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Although liver cancer is a malignant tumor with the highest mortality across the world, its pathogenesis and therapeutic targets remain unclear. Apoptosis, a natural cell death mechanism, is an important target of anticancer therapy. The discovery of effective apoptotic regulators can lead to the identification of novel therapeutic targets for treating cancer. Neurotrophin 3 (NTF3) is a member of the nerve growth factor (NGF) family that is involved in the progression of various cancers, including medulloblastoma, primitive neuroectodermal brain tumors, and breast cancer. NTF3 is under-expressed in human hepatocellular carcinoma (HCC), albeit its specific effects and the action mechanism have not been elucidated. Here, we confirmed that NTF3 expression was significantly low in HCC with reference to the GSEA database. By collecting patient data from our center and performing qRT-PCR analysis, we found that NTF3 expression was significantly downregulated in 74 patients with HCC. Low NTF3 expression was associated with a shorter overall survival (OS), recurrence-free survival (RFS), progression-free survival (PFS), and disease-specific survival (DSS). Both in vivo and in vitro experiments revealed that NTF3 considerably inhibited the progression of HCC cells. We found that the ligand NTF3 is regulated by c-Jun and binds to the p75 neurotrophin receptor (p75NTR) and then activates the JNK and P38 MAPK pathways to induce apoptosis. Entinostat (the target of HDAC1/HDAC3) can activate the NTF3/p75NTR pathway. These results indicate that NTF3 is a tumor suppressor, and that its low expression can help in predict poor clinical outcomes in HCC. Therefore, NTF3 can be used as a potential treatment molecule for HCC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Although nicotine is known to protect against β-amyloid (Aβ)-induced neurotoxicity, the effect of nicotine on colchicine-induced neurotoxicity remains unknown. Colchicine is a microtubule-interfering agent and is able to induce neural apoptosis. Here we investigated whether nicotine exhibits similar neuroprotective effects and the mechanism against colchicine-induced neurotoxicity of the primarily cultured cortical neurons. In this study, we investigated the effect of nicotine on the protection of neurons against colchicine damage and evaluated the associated intracellular signaling pathways. Nicotine-induced protection was blocked by an α7 nicotinic acetylcholine receptors (nAChRs) antagonist and a phosphatidylinositol 3-kinase (PI3K) inhibitor. These results suggest that the neuroprotective effects of nicotine are mediated by the α7 nAChRs and PI3K-Akt signaling pathway. In addition, we reveal that blockade of p38 and JNK (c-Jun N-terminal kinase) signaling increased Akt signaling, thus enhancing the survival of cell treatment with colchicine. On the other hand, inhibition of constitutively active Akt enhanced p38 or JNK signaling phosphorylation. These data suggested that crosstalk between PI3K Akt and p38 or JNK signaling pathways contributed to nicotine against colchicine-induced cytotoxicity.