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Small molecules that restore the expression of growth-inhibitory microRNAs (miRNA) downregulated in tumors may have potential as anticancer agents. miR34a functions as a tumor suppressor and is downregulated or silenced commonly in a variety of human cancers, including hepatocellular carcinoma (HCC). In this study, we used an HCC cell-based miR34a luciferase reporter system to screen for miR34a modulators that could exert anticancer activity. One compound identified as a lead candidate, termed Rubone, was identified through its ability to specifically upregulate miR34a in HCC cells. Rubone activated miR34a expression in HCC cells with wildtype or mutated p53 but not in cells with p53 deletions. Notably, Rubone lacked growth-inhibitory effects on nontumorigenic human hepatocytes. In a mouse xenograft model of HCC, Rubone dramatically inhibited tumor growth, exhibiting stronger anti-HCC activity than sorafenib both in vitro and in vivo. Mechanistic investigations showed that Rubone decreased expression of cyclin D1, Bcl-2, and other miR34a target genes and that it enhanced the occupancy of p53 on the miR34a promoter. Taken together, our results offer a preclinical proof of concept for Rubone as a lead candidate for further investigation as a new class of HCC therapeutic based on restoration of miR34a tumor-suppressor function. Cancer Res; 74(21); 6236-47. Ó2014 AACR.

Electrospun fibrous scaffolds have been extensively used as cell-supporting matrices or delivery vehicles for various biomolecules in tissue engineering. Biodegradable scaffolds with tunable degradation behaviors are favorable for various resorbable tissue replacements. In nerve tissue engineering, delivery of growth factors (GFs) such as nerve growth factor (NGF) and glial cell line-derived neurotrophic factor (GDNF) from scaffolds can be used to promote peripheral nerve repair. In this study, using the established dual-source dual-power electrospinning technique, bicomponent scaffolds incorporated with NGF and GDNF were designed and demonstrated as a strategy to develop scaffolds providing dual GF delivery. NGF and GDNF were encapsulated in poly(D, L-lactic acid) (PDLLA) and poly(lactic-co-glycolic acid) (PLGA) nanofibers, respectively, via emulsion electrospinning. Bicomponent scaffolds with various mass ratios of GDNF/PLGA fibers to NGF/PDLLA fibers were fabricated. Their morphology, structure, properties, and the in vitro degradation were examined. Both types of core-shell structured fibers were evenly distributed in bicomponent scaffolds. Robust scaffolds with varying component ratios were fabricated with average fiber diameter ranging from 307 ± 100 nm to 688 ± 129 nm. The ultimate tensile stress and elastic modulus could be tuned ranging from 0.23 ± 0.07 MPa to 1.41 ± 0.23 MPa, 11.1 ± 3.0 MPa to 75.9 ± 3.3 MPa, respectively. Adjustable degradation was achieved and the weight loss of scaffolds ranged from 9.2% to 44.0% after 42 day degradation test. GDNF and NGF were incorporated with satisfactory encapsulation efficiency and their bioactivity were well preserved. Sustained release of both types of GFs was also achieved.

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