Double-sided RNA from Cancer
Inputtime：2017-03-23 14:40:00 Views：
At the beginning of the 21st century, scientists began to think for the first time that microRNA, a small, non coding RNA molecule, can interfere with the translation of proteins and may be related to cancer. The clue came from developmental biology, when Frank slack and his colleagues found at Yale that a variation in microRNA called let-7 led to increased cell division. Then in 2002, researchers from the Carlo Croce laboratory found two very common gene deletions in the samples of chronic lymphoblastic leukemia at Thomas Jefferson University in Philadelphia, which were the gene loci of two kinds of microRNAs, mir15 and mir16. Now, more than ten years later, we know that microRNA level is basically abnormal in every type of tumor detection. In some tumors, microRNA can be overexpressed, while in other cases, it may be completely lost.
Some experimental studies have shown that manipulation of cancer-related microRNAs, such as deletion of overexpression or promotion of low expression, may reverse the tumor. Taking mir15 and mir16 as examples, after Croce and his colleagues found that the expression of these two gene loci in chronic B-cell lymphocytic leukemia (CLL) was lost or down regulated more than half of the time, another laboratory confirmed that deleting this region in mouse experiments would cause symptoms similar to human CLL. "This is great direct evidence that microRNA deletions have a causal relationship with cancer," slack said. But the scientists also showed that calling a microRNA a tumor suppressor gene or a cancer promoter gene was too hasty.
In 2009, Joshua Mendell, a microRNA researcher at the University of Texas Southwestern Medical Center, was studying mir-26, whose expression in liver cancer was inhibited. They hope that based on previous research results, restoring the expression of mir-26 may be beneficial to the treatment of liver cancer. So he and his colleagues raised mir-26 levels in transgenic mice, and tumor growth stopped as expected. But then his paper was published, and another study confirmed that mir-26 had the opposite effect in the mouse model of brain tumor: mir-26 could down regulate PTEN. This shows that microRNA seems to be a carcinogenic gene.
The results of these conflicts are confusing. Mendell said there is not a large amount of evidence that microRNA targets are tissue-specific. So Mendell decided to do another series of experiments to find ways to more precisely control the level of mir-26 in any tissue of the body. He found that mir-26 may have both tumor suppressor and carcinogenic pathways. Although Mendell's team confirmed that mir-26 inhibits tumor suppressor gene PTEN, the phenotype observed by overexpression of mir-26 is not consistent with that of PTEN reduction. When mir-26 was over expressed in mice, the tumor did not bubble around the body as expected, but in fact, the growth of intestinal tumor was inhibited.
The key to this explanation may lie in other targets of mir-26. Although microRNA suppresses PTEN, mir-26 also covers a wide range of other proliferative genes, making the overall effect of over expression of mir-26 is tumor suppression. "When you summarize the function of a microRNA, you need to see that it's an overall target," Mendell said. If you stress only one of them, you will not get the right conclusion. "
Mir-26 is not the only example. Croce says it has been found that some microRNAs behave like a carcinogen gene or a tumor suppressor gene depending on the cell example. Cell environment is the key determinant of microRNA. For example, miR-221 / 221 acts as a oncogene in the liver and a tumor suppressor gene in other tissues, such as tongue squamous cell carcinoma. In fact, it all depends on which microRNA targets are contained in the cell.
Christopher Park, a researcher who studies blood diseases at Sloan Kettering Memorial cancer center, added that the role of microRNA in cancer has another layer of complexity. Scientists also have to consider the stage of cancer: do they control microRNA artificially on established tumor models, or is it the stage of cancer development? For example, miR-29a has been found to slow down the growth of leukemia cell lines by Croce research team, suggesting that miR-29a is a tumor suppressor gene. However, park's team found that increasing the circulating level of miR-29a in mice can induce the development of leukemia. This clearly indicates that microRNA can play different roles in carcinogenesis.
The first microRNA cancer treatment is in the early stage of human clinical trials. Croce said he was not concerned that microRNA therapy might promote one tumor while promoting another, mainly because of the time frame. As he saw before clinical trials, microRNA targeted drugs can act quickly on cells without any side effects of carcinogenesis. But the final answer will come from clinical trials. Now I pray that there will be no strange results in these patients. After all, the human system is still too complex.
Further knockout or overexpression studies in mouse models will help to determine the role of microRNA in tumorigenesis and development. It is very important to detect the role of microRNA in the natural background and in the whole animal, because it is true that microRNA is often found to play a very different role in the whole animal phenotype and in the cell line. In addition to surprise, we have to dig deeper. It's a double-sided RNA. Maybe you can see that it has n sides.
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