Background Circular RNAs (circRNAs) are a class of noncoding RNAs (ncRNAs) and can modulate gene expression by binding to miRNAs; further, circRNAs have been shown to participate in several pathological processes. However, the expression and biological function of circCUL2 in gastric cancer (GC) remains largely unknown. Methods circRNA microarrays and quantitative real-time PCR (qRT-PCR) were used to identify differentially expressed circRNAs in GC tissues and cell lines. circCUL2 knockdown and overexpression were performed to indicate the functional role of circCUL2 in vitro and in vivo. The expression and regulation of circCUL2, miR-142-3p and ROCK2 were evaluated using fluorescence in situ hybridization (FISH), dual-luciferase assays, RNA pull-down assays, RNA immunoprecipitation (RIP) and rescue experiments. Furthermore, the regulation of cisplatin sensitivity and autophagy by circCUL2/miR-142-3p/ROCK2 was demonstrated by cellular apoptosis assays, western blot, immunofluorescence and transmission electron microscopy analyses. Results The level of circCUL2, which is stable and cytoplasmically localized, was significantly reduced in GC tissues and cells. Overexpressed circCUL2 inhibited malignant transformation in vitro and tumorigenicity in vivo. In the AGS and SGC-7901 cell lines, circCUL2 sponged miR-142-3p to regulate ROCK2, thus modulating tumor progression. Furthermore, in the AGS/DDP and SGC-7901/DDP cell lines, circCUL2 regulated cisplatin sensitivity through miR-142-3p/ROCK2-mediated autophagy activation. Conclusion circCUL2 may function as a tumor suppressor and regulator of cisplatin sensitivity through miR-142-3p/ROCK2-mediated autophagy activation, which could be a key mechanism and therapeutic target for GC.

SR-A (class A macrophage scavenger receptor) is a transmembrane receptor that can bind many different ligands, including modified lipoproteins that are relevant to the development of vascular diseases. However, the precise endocytic pathways of SR-A/mediated ligands internalization are not fully characterized. In this study, we show that the SR-A/ligand complex can be endocytosed by both clathrin-and caveolae-dependent pathways. Internalizations of SR-A-lipoprotein (such as acLDL) complexes primarily go through clathrin-dependent endocytosis. In contrast, macrophage apoptosis triggered by SR-A-fucoidan internalization requires caveolae-dependent endocytosis. The caveolae-dependent process activates p38 kinase and JNK signaling, whereas the clathrin-mediated endocytosis elicits ERK signaling. Our results suggest that different SR-A endocytic pathways have distinct functional consequences due to the activation of different signaling cascades in macrophages.

Purpose: Fumarate hydratase–deficient renal cell carcinoma (FH-deficient RCC) is a rare but lethal subtype of RCC. Little is known about the genomic profile of FH-deficient RCC, and the therapeutic options for advanced disease are limited. To this end, we performed a comprehensive genomics study to characterize the genomic and epigenomic features of FH-deficient RCC. Experimental Design: Integrated genomic, epigenomic, and molecular analyses were performed on 25 untreated primary FH-deficient RCCs. Complete clinicopathologic and follow-up data of these patients were recorded. Results: We identified that FH-deficient RCC manifested low somatic mutation burden (median 0.58 mutations per megabase), but with frequent somatic copy-number alterations. The majority of FH-deficient RCCs were characterized by a CpG sites island methylator phenotype, displaying concerted hypermethylation at numerous CpG sites in genes of transcription factors, tumor suppressors, and tumor hallmark pathways. However, a few cases (20%) with low metastatic potential showed relatively low DNA methylation levels, indicating the heterogeneity of methylation pattern in FH-deficient RCC. Moreover, FH-deficient RCC is potentially highly immunogenic, characterized by increased tumor T-cell infiltration but high expression of immune checkpoint molecules in tumors. Clinical data further demonstrated that patients receiving immune checkpoint blockade–based treatment achieved improved progression-free survival over those treated with antiangiogenic monotherapy (median, 13.3 vs. 5.1 months; P = 0.03). Conclusions: These results reveal the genomic features and provide new insight into potential therapeutic strategies for FH-deficient RCC.