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MicroRNA-320a regulated glycolysis, growth rate of lung adenocarcinomas in ventilator-assisted patients
The molecule microRNA-320a regulated the rate-limiting glycolytic enzyme phosphofructokinase present in the lung adenocarcinomas and disused diaphragm tissues of patients using ventilators, according to a research report published online.
Based on the apparently comparable pathogenetic bases of the increased glycolysis observed in both mechanically-ventilated diaphragm tissues and in lung adenocarcinoma cells, Joseph B. Shrager, MD, professor of cardiothoracic surgery, and chief of the Division of Thoracic Surgery at Stanford University School of Medicine, and colleagues evaluated whether there were shared molecular mechanisms causing this up-regulation.
According to the researchers, “In malignancy, blocking glycolysis could deprive cancers of a pathway that likely provides both an alternative energy supply and important building blocks for synthesis that allow cancer cell proliferation.”
Shrager and colleagues evaluated samples of human lung adenocarcinoma tissues and tissue samples from the diaphragms of patients who had been mechanically-ventilated for at least 18 hours prior to biopsy. The researchers compared diaphragm tissue samples against a group of control subjects, consisting of patients who were undergoing throacotomy and had been mechanically-ventilated 1-2 hours before biopsy.
The researchers used proteomics to systemically profile the altered protein expression in mechanically-ventilated human diaphragms, which confirmed that there were significant important changes in glycolytic pathways. The researchers then used microRNA microarray to inspect the regulatory factors that control expression of the gene coding for the rate-limiting glycolytic enzyme muscle-type phosphofructokinase (PFKm).
“We show here for the first time that glycolytic activity is increased in diaphragm tissue that is noncontractile as a result of full mechanical ventilatory support,” the researchers wrote. “We also confirm that the up-regulation of glycolysis is present in lung adenocarcinoma, and we show that the rate-limiting glycolytic enzyme PFKm is induced in disused diaphragm, lung cancer, and our in vitro model of oxidative stress.”
This shared mechanism for increased glycolysis in response to mitochondrial dysfunction in both ventilator-induced diaphragm dysfunction and cancer suggests a regulatory mechanism that may control glycolysis largely across biological systems, as well as providing a potential therapeutic target for cancer.
“We hope that this discovery will yield a new avenue of molecular treatment for cancers, particularly lung cancer, which is the number one cause of cancer deaths worldwide,” Shrager said in a press release. “We also hope it can lead to a treatment to be given to intensive care unit patients who require the breathing machine, reducing the length of time they require the machine, and thereby reducing complications and deaths.”
Disclosure: This research was supported by a Veterans Affairs Merit Review grant and in part by U.S. National Institutes of Health grant RO1-HL-078834.