Vascular endothelial growth factor (VEGF) plays a crucial role in tumor angiogenesis. VEGF induces new vessel formation and tumor growth by inducing mitogenesis and chemotaxis of normal endothelial cells and increasing vascular permeability. However, little is known about VEGF function in the proliferation, survival or migration of hepatocellular carcinoma cells (HCC). In the present study, we have found that VEGF receptors are expressed in HCC line BEL7402 and human hepatocellular carcinoma specimens. Importantly, VEGF receptor expression correlates with the development of the carcinoma. By using a comprehensive approaches including TUNEL assay, transwell and wound healing assays, migration and invasion assays, adhesion assay, western blot and quantitative RT-PCR, we have shown that knockdown of VEGF165 expression by shRNA inhibits the proliferation, migration, survival and adhesion ability of BEL7402. Knockdown of VEGF165 decreased the expression of NF-κB p65 and PKCα while increased the expression of p53 signaling molecules, suggesting that VEGF functions in HCC proliferation and migration are mediated by P65, PKCα and/or p53.

Herein, the heterogeneity of the facets potentials is used to improve the SERS activity of anatase TiO2 single crystals co-exposed with {0 0 1} and {1 0 1} facets. Using...

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MicroRNAs (miRNAs) have been shown to participate in development of neuropathic pain. However, the role of microRNA‐144 (miR‐144) in neuropathic pain remains unclear. In the present study, we established a neuropathic pain mouse model via chronic constriction injury (CCI)‐induction. The successful establishment of this model was confirmed via evaluation of paw withdrawal threshold (PWT) and paw withdrawal latency (PWL). By using this model, we found that miR‐144 was significantly downregulated in CCI‐induced neuropathic pain mice. In addition, intrathecal injection of miR‐144 agomiR alleviated mechanical and thermal hyperalgesia in neuropathic pain mice as shown by the increased of PWT and PWL. Moreover, miR‐144 negatively regulated neuroinflammation by decreasing the expression of proinflammatory mediators, including TNF‐α (tumor necrosis factor‐α), IL (interleukin)‐1β, and IL‐6, thus facilitating the inhibition of neuropathic pain development. Mechanistically, RASA1 (RAS P21 Protein Activator 1) was downregulated following the injection of agomiR‐144, and was verified to be a target of miR‐144. Furthermore, overexpression of RASA1 reversed the inhibitory effect of miR‐144 on neuropathic pain. Therefore, the present study suggested that miR‐144 has the potential to be explored as therapeutic target for treatment of neuropathic pain.

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SUMMARY OBJECTIVE In this study, we aimed to investigate the role of COL6A3 on cell motility and the PI3K/AKT signaling pathway in osteosarcoma. METHODS The relative expression of COL6A3 was achieved from a GEO dataset in osteosarcoma tissue. siRNA technology was applied to decrease the COL6A3 expression in cells, and cell counting kit-8 (CCK-8) assay and colony formation analysis were used to examine the cell proliferation potential. Knockdown COL6A3 made the proliferation and colony formation abilities worse than the COL6A3 without interference. Likewise, in contrast to the si-con group, cell invasion and migration were inhibited in the si-COL6A3 group. Moreover, the western blot results suggested that the PI3K/AKT signaling pathway was manipulated by measuring the protein expression of the PI3K/AKT pathway-related markers, due to the COL6A3 inhibition. CONCLUSION COL6A3 plays a crucial role in modulating various aspects of the progression of osteosarcoma, which would provide a potentially effective treatment for osteosarcoma.

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Indoleamine-2,3-dioxygenase (IDO1) is well-recognized as an important target for immunotherapeutic intervention. Growing interests on this target have been demonstrated by the recent expansion of enthusiasms to inhibit the Trp-to-Kyn pathway as a means to control immunosuppression for cancer treatment. Clinical validation of IDO1 inhibitors for treating various tumors including glioblastoma, melanoma, non-small cell lung, pancreatic, and/or breast cancer, as well as metastatic diseases are currently pursued by pharmaceutical companies and other sponsors. These IDO1 inhibitors include several pioneering clinical compounds such as INCB024360 (epacadostat), GDC-0919, indoximod, and BMS-986205, etc. At the 2017 Annual Meeting of the American Society of Clinical Oncology (ASCO), it was reported that patients with squamous cell carcinoma of head and neck were responded well to the combinations of epacadostat plus pembrolizumab and epacadostat plus nivolumab. In addition, epacadostat also demonstrated very promising efficacy in combination with PD-1 checkpoint inhibitors for treating various kind of solid tumors. Most recently, at the 32nd SITC annual meeting held in this month, very exciting and encouraging results were just reported by BMS from an early clinical trials for the combo studies of BMS-986205 with Opdivo. Previously we reported a moderately potent IDO1/TDO dual inhibitor DN131 for cancer immunotherapy (AACR2015 Abstract# 4877), herewith we wish to present a much more potent and selective IDO1 inhibitor DN-016 with superior drug-like properties. DN-016 is a novel heterocyclic compound that was discovered through structure-based drug design and medicinal chemistry approaches. In in vitro studies, DN-016 showed very high potency in inhibiting hela IDO1 cell with an IC50 of 0.71 nM. It exhibited good ADME properties and safe hERG parameter with IC50 over 30 μM. Compared to the reference compounds in clinical stages, DN-016 exhibited much superior permeability with excellent efflux ratio (A-B/B-A: 22 × 10-6 cm.s-1 / 24 × 10-6 cm.s-1). In in vivo rat PK studies, DN-016 showed very high oral bioavailability (100% F) when dosing at 10 mg/kg via po. Currently DN-016 is under preclinical evaluation as a single agent and together with a PD-1 inhibitor. In summary, as a new anticancer agent, DN-016 demonstrated a remarkable in vitro potency and selectivity with favorable pharmacokinetic properties. Detailed preclinical evaluation of DN-016 will be presented. Citation Format: Shoujun Chen, Fengtao Liu, Hongli Guo, Shuwen Ren, Yikun Zeng, Wei Yang, Ping Qing, Tao Chen, Feng Zhou, Guocheng Li, Mingliang Sun, Xiaogang Ye, Xingzhong Zhang, Panhu Zhu, Hui Xu, Pei Li, Donghai Li, Zang Jie, Huanping Li, Shuda Zhao, Jiangjing Tan, Heping Yang, Longsheng Wang, Fang Liu, Guangliang Fu, Jianggang Du, Hongye Yang, Wenting Xue, Pei Wang, Lan Guo, Lu Wang, Qun Li, Yuxun Wang, Daxin Gao. Discovery of DN-016: A highly potent, selective and orally available IDO1 inhibitor for treating cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5555.