Resveratrol and pterostilbene epigenetically restore PTEN expression by targeting oncomiRs of the miR-17 family in prostate cancer

In recent years, not only has the role of miRNAs in cancer become increasingly clear but also their utilization as potential biomarkers and therapeutic targets has gained ground. Although the importance of dietary stilbenes such as resveratrol and pterostilbene as anti-cancer agents is well recognized, our understanding of their miRNA-targeting capabilities is still limited. In our previous study, we reported that resveratrol downregulates PTEN-targeting members of the oncogenic miR-17 family, which are overexpressed in prostate cancer. This study investigates the resveratrol and pterostilbene induced miRNA-mediated regulation of PTEN in prostate cancer. Here, we show that both compounds decrease the levels of endogenous as well as exogenously expressed miR-17, miR-20a and miR-106b thereby upregulating their target PTEN. Using functional luciferase reporter assays, we demonstrate that ectopically expressed miR-17, miR-20a and miR-106b directly target PTEN 3′UTR to reduce its expression, an effect rescued upon treatment with resveratrol and pterostilbene. Moreover, while stable lentiviral expression of miR-17/106a significantly decreased PTEN mRNA and protein levels and conferred survival advantage to the cells, resveratrol and more so pterostilbene was able to dramatically suppress these effects. Further, pterostilbene through downregulation of miR-17-5p and miR-106a-5p expression both in tumors and systemic circulation, rescued PTEN mRNA and protein levels leading to reduced tumor growth in vivo. Our findings implicate dietary stilbenes as an attractive miRNA-mediated chemopreventive and therapeutic strategy, and circulating miRNAs as potential chemopreventive and predictive biomarkers for clinical development in prostate cancer.     

Surgical placement of biologic mesh spacers prior to external beam radiation for retroperitoneal and pelvic tumors

PurposeTo determine the feasibility of surgical placement of biologic mesh spacers to displace bowel and other radiation-sensitive organs prior to external beam radiation for difficult retroperitoneal and pelvic tumors.Methods and MaterialsTumors were resected if possible, and intraoperative electron radiation therapy (IOERT) was directed to the tumor or tumor bed in selected patients. Biologic mesh spacers comprised of cadaveric human skin treated to remove cells and preserve extracellular matrix (Alloderm; Lifecell, Branchburg, NJ) were then placed around the tumor or tumor bed. External radiation techniques included proton beam radiation therapy (PBRT) and intensity modulated radiation therapy (IMRT).ResultsPatients had primary sarcomas (n = 2), radiation-associated sarcomas (n = 1), or isolated metastases (n = 2) in the retroperitoneum or pelvis. One patient received preoperative radiation. Three tumors were marginally resected (R1 resection) while 2 tumors were left in situ, and 3 patients received IOERT (10-17 Gy) to the tumor or tumor bed. Up to 4 sheets of biologic mesh were used as spacers around the tumor or tumor bed to displace small bowel, colon, ureter, bladder, or pancreas. The average distance of the 4 closest organs prior to mesh placement was 1.3-9 mm and after mesh placement was 8.0-23.5 mm. Preoperative or postoperative radiation 36-76 Gy was delivered by IMRT or PBRT. There were no early complications from mesh placement and late complications possibly related to radiation included 1 vertebral body compression fracture and 1 deep vein thrombosis. There were no mesh-related infections and none of the meshes required removal. All 5 patients currently remain free of disease progression after 3-38 months.ConclusionsBiologic mesh spacers can be placed around tumors or tumor beds to displace radiation-sensitive organs and may allow for safer delivery of external beam radiation.