MicroRNA-21 (miR-21) is an oncomir overexpressed in most human tumors in that it promotes malignant growth and progression by acting on multiple targets. Here, we broaden the impact of miR-21 in cancer by showing that it regulates the formation of reactive oxygen species (ROS) that promote tumorigenesis. Key targets of miR-21 in mediating this function were SOD3 and TNFa. We found that miR-21 inhibited the metabolism of superoxide to hydrogen peroxide, produced either by endogenous basal activities or exposure to ionizing radiation (IR), by directing attenuating SOD3 or by an indirect mechanism that limited TNFa production, thereby reducing SOD2 levels. Importantly, both effects contributed to an elevation of IR-induced cell transformation. Our findings, therefore, establish that miR-21 promotes tumorigenesis to a large extent through its regulation of cellular ROS levels. Cancer Res; 72(18); 4707-13. Ó2012 AACR.

Objective Molecular imaging and clinical endpoints are frequently discordant in Parkinson disease (PD) clinical trials raising questions about validity of these imaging measures to reflect disease severity. We compared striatal uptake for 3 PET tracers with in vitro measures of nigral cell counts and striatal dopamine in MPTP treated monkeys. Methods Sixteen macaques had MRI and baseline PETs using 6-[18F]fluorodopa (FD), [11C] dihydrotetrabenazine (DTBZ) and [11C] 2beta-carbomethoxy-3beta-4-fluorophenyltropane (CFT). MPTP (0 to 0.31 mg/kg) infused unilaterally via the internal carotid artery produced stable hemiparkinsonism by three weeks. After eight weeks, PETs were repeated and animals euthanized for striatal dopamine measurements and unbiased counts of tyrosine hydroxylase stained nigral cells. Results Striatal uptake for each radiotracer (FD, DTBZ, CFT) correlated with stereologic nigral cell counts only for nigral loss < 50% (r2= 0.84; r2= 0.86; r2= 0.87, p<0.001 respectively; n=10). In contrast, striatal uptake correlated with striatal dopamine over the full range of dopamine depletion (r2= 0.95; r2= 0.94; r2= 0.94, p<0.001; n=16). Interestingly, indices of striatal uptake of FD, DTBZ and CFT correlated strongly with each other (r2=0.98, p<0.001). Interpretation Tracer uptake correlated with nigral neurons only when nigral loss < 50%. This along with previous work demonstrating that nigral cell counts correlate strongly with parkinsonism ratings may explain discordant results between neuroimaging and clinical endpoints. Furthermore, strong correlations among striatal uptake for these tracers support lack of differential regulation of decarboxylase activity (FD), vesicular monoamine transporter type 2 (DTBZ), and dopamine transporter (CFT) within 2 months after nigrostriatal injury.

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Primary duodenal GISTs are generally large, well-defined, heterogeneously enhancing, and hypervascular masses with a prominent mixed growth pattern on CT images. Our findings suggest that CT can help depict the origin of the tumoral arteries and draining veins on the arterial phase and may be a key defining diagnostic feature for duodenal GISTs.

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