Activity

MicroRNAs are the hope of cancer personalized medicine, and people have been hoping to analyze their exact mechanisms of action and apply them to the clinic. However, it turns out that this is a challenging job.
MicroRNAs are non-coding single-stranded short RNA molecules that can silence gene expression. Although growing evidence shows that the role of microRNAs in cancer is important, little is known by us. Xiling Shen, a system biologist at Cornell University, used immunofluorescence and RNA fluorescence in situ hybridization to study the early division of colon cancer stem cell CCSC. He discovered a tumor suppressor microRNA (miR-34a) that determines whether cancer stem cells are self-renewing or begin to differentiate. Studies have shown that high levels of miR-34a reduce Notch signaling and promote cell differentiation; while low levels of miR-34a increase Notch signaling, allowing cells to maintain stem cell status.
The researchers pointed out that miR-34a, as a switch to determine cell fate, performs an all-or-nothing selection, either self-renewal or cell differentiation. In contrast, the regulation of Notch levels by Numb proteins is a continuous gradient pattern. Studies have shown that miR-34a has a stronger effect on cell fate than Numb protein.
“We originally thought that microRNAs are fine-tuning,” Shen said. “But miR-34a is dominant, and the role of Numb protein is small. This finding runs counter to the traditional view.”
Another study published in the journal Nature pointed out that microRNAs are primarily used as spinners for mRNA-mRNA interactions rather than on/off molecular switches. Carlos Caldas of the University of Cambridge studied microRNA and mRNA expression in a large number of human breast cancer tumors through high-throughput sequencing and chip analysis. Studies have shown that at the genome-wide level, the role of microRNAs is primarily to influence the interaction between mRNAs.
The conclusions of these studies seem contradictory, but actually reflect the coexistence of microRNA mechanisms of action, said Jin Cheng of H. Lee Moffitt Cancer Center. “People found that microRNAs have multiple modes of action, for example, some prevent translation, while others promote mRNA degradation.”
In determining cell fate (such as cell differentiation or programmed cell death), microRNAs act as molecular switches. But in some more subtle processes (such as metabolism), microRNAs can also be fine-tuned. Sometimes the same microRNA may have both forms of action. This is because microRNAs act on many different mRNA targets and can function flexibly, and their mechanism of action may depend on their targets. For example, if a microRNA target has multiple binding sites, its effect is even stronger.
In 2011, an article on Nature Genetics magazine supported this view. Alexander van Oudenaarden of MIT used quantitative fluorescence imaging and flow cytometry to study the effects of microRNAs on gene expression in individual cells. He found that the role of microRNAs in different cells is quite different. Studies have shown that microRNAs have both on-off and fine-tuning, and their influence depends on their interaction with the target.
In general, different microRNA experiments have shown different results. “We usually study the average of a large number of cells,” said OSU’s Stefano Volinia. “In order to improve the reliability of the results, we should try to improve the throughput and precision of microRNA detection. Tumors have a variety of cell types, in addition to cancer cells, there are normal interstitial cells and immune cells.”
Ou’s Volinia and his colleague Carlo Croce applied the findings to clinic. In an article published in the Proceedings of the National Academy of Sciences, PNAS, the second generation of sequencing data for mRNA, microRNA and DNA methylation in Cancer Genome Atlas can help predict the prognosis of patients with common breast cancer (invasive ductal carcinoma of the breast). Compared with other RNA indicators, such comprehensive indicators can better separate low-risk patients from high-risk patients.
“Research shows that comprehensive indicators have the strongest predictive power,” Volinia said. “The new technology we are now using is capable of simultaneously detecting microRNAs and mRNA in samples. Such tests can help doctors choose the appropriate treatment for their individual condition based on their condition.”
Studies have shown that these indicators are more helpful for invasive cancers that are short of effective treatment, such as triple negative breast cancer (TNBC). TNBC patients lack estrogen, progesterone and HER2/neu receptors and are unable to respond to drugs that target these receptors. Molecular indicators can help clinicians divide TNBC into different subtypes to develop more personalized treatment options.
“I have studied breast cancer from a protein perspective for a long-term,” said Kay Huebner of the OSU Comprehensive Cancer Center. “I think microRNAs are better than other methods in breast cancer grading.” Huebner and Pierluigi Gasparini published an article on PLoS ONE, which identified four TNBC molecular subtypes by analyzing microRNA and mRNA expression profiles. Studies have shown that patients with different microRNA and mRNA profiles can benefit from different types of drugs, and patients with high-risk indicators are more suitable for more powerful treatments. They also found that miR-155 predicts the survival of all patients.
Previously, studies have indicated that miR-155 is involved in the growth and cell survival of cancer cells. For example, Cheng and colleagues published an article on Oncogene pointed out that miR-155 promotes the growth of new blood vessels in breast cancer. It is associated with poor prognosis, cancer metastasis, and triple-negative tumors. “miR-155 is a key factor in breast cancer metastasis,” Cheng said. “Our research shows that miR-155 can be used as a therapeutic target to help people treat breast cancer.”
However, Volinia’s research shows that although miR-155 is indeed overexpressed in breast cancer (especially TNBC), it does not appear to be associated with the patient’s prognosis. These conflicting conclusions reflect the complexity of microRNA function. “To fully understand a microRNA is a very long process,” Huebner said.
View More: microRNA detection https://www.creative-biolabs.com/suprecision/micro-rna-sequencing-mirna-seq-service.htm