated by the miRNA.)

MiR-218 was especially noteworthy. It is known to be strongly affected by smoking. The conclusion is that miR-218 levels modulate airway epithelial gene expression response to cigarette smoke, suggesting a role for miRNAs in regulating response to environmental toxins.

Research abstract: MicroRNAs as modulators of smoking-induced gene expression changes in human airway epithelium
Molecule Linked To Muscle Maturation, Muscle Cancer (12/31/08): The study clarified the role of MiR-29 in myogenesis (muscle cell formation) and found that its down-regulation is associated with rhabdomyosarcoma (RMS), a cancer caused by the proliferation of immature muscle cells. While miR-29 is required for maturation of myoblasts (immature muscle cells), it is also found to be mostly absent from RMS cells.

The study found, further, that the transcription factor NF-κB is responsible for down-regulating miR-29. (NF-κB is an old friend of ours. See here for a small part of the story about its role in inflammation. There's also much more to be said about the role of NF-κB in cancer, where it provides an important connection between inflammation and cancer.)

NF-κB acts to repress miR-29 through another transcription factor, YY1, and Polycomb-group proteins (which remodel chromatin to block transcription factors from DNA promoter sequences).

During myogenesis, NK-κB and YY1 are down-regulated, permitting expression of miR-29, which then further down-regulates YY1 and accelerates cell differentiation. However, in RMS the NF-κB–YY1 pathway remains active, silencing miR-29 and inhibiting differentiation. But reconstitution of miR-29 in RMS in mice inhibits tumor growth and stimulates differentiation,

Research abstract: NF-κB–YY1–miR-29 Regulatory Circuitry in Skeletal Myogenesis and Rhabdomyosarcoma
Harnessing MiRNA Natural Gene Repressors For Anticancer Therapy (12/1/08): This research investigates the potential therapeutic use of miR-181a through its ability to repress expression of selected genes. If successful, this would provide a very clever kind of immunotherapy for cancer and possibly other diseases.

In immune system T cells miR-181a is highly expressed in developing T cells, but is markedly down-regulated in mature T cells. Mouse bone marrow cells were engineered to express desired therapeutic genes only when miR-181a is down-regulated. These cells were transplanted into mice and allowed to develop into mature T cells. The proteins repressed by miR-181a would therefore not be found in the immature cells, but would show up in the mature T cells. And so when the genes repressed by miR-181a corresponded to proteins that direct T cells to attack tumor cells expressing the protein hCD19, mice with the engineered bone marrow cells were able to reject tumors expressing hCD19.

Research article (open access): Harnessing endogenous miR-181a to segregate transgenic antigen receptor expression in developing versus post-thymic T cells in murine hematopoietic chimeras
Molecule Linked To Aggressive Cancer Growth And Spread Identified (11/13/08): EZH2 is a polycomb group protein, which helps maintain transcriptional repression of genes over successive cell generations. It contributes to the epigenetic silencing of target genes and enables the survival and metastasis of cancer. The research indicates that miR-101 inhibits the expression and function of EZH2 in cancer cells.

The researchers found that miR-101 is significantly underexpressed in a variety of cancers, including prostate and breast cancer. In human prostate tumors miR-101 expression decreases as cancer progresses and expression of EZH2 increases. MiR-101 is coded for at two locations in cell DNA. One or both of those locations is found to be defective in 37.5% of localized prostate cancer cells and in 66.7% of metastatic cells. This suggests that that underexpression of miR-101 is responsible for overexpression of EZH2 and consequent cancer progression.

More: here (11/13/08)

Research abstract: Genomic Loss of microRNA-101 Leads to Overexpression of Histone Methyltransferase EZH2 in Cancer