Science and Reason: MicroRNA and cancer

MicroRNAs are 18 to 25 nucleotide, noncoding RNA molecules that have been found to regulate a wide variety of cellular processes. Unusual levels of varions miRNAs have been shown to be diagnostic of pathology in a number of different cancers, such as chronic lymphocytic leukemia, lung cancer and pancreatic cancer.

The first microRNA was discovered in 1993, in C. elegans, but the term microRNA was not introduced until 2001. It took seven years for the second miRNA to be found, also in C. elegans, but many others then followed. Over 500 microRNAs have been identified in the human genome. Over a third of the human genome appears to be regulated by miRNAs orginally found is some mammal or another.

In some cases, changes to gene expression caused by miRNA seem to promote cancer. But in other cases, a miRNA may repress genes that promote cancer or its metastasis.

The p53 anti-cancer gene is affected by some miRNAs, but we will cover that in a separate note. Some miRNAs also seem to be related to cancer stem cells, which is a large topic that merits broader coverage. (See here, here.)

We've already looked at one example (here, and see below) where a gene associated with cancer can affect levels of some miRNAs. Unlike most other findings, this is a case where cancer-related pathology seems to affect miRNA expression levels, rather than the reverse.

One miRNA, in particular, stands out for the variety of genes it may affect. This miRNA is let-7, and it is known to be expressed in the later stages of animal development. Some estimates put the number of human genes affected by let-7 in the hundreds, though most of those may not be related to cancers. Ras is an important cancer-related protein that is suppressed by let-7 (See here, here.) (This report has more on let-7. See also here, here, here, here.)

The miRNA miR-21 has been associated with cancers of the colon, liver, and thyroid.

It's difficult to summarize the following research findings – they involve a variety of cancer types and many different miRNAs. Unusually high or low levels of some miRNAs seem to promote cancer in some cases, but suppress cancer in others. MiRNAs also work in a variety of different ways to affect gene expression and protein activity.

This diversity of effects due to miRNAs may well be the most interesting current finding to come out of research in this area.

Molecules may help predict survival in liver cancer (1/30/08): In a long-term study of patients with liver cancer, it was found that those with the poorest survival history also had lower levels of 19 specific microRNAs in cancer cells compared to nearby noncancer cells than did patients with significantly better survival. This result is out of a total of 196 different microRNAs whose levels were measured.
Expression Patterns Of MicroRNAs Appear Altered In Colon Cancer, And Associated With Poor Outcomes (1/29/08): In one cohort of 84 patients with colon cancer 37 different microRNAs were differently expressed in cancer cells compared with noncancer cells. 5 of these miRNAs could reliably discriminate between tumorous and nontumor tissue. The same 5 miRNAs had similar discriminatory powers in a different cohort of 113 patients. For the specific miRNA known as miR-21, high expression levels were associated with poor survival outcomes in both patient cohorts. (High levels of miR-21 are also associated with thyroid cancer, see here, and with liver cancer, see here.)
Two MicroRNAs Promote Spread Of Tumor Cells (1/28/08): MicroRNAs have been shown in many studies to block translation of tumor suppressor genes. In this study, two specific miRNAs (out of 450 tested) have been shown to transform non-invasive human breast cancer cells into cells that rapidly metastasized in cell cultures and laboratory mice. One of the miRNAs, miR-373, was previously identified as a possible oncogene in testicular cancer. The other miRNA, miR-520c, hasn't previously been associated with cancer, but is similar to miR-373. Both miRNAs are found only in cancer cells. There is evidence that they downregulate the CD44 gene, and that in turn leads to metastasis of non-metastatic tumor cells. In human patients, metastatic cells are found to have higher levels of miR-373 and lower expression of CD44 than non-metastatic tumor cells.
Molecules Might Identify High-risk Acute-leukemia Patients (1/15/08): In a study of leukemia cells from 122 patients with high- and intermediate-risk acute myeloid leukemia (AML) the same miRNAs could be found in both normal and leukemic cells, but there were differences in levels of various miRNAs present. Two specific miRNAs (miR-191 and miR-199a) were present at abnormally high levels that were clearly associated with patient survival. The same two miRNAs have been previously found to be associated with cancers of the lung, prostate, colon, stomach and breast. Another miRNA (miR-155) was associated with a gene mutation, and high levels of it have been reported in other cancers (see here, here) and to cause leukemia in mice.
Small Molecule Can Prevent Spread Of Breast Cancer, Study Suggests (1/9/08): Three miRNAs have been found that prevent breast cancer metastasis by interfering with the expression of genes that give cancer cells the ability to proliferate and migrate. Researchers found lower levels of a few miRNAs (miR-335, miR-126 and miR-206) in metastatic cells compared to non-metastatic tumor cells. Testing in mice showed that raising levels of these miRNAs inhibited metastasis. Further analysis showed that miR-126 influences the proliferation rate of metastatic cells, while miR-335 and miR-206 influence the cancer cells' ability to migrate into lungs or bone. miR-335 was found to inhibit expression of SOX4 and TNC genes, which affect cell migration.

More: here, here
Virus Discovered Using Same Tools As Host Cell (12/17/07): A microRNA expressed in the genome of the Kaposi's Sarcoma Associated Herpesvirus (KSHV) appears to be very similar in stucture and function to a miRNA associated with lymphoma – miR-155, mentioned above. KSHV itself causes a rare skin cancer that disproportionately affects HIV-infected individuals. Both miR-155 and the KSHV miRNA regulate the same genes, including several associated with B cell function and cell cycle regulation. Hence KSHV may promote B cell tumors by repressing one or more of these genes, as miR-155 seems to do.
Scientists Identify And Repress Breast Cancer Stem Cells In Mouse Tissue (12/17/07): Since 2001 stem-like cells that appear to initiate cancer development have been discovered in breast, lung, brain and colon tissues, as well as in the blood. A microRNA (let-7) has now been found that can help to identify such cancer stem cells in breast cancer tissue of mice. Further tests indicate that let-7 can attack and eliminate these cancer progenitors.
MicroRNA Regulates Cancer Stem Cells: Could Lead To Treating Cancer As A Whole (12/13/07): Another study involving the interaction of miRNA let-7 and cancer stem cells was conducted independently and published just before the one described above. In this study, researchers found a way to grow large quantities of tumor stem cells by growing human breast cancer cells in immunosuppressed mice. They found that these stem cells contained low amounts of several miRNAs, compared to more mature tumor cells or stem cells that had differentiated in culture. When let-7 was activated in these cells, they lost their ability to self-renew and began to differentiate. They also became less able to form tumors in mice or to metastasize. It appears that let-7 did this by switching off two cancer-related genes: the oncogene Ras, and HMG2A (see here, here).
Silencing Small But Mighty Cancer Inhibitors (12/10/07): As discussed here, the important transcription factor Myc, which is overexpressed in many cancers, can also stop the production of at least 13 microRNAs. Some of these miRNAs have an inhibiting effect on cancer. In some cases re-introducing repressed miRNAs into Myc-containing cancer cells suppressed tumor growth in mice. So repression of miRNAs may be another pathway through which overexpression of Myc promotes cancer. The research involved lymphoma cells in mice, and showed that Myc repressed the miRNAs by directly attaching to the DNA at the miRNA genes.
Scientists discover new role for miRNA in leukemia (12/10/07): A microRNA has been found to play a new role in the development of cancer, in this case chronic myeloid leukemia (CML). The miRNA is miR-328, and normally it is able to directly bind to a certain protein, inhibiting the activity of that protein. But if levels of miR-328 become abnormally low, the protein prevents white blood cells maturing as they should. The result is the build-up of immature white blood cells and entrance to what is called the "blast-crisis" phase of the disease.
Cellular Pathway Identified That Makes Prostate Cancer Fatal (11/27/07): Expression levels of microRNAs were measured in samples of prostate cancer cells. Five different miRNAs were found to have unusual expression levels. One of these, miR-125b, was found at high levels in both androgen-dependent and the more dangerous androgen-independent prostate cancer cells.