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Stanford Study Finds miRNA-320a a Broad Regulator of Glycolysis, Potential Drug Target

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A study by Stanford researchers has found that microRNA-320a appears to regulate glycolysis in response to oxidative stress in several biological systems, including lung cancer and wasting of disused muscle.

The finding has implications for cancer treatment, as well as more effective treatment for dysfunctional diaphragm muscles following breathing support using a ventilator, according to the team, which published the study online in the FASEB Journal earlier this month.

Glycolysis is the process of converting sugar into energy, and is implicated in the growth of some cancers through a process called the Warburg effect. To the Stanford team, the Warburg effect seen in lung adenocarcinoma "appears to closely mimic" that of dysfunctional human diaphragm tissue after mechanical ventilation therapy, a condition called ventilator-induced diaphragm dysfunction, or VIDD.

The Stanford researchers claim that their study shows that these very divergent biological systems share the same glycolysis regulatory apparatus involving miR-320a, which the authors believe they are the first to identify.

Additionally, "miR-320 regulation of glycolysis may represent a general mechanism underlying other clinical diseases that are associated with changes in energy supply," the researchers wrote, such as cardiac ischemia, to insulin resistance.

In cancer specifically, down-regulation of miR-320a has been previously reported in a number of malignancies, the group reported. Coupled with the fact that the Warburg effect is thought to be important in many cancers, and the results of the group's study in adenocarcinoma, this suggests that miR-320a "may be directly related” to the development of cancer, and that the associated glycolysis may be a potential drug target.

For VIDD, meanwhile, the team wrote that the study results suggest that mitochondria-targeted antioxidants may be valuable to better treat the disorder.

The Stanford team was initially interested in better understanding the wasting of diaphragm muscles due to mechanical ventilation, but expanded its study to look at lung cancer and an experimental in vitro model of oxidative stress, as well as the similarity of pathogenic glycolytic pathways across these biological systems.

The group profiled miRNA and protein expression in samples from human diaphragm muscles under mechanical ventilation to identify miRNAs associated with the glycolytic rate-limiting enzyme phosphofructokinase, or PFKm, without which glycolysis is reduced.

The group initially identified 28 miRNAs that were significantly downregulated and three that were upregulated in the ventilated human diaphragm samples. Using predictive software, the group pinpointed miR-320a as being potentially involved in the regulation PFKm.

To validate miR-320a, the researchers looked at all three experimental systems — samples of diaphragm tissue, lung cancer, and an in vitro cell model under oxidative stress. In all three, miR-320a was down-regulated in the samples versus the control.

The group also confirmed that miR-320a influences PFKm in each system, and further demonstrated that miR-320a knockdown increased lactate levels in vitro; and thathigher miR-320a levels reduced lactate levels in in vivo mouse experiments.

The group wrote that the study shows for the first time that glycolytic activity "is increased in diaphragm tissue that is noncontractile as a result of full mechanical ventilator support." The results also confirmed that glycolysis up-regulation, or the Warburg effect, is present in lung adenocarcinoma, and that both otherwise divergent disorders are in fact linked by the influence of miR-320a.

According to the paper, the team plans future work to block miR-320a in tumor and animal models of mechanical ventilation to measure whether this prevents upregulation of glycolysis and the associated disorder of diaphragm muscle.

They suggest other studies might also examine additional biological areas associated with up-regulated glycolysis to test the hypothesis that miRNA-320a and its associated pathways are involved more broadly across biological systems.

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