MicroRNA for treating cancer and asthma

A microRNA that regulates inflammation shows promise as a treatment for inflammatory diseases such as asthma and cancer. The microRNA, known as miR-223, is highly expressed in blood cells that cause inflammation (neutrophils). When they're working correctly, those blood cells protect the body against infections, but sometimes they damage host tissue instead of microbes, causing chronic inflammation and disease.

To uncover the link between miR-223 and inflammation, a Purdue University research team created a zebrafish totally deficient of miR-223. Then they cut off a small chunk of its fin. "The inflammation was really robust," said Qing Deng, a professor of biological sciences at Purdue and corresponding author of the paper. "Neutrophils accumulated at the wound and they just kept coming. This is consistent with the literature, but we wanted to understand why."

Extensive gene expression analysis led them to pathway NF-kB, a protein complex found in nearly all animal cell types that regulates inflammation and cell proliferation. Heightened activation of this pathway is the cause of increased inflammation, although it's limited to the deeper, or basal, layer of the epithelium. This means any therapeutics would need to reach the basal layer to work.

The same pathway plays an important role in human bronchial epithelial cells, which are critical in the development of asthma, according to the study. MiR-223 suppresses the pathway, which means supplementing it to epithelial cells could help control inflammatory disease.
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Effects of stress on sperm

Children of stressed fathers are at greater risk of developing PTSD and depression, according to a new study. Researchers found life's pressures can change the DNA of a man's sperm - leading to brain development changes in his yet unborn baby. It's widely known that a mother's environment during pregnancy, including factors such as poor diet, stress and infection, can negatively impact the offspring.

Learning how a father's behavior and environment can impact his child's development could lead to the detection and prevention of many mental health disorders. Researchers have known for years that stress can increase the risk of mental disorders,' Dr Tracy Bale, professor of neuroscience at the University of Maryland School of Medicine, told Daily Mail Online. 'What’s interesting here is that we are finding intergenerational effects.'

Researchers, led by Dr Bale, conducted a mice experiment to examine how a father's lifestyle impacts his children. Previously, the team has found male mice experiencing chronic periods of mild stress passed down genetic coding for a less effective hormonal response to stress in children. Three major hormones are released by the nervous system when the body is under stress. These are adrenaline, cortisol and norepinephrine. Collectively, these hormones send human bodies into ''fight''mode, which is important to the body's ability to cope with the effects of stress.

Stress resulted in changes in sperms genetic material known as microRNA, which plays a key role in which genes become functional proteins. These changes in stress reactivity have been linked to some mental disorders, including depression and PTSD.

In the new study, presented at the 2018 AAAS annual meeting in Austin, Texas, Dr Bale and her colleagues unraveled new details about the microRNA changes in the sperm. The caput epididymis, the structure where sperm matures, release vesicles which contain microRNA that can fuse with sperm to change its cargo delivered to the egg. When males mice were stressed, the caput epididymis responded by altering the content of these vesicles.

This suggests even mild environmental stress, such as workplace stress, can have a significant impact on the development and potentially the health of future offspring. This is through a process known as epigenetics where DNA is changed through lifestyle factors such as diet, exercise - or even stress. Scientists have known a mother's environment during pregnancy can damage a fetus by diet, stress or infection affecting the expression of certain genes in the same way.

Father's stress can affect offspring development by altering important aspects of his sperm. Her previous studies on the placenta have revealed novel sex differences during pregnancy that may predict increased pre-natal risk for neurodevelopmental disorders in males. Historically, most research on how a parent's lifestyle, behavior and environment can affect their children has focused on the mother. But scientists have recently been paying increasing attention to how a father's health impacts his children.
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Small molecule reduce the spread of cancer

One small molecule that regulate gene expression plays a big role in keeping human safe from the machinations of cancer. In human lung cancer cells, low levels of the microRNA, miR-125a-5p, which enables the death of aberrant cells like cancer cells, correlates with high levels of the protein TIMP-1, which is already associated with a poor prognosis in patients with cancer.

Conversely, when they decrease TIMP-1 levels in these highly lethal cancer cells, tumor spread goes down while rates of cell death go up along with expression of miR-125a-5p, says Dr. Mumtaz V. Rojiani, cancer biologist in the Department of Medicine at the Medical College of Georgia and a member of the Molecular Oncology and Biomarkers Program at the Georgia Cancer Center at Augusta University.

While increasing microRNA levels is technically difficult, further delineating how cancer hijacks these normal body systems may help identify new treatment targets. TIMP-1 has a positive role in a healthy body to balance levels of enzymes the body makes to ease cell movement for things like wound healing or reproduction.

The healthy body and cancer make these enzymes, matrix metalloproteinases, or MMPs, to break down the surrounding matrix that helps keep cells stable. While it's critical to positives like wound healing, when the matrix breakdown is usurped by cancer, it also gives cancer cells this freedom to move.

In cancer, TIMP-1 levels rise dramatically and it has a distinctive role enabling both growth of new blood vessels and inhibition of apoptosis, a cell's natural inclination to die if something unfixable is wrong. In cancer, what the tumor cells do is start secreting a lot more of these enzymes so they can break down the matrix and start migrating and metastasizing.

Classically, TIMP-1 should be inhibiting MMPs but over the years it has been found to have other functions that actually increase tumor aggressiveness. In their studies of TIMP-1 expression in human lung cancer cells, they saw this aggressive response. It turned out that TIMP-1 is like a two-faced individual smiling at cancer sometimes and other times cutting it off.

Increased levels of two-faced TIMP-1 have been found in increased tumor spread and poor prognosis in breast, gastric and colorectal cancers as well as the non-small cell lung cancer the MCG scientists studied, which accounts for about 85 percent of all lung cancers and has a five-year survival rate of under 20 percent.

TIMP-1 overexpression also is associated with increased upregulation of Bcl-2, a protein which can prevent apoptosis, or cell death. To make bad matters worse, a key way chemotherapy works is by inducing apoptosis and TIMP-1 has been associated with potentially deadly drug resistance.
However, with high expression of miR-125a-5p, TIMP-1 becomes the target. One result is increased expression of the gene p53, a known tumor suppressor, which enables cell death.

When ressearchers knocked down TIMP-1 expression, it significantly increased expression of miR-125a-5p. Conversely, when they restored higher levels of TIMP-1, miR-125a-5p expression went down. The look of the cancer cells changed with the level of TIMP-1. At high levels they looked more like cells unshackled from their current location and able to migrate and invade. When they decreased TIMP-1 levels, the cells pretty much stayed put.

 Adding more synthetic miR-125a-5p to the cancer cells, and the lung cancer cells moved more toward a stationary normal look and cell death increased. When they inhibited miR-125a-5p, the cells were ready to roam. Looking at the biopsies of lung cancer patients, they found as expected TIMP-1 expression much higher in the lung cancer tissue than nearby healthy tissue. But they also saw an inverse relationship between high levels of TIMP-1 and miR-125a-5p levels. In fact, tumor cells had almost no miR-125a-5p.
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MicroRNA regulates movements of tumour cells

Cancer cells can reactivate a cellular process that is an essential part of embryonic development. This allows them to leave the primary tumor, penetrate the surrounding tissue and form metastases in peripheral organs.

During an embryo's development, epithelial cells can break away from the cell cluster, modify their cell type-specific properties, and migrate into other regions to form the desired structures. This process is known as an epithelial–mesenchymal transition EMT is reversible and can also proceed in the direction from mesenchymal cells to epithelial cells (MET).

It is repeated multiple times during embryonic development and ultimately paves the way for the formation of organs in the human body. Tumor cells can reactivate the program. Although this is a completely normal process during embryogenesis, it also plays an important role in the spread of tumor cells within the body and in the formation of metastases.

Tumor cells are able to reactivate the EMT/MET program. By doing so, they obtain characteristics of stem cells and develop strong resistance to classical and state-of-the-art targeted cancer therapies. An EMT also makes it easier for cancer cells to break away from the primary tumor, to penetrate into surrounding tissue and into blood vessels, to spread throughout the body and to form metastases in distant organs, which is ultimately responsible for the death of most cancer patients.

Regulation the cellular EMT program prevents the development of malignant tumors and the formation of metastases such as in the case of breast cancer, researchers focused specifically on microRNAs (miRNAs), a class of very short non-coding RNAs with a considerable effect on gene regulation.
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Growing tumors evade anti-tumor immunity

The immunological pressure occurring during tumor progression might be harmful for the tumor to survive but the cancer cells evade the condition by restraining the anti-tumor immune response.

Cancerous tumors often grow so fast that they use up their available blood supply, creating a low-oxygen environment called hypoxia. Cells normally start to self-destruct under hypoxia, but in some tumors, the microenvironment surrounding hypoxic tumor tissue has been discovered to protect the tumor with the help of MicroRNA.

MicroRNAs are small, noncoding RNA molecules that regulate genes by silencing RNA, they have increasingly been implicated in tumor survival and progression. Researchers examined different types of tumor for altered levels of microRNAs. They identified two microRNAs ;miR25 and miR93 whose levels increased in hypoxic tumors.

The team then measured levels of those two microRNAs in the tumors of cancer patients and found that tumors with high levels of miR25 and miR93 led to a worse prognosis in patients compared to tumors with lower levels. The reverse was true for another molecule called cGAS: the lower the level of cGAS in a tumor, the worse the prognosis for the patient.
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