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Impaired synaptic plasticity and neuron loss are hallmarks of Alzheimer's disease and vascular dementia. Here, we found that chronic brain hypoperfusion (CBH) by bilateral common carotid artery occlusion (2VO) decreased the total length, numbers and crossings of dendrites and caused neuron death in rat hippocampi and cortices. It also led to increase in N-terminal β-amyloid precursor protein (N-APP) and death receptor-6 (DR6) protein levels and in the activation of caspase-3 and caspase-6. Further study showed that DR6 protein was downregulated by miR-195 overexpression, upregulated by miR-195 inhibition, and unchanged by binding-site mutation and miR-masks. Knockdown of endogenous miR-195 by lentiviral vector-mediated overexpression of its antisense molecule (lenti-pre-AMO-miR-195) decreased the total length, numbers and crossings of dendrites and neuron death, upregulated N-APP and DR6 levels, and elevated cleaved caspase-3 and caspase-6 levels. Overexpression of miR-195 using lenti-pre-miR-195 prevented these changes triggered by 2VO. We conclude that miR-195 is involved in CBH-induced dendritic degeneration and neuron death through activation of the N-APP/DR6/caspase pathway.

Cisplatin is widely used for chemotherapy of a variety of malignancies. However, the clinical application of cisplatin is hampered by the resultant irreversible hearing loss due to hair cell apoptosis. To date, no practical regimen to resolve this has been developed. Meanwhile, the role of microRNA in protecting hair cells from cisplatin-induced apoptosis in the inner ear has not been extensively investigated. In this study, we monitored miR-183, -96, and -182 turnover in the cochlea during cisplatin treatment in vitro. We found that overexpression of miR-182, but not miR-183 and -96, improved hair cell survival after 3 μM cisplatin treatment in vitro. We demonstrated that overexpression of miR-182 repressed the intrinsic apoptotic pathway by inhibiting the translation of FOXO3a. Our study offers a new therapeutic target for alleviating cisplatin-induced hair cell apoptosis in a rapid and tissue-specific manner.

Recently, long non-coding RNAs (lncRNAs) are identified as new crucial regulators of diverse cellular processes, including cell proliferation, differentiation and cancer cells metastasis. Accumulating evidence has revealed that aberrant lncRNA expression plays important roles in carcinogenesis and tumor progression. However, the expression pattern and biological function of lncRNAs in non-small-cell lung cancer (NSCLC) remain largely unknown. In this study, we performed comprehensive analysis of lncRNA expression in human NSCLC samples by using microarray data from Gene Expression Omnibus. After validation in a cohort of 80 pairs of NSCLC tissues, we identified a differentially expressed novel oncogenic lncRNA termed as AGAP2-AS1. The AGAP2-AS1 expression level was significantly upregulated in NSCLC tissues and negatively correlated with poor prognostic outcomes in patients. In vitro loss- and gain-of-function assays revealed that AGAP2-AS1 knockdown inhibited cell proliferation, migration and invasion, and induced cell apoptosis. In vivo assays also confirmed the ability of AGAP2-AS1 to promote tumor growth. Furthermore, mechanistic investigation showed that AGAP2-AS1 could bind with enhancer of zeste homolog 2 and lysine (K)-specific demethylase 1A, and recruit them to KLF2 and LATS2 promoter regions to repress their transcription. Taken together, our findings indicate that AGAP2-AS1 may act as an oncogene by repressing tumor-suppressor LATS2 and KLF2 transcription. By clarifying the AGAP2-AS1 mechanisms underlying NSCLC development and progression, these findings might promote the development of novel therapeutic strategies for this disease.

Long intergenic noncoding RNAs (lincRNAs) have important roles in biological functions, molecular mechanisms and prognostic values in colorectal cancer (CRC). In this context, the roles of linc-UFC1 remain to be elucidated. In this study, linc-UFC1 was overexpressed in CRC patient tissues and positively correlated with tumor grade, N stage and M stage. Inhibition of linc-UFC1 resulted in cell proliferation inhibition and G1 cell cycle arrest, which was mediated by cyclin D1, CDK4, Rb and phosphorylated Rb. In addition, inhibition of linc-UFC1 induced cell apoptosis through the intrinsic apoptosis signaling pathway, as evidenced by the activation of caspase-9 and caspase-3. An investigation of the signaling pathway revealed that the effects on proliferation and apoptosis following linc-UFC1 knockdown were mediated by suppression of β-catenin and activation of phosphorylated P38. Furthermore, the P38 inhibitor SB203580 could attenuate the apoptotic effect achieved by linc-UFC1 knockdown, confirming the involvement of P38 signaling in the induced apoptosis. Taken together, linc-UFC1 might have a critical role in pro-proliferation and anti-apoptosis in CRC by regulating the cell cycle, intrinsic apoptosis, and β-catenin and P38 signaling. Thus, linc-UFC1 could be a potential therapeutic target and novel molecular biomarker for CRC.

Long noncoding RNAs (lncRNAs) are known to regulate the development and progression of various cancers. However, few lncRNAs have been well characterized in lung adenocarcinoma (LUAD). Here, we identified the expression profile of lncRNAs and protein-coding genes via microarrays analysis of paired LUAD tissues and adjacent non-tumor tissues from five female non-smokes with LUAD. A total of 498 lncRNAs and 1691 protein-coding genes were differentially expressed between LUAD tissues and paired adjacent normal tissues. A novel lncRNA, LUAD transcript 1 (LUADT1), which is highly expressed in LUAD and correlates with T stage, was characterized. Both in vitro and in vivo data showed that LUADT1 knockdown significantly inhibited proliferation of LUAD cells and induced cell cycle arrest at the G0-G1 phase. Further analysis indicated that LUADT1 may regulate cell cycle progression by epigenetically inhibiting the expression of p27. RNA immunoprecipitation and chromatin immunoprecipitation assays confirmed that LUADT1 binds to SUZ12, a core component of polycomb repressive complex 2, and mediates the trimethylation of H3K27 at the promoter region of p27. The negative correlation between LUADT1 and p27 expression was confirmed in LUAD tissue samples. These data suggested that a set of lncRNAs and protein-coding genes were differentially expressed in LUAD. LUADT1 is an oncogenic lncRNA that regulates LUAD progression, suggesting that dysregulated lncRNAs may serve as key regulatory factors in LUAD progression.