HULC is a long noncoding RNA overexpressed in hepatocellular carcinoma (HCC), but its functional contributions in this setting have not been determined. In this study, we explored the hypothesis that HULC contributes to malignant development by supporting abnormal lipid metabolism in hepatoma cells. HULC modulated the deregulation of lipid metabolism in HCC by activating the acyl-CoA synthetase subunit ACSL1. Immunohistochemical analysis of tissue microarrays revealed that approximately 77% (180/233) of HCC tissues were positive for ACSL1. Moreover, HULC mRNA levels correlated positively with ACSL1 levels in 60 HCC cases according to real-time PCR analysis. Mechanistic investigations showed that HULC upregulated the transcriptional factor PPARA, which activated the ACSL1 promoter in hepatoma cells. HULC also suppressed miR-9 targeting of PPARA mRNA by eliciting methylation of CpG islands in the miR-9 promoter. We documented the ability of HULC to promote lipogenesis, thereby stimulating accumulation of intracellular triglycerides and cholesterol in vitro and in vivo. Strikingly, ACSL1 overexpression that generates cholesterol was sufficient to enhance the proliferation of hepatoma cells. Further, cholesterol addition was sufficient to upregulate HULC expression through a positive feedback loop involving the retinoid receptor RXRA, which activated the HULC promoter. Overall, we concluded that HULC functions as an oncogene in hepatoma cells, acting mechanistically by deregulating lipid metabolism through a signaling pathway involving miR-9, PPARA, and ACSL1 that is reinforced by a feed-forward pathway involving cholesterol and RXRA to drive HULC signaling. Cancer Res; 75(5); 846-57. Ó2015 AACR.

van der Waals layered structures, notably the transitional metal dichalcogenides (TMDs) and TMD-based heterostructures, have recently attracted immense interest due to their unique physical properties and potential applications in electronics, optoelectronics, and energy harvesting. Despite the recent progress, it is still a challenge to perform comprehensive characterizations of critical properties of these layered structures, including crystal structures, chemical dynamics, and interlayer coupling, using a single characterization platform. In this study, we successfully developed a multimodal nonlinear optical imaging method to characterize these critical properties of molybdenum disulfide (MoS2) and MoS2-based heterostructures. Our results demonstrate that MoS2 layers exhibit strong four-wave mixing (FWM), sum-frequency generation (SFG), and second-harmonic generation (SHG) nonlinear optical characteristics. We believe this is the first observation of FWM and SFG from TMD layers. All three kinds of optical nonlinearities are sensitive to layer numbers, crystal orientation, and interlayer coupling. The combined and simultaneous SHG/SFG-FWM imaging not only is capable of rapid evaluation of crystal quality and precise determination of odd-even layers but also provides in situ monitoring of the chemical dynamics of thermal oxidation in MoS2 and interlayer coupling in MoS2-graphene heterostructures. This method has the advantages of versatility, high fidelity, easy operation, and fast imaging, enabling comprehensive characterization of van der Waals layered structures for fundamental research and practical applications.

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Highly up-regulated in liver cancer (HULC) is a long non-coding RNA (lncRNA). We found that HULC up-regulated sphingosine kinase 1 (SPHK1), which is involved in tumor angiogenesis. Levels of HULC were positively correlated with levels of SPHK1 and its product, sphingosine-1-phosphate (S1P), in patients HCC samples. HULC increased SPHK1 in hepatoma cells. Chicken chorioallantoic membrane (CAM) assays revealed that si-SPHK1 remarkably blocked the HULC-enhanced angiogenesis. Mechanistically, HULC activated the promoter of SPHK1 in hepatoma cells through the transcription factor E2F1. Chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assay (EMSA) further showed that E2F1 was capable of binding to the E2F1 element in the SPHK1 promoter. HULC increased the expression of E2F1 in hepatoma cells and levels of HULC were positively correlated with those of E2F1 in HCC tissues. Intriguingly, HULC sequestered miR-107, which targeted E2F1 mRNA 3′UTR, by complementary base pairing. Functionally, si-SPHK1 remarkably abolished the HULC-enhanced tumor angiogenesis in vitro and in vivo. Taken together, we conclude that HULC promotes tumor angiogenesis in liver cancer through miR-107/E2F1/SPHK1 signaling. Our finding provides new insights into the mechanism of tumor angiogenesis.