Breaking News
August 19, 2018 - HPV Legislation Doesn’t Impact Teen Sexual Behaviors
August 19, 2018 - Exenatide treatment alleviated symptoms of depression in patients
August 19, 2018 - Tufts researchers win grant to study integration of genomic sequencing into neonatal care
August 19, 2018 - Novel finger-prick test can help prevent toxoplasmosis
August 19, 2018 - Cosmetic Procedures Boost Well-Being, Poll Shows
August 19, 2018 - Responsive parenting intervention results in lower BMIs through age three
August 19, 2018 - Anticancer drugs can help plants to battle infection
August 19, 2018 - Sunscreen from bathers releases significant quantities of polluting titanium dioxide into the sea
August 19, 2018 - Case Western Reserve gets three-year grant to enhance food systems in Cleveland neighborhoods
August 19, 2018 - Teenagers can thank their parents’ positive attitude for avoiding obesity
August 19, 2018 - Body mass index positively linked with blood pressure
August 19, 2018 - New tool fills gap in Small Molecules market
August 19, 2018 - Study compares survival outcomes in rural and urban cancer patients enrolled in clinical trials
August 19, 2018 - Researchers develop molecular matrix that delivers healing stem cells to injured elderly muscles
August 19, 2018 - Teva and Regeneron Announce Positive Topline Phase 3 Fasinumab Results in Patients with Chronic Pain from Osteoarthritis of the Knee or Hip
August 19, 2018 - New study pinpoints ways to improve quality of food and nutrition research
August 19, 2018 - Ology Bioservices wins $8.4 million worth agreement to manufacture anti-Ebola monoclonal antibody
August 19, 2018 - New CRISPR technology may help eliminate mutated gene sequence
August 19, 2018 - “Zombie gene” protects elephants from cancer finds study
August 19, 2018 - Study explores how many American cities protect the rights of employed breastfeeding mothers
August 19, 2018 - FDA Approves Lenvima (lenvatinib) for First-line Treatment of Unresectable Hepatocellular Carcinoma (HCC)
August 19, 2018 - Pain: Considering Complementary Approaches (eBook)
August 19, 2018 - Autoimmune response drives vision loss in glaucoma
August 19, 2018 - Tandem Diabetes Care introduces t:slim X2 Insulin Pump with Basal-IQ Technology in the US
August 19, 2018 - Innovative platform developed to destroy cancer cells
August 19, 2018 - Lowering pH inside tumor cells can slow down spread of cancer
August 19, 2018 - Biomarker predicts kidney cancer risk years before diagnosis
August 19, 2018 - Consequences of healthcare-associated infections go beyond patients’ physical health
August 19, 2018 - New drug- free, nanotechnology-based method detects and treats oral plaque
August 19, 2018 - Integration of Opioid, Infectious Disease Treatment Needed
August 19, 2018 - How eye disorders may have influenced the work of famous painters
August 18, 2018 - Blood biomarker could help predict kidney cancer up to five years prior to diagnosis
August 18, 2018 - Dartmouth scientists create more sustainable feed for aquaculture
August 18, 2018 - Immigrants Not a Burden on U.S. Health Care: Study
August 18, 2018 - Women who eat fast food take longer to become pregnant
August 18, 2018 - Most YouTube videos on plastic surgery are misleading marketing campaigns
August 18, 2018 - The essential guide to make your laboratory more sustainable
August 18, 2018 - Loyola Medicine offers scalp cooling treatment to reduce risk of chemotherapy hair loss
August 18, 2018 - Researchers describe promising strategy to remove melanoma’s most powerful defenses
August 18, 2018 - Women with polycystic ovary syndrome dissatisfied with medical care
August 18, 2018 - Research discoveries reveal insights behind neurological degeneration
August 18, 2018 - Researchers win multi-million Euro award to conduct research into liver disease
August 18, 2018 - Survey highlights variations in practice of airway management in pediatric intensive care units
August 18, 2018 - UK students win sponsorship from Promega Corporation
August 18, 2018 - Janssen Reports Positive Topline Results for ATLAS Phase III Study of a Novel, Long Acting Injectable Two-Drug Regimen for the treatment of HIV-1
August 18, 2018 - PSD as a molecular platform for understanding synapse formation and plasticity
August 18, 2018 - Improved visual communication could help patients to make informed health-care decisions
August 18, 2018 - New algorithm helps identify and manage diabetic patients at increased fracture risk
August 18, 2018 - Microscopic insect odour detecting mechanisms discovered
August 18, 2018 - Researchers develop new approach to study how tuberculosis infects people
August 18, 2018 - FDA Approves Kalydeco (ivacaftor) for Cystic Fibrosis in Children Ages 12 to
August 18, 2018 - An ion channel differentiates newborn and mature neurons in the adult brain
August 18, 2018 - Conditions of first sexual encounter can be indicators of future HIV risk and gender-based violence
August 18, 2018 - Socio-economic position associated with pregnant women’s exposure to environmental hazards
August 18, 2018 - Study evaluates how students change their breakfast consumption when given extra time
August 18, 2018 - Chronic perinatal hypoxia linked to locomotor miscoordination, long-term cerebellar learning deficits
August 18, 2018 - Voters to settle dispute over ambulance employee break times
August 18, 2018 - AGA urges policymakers and stakeholders to improve affordability of drugs
August 18, 2018 - Increasing dietary protein may lower risk of diabetes in people with NAFLD
August 18, 2018 - New HIV therapy suppresses viral replication and increases immune cells in drug-resistant patients
August 18, 2018 - Broad Genetic Testing for NSCLC May Not Improve Survival
August 18, 2018 - Discovery opens door for synthetic opioids with less addictive qualities
August 18, 2018 - Transgenic rice plant extracts could help stop the spread of HIV
August 18, 2018 - Hologic’s Cynosure division partners with Porter Instrument to distribute nitrous oxide and oxygen system
August 18, 2018 - Two thyroid medications recalled by FDA
August 18, 2018 - Forecast Sees Abnormal Heat Worldwide Through 2022
August 18, 2018 - Childhood absence epilepsy – Genetics Home Reference
August 18, 2018 - Fearing hard Brexit, UK drugmakers stockpile to protect lives
August 18, 2018 - Discovery may help broaden the scope of defenses against HPV
August 18, 2018 - When they start thinking green, they see green
August 18, 2018 - Scientists introduce microfluidics-based chip for manipulation and analysis of single cells
August 18, 2018 - Researchers design new way to grow nose cells for treating spinal cord injuries
August 18, 2018 - New light shed on relationship between calorie-burning fat and muscle function
August 18, 2018 - Surgery Saturday Instagram series takes you inside Stanford’s OR
August 18, 2018 - Researchers uncover surprising new role for inhibition in the cerebellum
August 18, 2018 - Children have better nutrition when they live near forests, global study shows
August 18, 2018 - OHSU professor conducts clinical trial with artificial pancreas using Xeris’ liquid glucagon
August 18, 2018 - HSS takes young patients with physical challenges on a surfing trip
August 18, 2018 - Study shows electronic health records leave doctors and patients unsatisfied
August 18, 2018 - Study uncovers mechanism that affects multiplication of dengue virus lineage
Small molecule plays huge role in keeping people safe from machinations of cancer

Small molecule plays huge role in keeping people safe from machinations of cancer

image_pdfDownload PDFimage_print

One small molecule that helps regulate gene expression plays a big role in keeping us safe from the machinations of cancer, scientists report.

In human lung cancer cells, they have shown 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, says Rojiani, corresponding author of the study in the journal Oncotarget.

TIMP-1 has a positive role in a healthy body to help 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.

Dr. Amyn M. Rojiani, a study coauthor, likens the cancer cells to blueberries and the matrix to the pancake. “In order for these blueberries to move or become closer to each other, they secrete enzymes, matrix metalloproteinases, that break up the pancake, the matrix,” says the chair of the MCG Department of Pathology and Georgia Research Alliance Distinguished Cancer Scientist.

But 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,” Mumtaz Rojiani says.

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, says Dr. Sampa Ghoshal-Gupta, MCG postdoctoral fellow and the study’s first author. In fact, knocking TIMP-1 down also increases p53 levels.

They wanted to learn more about how, and Ghoshal-Gupta suspected there was more involved besides just protein-protein interactions. So they started also looking at microRNAs and found knocking down TIMP-1 in cancer cells affected a lot of them.

“At that moment, we were not sure if it was good or bad change, just change,” Mumtaz Rojiani says.

When they looked again at exactly what microRNAs were changing, they found miR-125a-5p, which was known to promote cell death, go up in the face of less TIMP-1. They knew they had something.

They would also find a site on the TIMP-1 gene for miR-125a-5p to bind, says Mumtaz Rojiani, and the binding results in less TIMP-1 being produced.

When they 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 even 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. They theorized that this benefit could be at least partially attributed to miR-125a-5p. So they added more synthetic miR-125a-5p to the cancer cells, and the lung cancer cells moved even more toward a stationary normal look and cell death increased. When they inhibited miR-125a-5p, the cells were even more ready to roam.

When they looked at the biopsies of lung cancer patients at Augusta University Health, 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.

Some previous studies have shown a relationship between microRNAs and TIMP-1 function. More than 35 studies have shown that if TIMP-1 levels are high, a patient’s cancer prognosis is poor, says Ghoshal-Gupta, but the MCG team figured it was good since they were knocking down TIMP-1. And they were right; they saw more apoptosis, the postdoc says. The exact opposite happened when they overexpressed TIMP-1.

Next steps include determining if there are other microRNA and TIMP-1 interactions that lead to decreased apoptosis. They also want to look more closely at the mechanism of suppression of miroRNAs that impacts TIMP-1 levels. They all agree that as tumors prepare remote locations for spread – like to the brain in the case of lung cancer – that includes adjustments that enable the production of more TIMP-1.

“There must be different gene mutations of the cancer that must be affecting TIMP-1,” Mumtaz Rojiani says. One of the early adjustments in this tumor progression must be miRNA level modulation, Amyn Rojiani says. They also want to know if cancer also sends some extra TIMP-1 to those remote sites via exosomes, little traveling sacs by which cells swap messages and content.

Despite the clear association between high TIMP-1 levels and poor prognosis, TIMP-1 levels in the blood have not yet been used clinically as a prognostic indicator, the scientists say.

Source:

Small molecule plays a big role in reducing cancer’s spread

Tagged with:

About author

Related Articles