Migfilin promotes migration and invasion in glioma by driving EGFR and MMP-2 signalings:A positive feedback loop regulation

Glioma is the most common type of primary brain tumors in the central nervous system（CNS）. Migfilin occurs in human glioma and enhances cellular motility via the epidermal growth factor receptor（EGFR）pathway. However, the underlying molecular mechanism is not fully understood. In this study, we found that Migfilin promoted matrix metalloproteinase-2（MMP-2） activity, and restrained the expression of tissue inhibitor of metalloproteinase 2（TIMP2）, which is an MMP-2 inhibitor. Functional and structural studies showed that the LIM1 domain of Migfilin was required for Migfilin-mediated TIMP2 expression inhibition and MMP-2 activity, and was also necessary in promoting cell motility. Furthermore, Migfilininduced EGFR phosphorylation was greatly reduced by MMP-2 inhibitor（GM6001） or si RNA, while Migfilin-induced MMP-2 activation was also blocked by the EGFR inhibitor（AG1478） or si RNA. MMP-2 and EGFR inhibitors and their si RNAs can block Migfilin-induced migration and invasion, respectively.These results demonstrated that EGFR and MMP-2 signalings may form a positive feedback loop to enhance Migfilin-induced migration and invasion. Finally, we detected that the expression of Migfilin,EGFR phosphorylation（Tyr1173） and MMP-2 activity had a positive correlation in the clinical glioma sample. Taken together, these results suggest that Migfilin is a critical regulator in cellular motility by driving the EGFR-MMP-2 feedback loop, and may be considered as a potential therapeutic target in glioma.

Efficient lung cancer-targeted drug delivery via a nanoparticle/MSC system

Low targeting efficiency limits the applications of nanoparticles in cancer therapy. The fact that mesenchymal stem cells(MSC) trapped in the lung after systemic infusion is a disadvantage for cell therapy purposes. Here, we utilized MSC as lung cancer-targeted drug delivery vehicles by loading nanoparticles(NP)with anti-cancer drug. MSC showed a higher drug intake capacity than fibroblasts. In addition, MSC showed predominant lung trapping in both rabbit and monkey. IR-780 dye, a fluorescent probe used to represent docetaxel(DTX) in NP, delivered via MSC accumulated in the lung. Both in vitro MSC/A549 cell experiments and in vivo MSC/lung cancer experiments validated the intercellular transportation of NP between MSC and cancer cells. In vivo assays showed that the MSC/NP/DTX drug delivery system exerted primary tumor inhibition efficiency similar to that of a NP/DTX drug system. Collectively, the MSC/NP drug delivery system is promising for lung-targeted drug delivery for the treatment of lung cancer and other lung-related diseases.