The microRNA miR-22 targets CDK6, SIRT1, and Sp1—genes involved in regulation of the senescence program—to suppress cell growth and proliferation.

It is widely accepted that the conversion of the soluble, nontoxic amyloid β-protein (Aβ) monomer to aggregated toxic Aβ rich in β-sheet structures is central to the development of Alzheimer's disease. However, the mechanism of the abnormal aggregation of Aβ in vivo is not well understood. We have proposed that ganglioside clusters in lipid rafts mediate the formation of amyloid fibrils by Aβ, the toxicity and physicochemical properties of which are different from those of amyloids formed in solution. In this paper, the mechanism by which Aβ-(1-40) fibrillizes in raftlike lipid bilayers composed of monosialoganglioside GM1, cholesterol, and sphingomyelin was investigated in detail on the basis of singular-value decomposition of circular dichroism data and analysis of fibrillization kinetics. At lower protein densities in the membrane (Aβ:GM1 ratio of less than ∼0.013), only the helical species exists. At intermediate protein densities (Aβ:GM1 ratio between ∼0.013 and ∼0.044), the helical species and aggregated β-sheets (∼15-mer) coexist. However, the β-structure is stable and does not form larger aggregates. At Aβ:GM1 ratios above ∼0.044, the β-structure is converted to a second, seed-prone β-structure. The seed recruits monomers from the aqueous phase to form amyloid fibrils. These results will shed light on a molecular mechanism for the pathogenesis of the disease.

The conversion of soluble, nontoxic amyloid β-proteins (Aβ) to aggregated, toxic forms rich in β-sheets is considered to be a key step in the development of Alzheimer's disease. Accumulating evidence suggests that lipid-protein interactions play a crucial role in the aggregation of amyloidogenic proteins like Aβ. Our group has previously reported that amyloid fibrils of Aβ formed on membranes containing clusters of GM1 ganglioside (M-fibrils) exhibit greater cytotoxicity than fibrils formed in aqueous solution (W-fibrils) [ Okada ( 2008 ) J. Mol. Biol. 382 , 1066 - 1074 ]. W-fibrils are considered to consist of in-register parallel β-sheets. However, the precise molecular structure of M-fibrils and force driving the formation of toxic fibrils remain unclear. In this study, we hypothesized that low-polarity environments provided by GM1 clusters drive the formation of toxic fibrils and compared the structure and cytotoxicity of W-fibrils, M-fibrils, and aggregates formed in a low-polarity solution mimicking membrane environments. First, we determined solvent conditions which mimic the polarity of raftlike membranes using Aβ-(1-40) labeled with the 7-diethylaminocoumarin-3-carbonyl dye. The polarity of a mixture of 80% 1,4-dioxane and 20% water (v/v) was found to be close to that of raftlike membranes. Aβ-(1-40) formed amyloid fibrils within several hours in 80% dioxane (D-fibrils) or in the presence of raftlike membranes, whereas a much longer incubation time was required for fibril formation in a conventional buffer. D-fibrils were morphologically similar to M-fibrils. Fourier-transform infrared spectroscopy suggested that M-fibrils and D-fibrils contained antiparallel β-sheets. These fibrils had greater surface hydrophobicity and exhibited significant toxicity against human neuroblastoma SH-SY5Y cells, whereas W-fibrils with less surface hydrophobicity were not cytotoxic. We concluded that ganglioside clusters mediate the formation of toxic amyloid fibrils of Aβ with an antiparallel β-sheet structure by providing less polar environments.

Head and neck squamous cell carcinoma (HNSCC) has a high capacity for invasion. To identify microRNAs (miRNAs) that regulate HNSCC invasion, we compared miRNA expression profiles between a parent HNSCC cell line and a highly invasive clone. The miR-200 family and miR-203 were downregulated in the clone. Here we focused on the role of miR-203 in invasion and epithelial-mesenchymal transition (EMT) induction in HNSCC. miR-203 was downregulated during EMT induction. Moreover, ectopic overexpression of miR-203 suppressed the invasion and induced mesenchymal-epithelial transition (MET) in HNSCC cells. Interestingly, we identified NUAK family SNF1-like kinase 1 (NUAK1) as a novel target gene of miR-203 by cyclopedic analysis using anti-Ago2 antibody. Increased expression of NUAK1 was observed during EMT induction, and ectopic expression of miR-203 delayed EMT induction by suppressing NUAK1 expression. Moreover, NUAK1 overexpression promoted the invasion of HNSCC cells. Importantly, NUAK1 expression was well correlated with poor differentiation, invasiveness, and lymph node metastasis in HNSCC cases. Overall, miR-203 has a tumor-suppressing role in invasion and EMT induction by targeting NUAK1 in HNSCC, suggesting miR-203 as a potential new diagnostic and therapeutic target for the treatment of HNSCC.

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