Gelofusine Attenuates Tubulointerstitial Injury Induced by cRGD-Conjugated siRNA by Regulating the TLR3 Signaling Pathway.

Integrin αvß3, which is selectively targeted by cyclic arginine-glycine-aspartic acid (cRGD) peptides, is significantly upregulated in tumors. Previous studies showed that small interfering RNA (siRNA) modified with cRGD (cRGD-siRNA) could significantly inhibit tumor growth through RNAi with oncogene expression. However, cRGD-siRNA is partially reabsorbed and trapped in the kidneys, causing renal injury in an unpredictable manner. This study aimed to investigate the influence of Gelofusine on tubulointerstitial injury induced by cRGD-siRNA in vitro and in vivo. The effect of Gelofusine on the distribution of cRGD-siRNA in tumor-bearing nude mice and wild-type mice was also explored. We found that Gelofusine inhibited apoptosis and activation of the innate immune response of human tubular epithelial cells induced by cRGD-siRNA in vitro. In addition, co-injection of Gelofusine efficiently reduced renal retention of cRGD-siRNA without affecting its tumor targeting in vivo. Further in vivo studies indicated that Gelofusine significantly attenuated tubulointerstitial injury induced by cRGD-siRNA through regulating Toll-like receptor 3 (TLR3)-mediated activation of the nuclear factor κ B (NF-κB) and caspase-3 apoptotic pathway. In conclusion, Gelofusine, acting as a novel and effective renal protective agent, could form a compound preparation with siRNA drugs for future clinical applications.

miR-3188 regulates nasopharyngeal carcinoma proliferation and chemosensitivity through a FOXO1-modulated positive feedback loop with mTOR-p-PI3K/AKT-c-JUN.

The biological role of miR-3188 has not yet been reported in the context of cancer. In this study, we observe that miR-3188 not only reduces cell-cycle transition and proliferation, but also significantly prolongs the survival time of tumour-bearing mice as well as sensitizes cells to 5-FU. Mechanistic analyses indicate that miR-3188 directly targets mTOR to inactivate p-PI3K/p-AKT/c-JUN and induces its own expression. This feedback loop further suppresses cell-cycle signalling through the p-PI3K/p-AKT/p-mTOR pathway. Interestingly, we also observe that miR-3188 direct targeting of mTOR is mediated by FOXO1 suppression of p-PI3K/p-AKT/c-JUN signalling. In clinical samples, reduced miR-3188 is an unfavourable factor and negatively correlates with mTOR and c-JUN levels but positively correlates with FOXO1 expression. Our studies demonstrate that as a tumour suppressor, miR-3188 directly targets mTOR to stimulate its own expression and participates in FOXO1-mediated repression of cell growth, tumorigenesis and NPC chemotherapy resistance.