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BackgroundCancer-associated fibroblasts (CAFs) play an important role in regulating tumor progression by transferring exosomes to neighboring cells. Our aim was to clarify the role of microRNA encapsulated in the exosomes derived from CAFs in oral squamous cell carcinoma (OSCC).MethodsWe examined the microRNA expression profiles of exosomes derived from CAFs and donor-matched normal fibroblasts (NFs) from patients with OSCC. We used confocal microscopy to examine the transportation of exosomal miR-34a-5p between CAFs and OSCC cells. Next, luciferase reporter and its mutant plasmids were used to confirm direct target gene of miR-34a-5p. Phenotypic assays and in vivo tumor growth experiments were used to investigate the functional significance of exosomal miR-34a-5p.FindingsWe found that the expression of miR-34a-5p in CAF-derived exosomes was significantly reduced, and fibroblasts could transfer exosomal miR-34a-5p to OSCC cells. In xenograft experiments, miR-34a-5p overexpression in CAFs could inhibit the tumorigenesis of OSCC cells. We further revealed that miR-34a-5p binds to its direct downstream target AXL to suppress OSCC cell proliferation and metastasis. Stable ectopic expression of AXL in OSCC cells overexpressing miR-34a-5p restored proliferation and motility abolished by the miRNA. The miR-34a-5p/AXL axis promoted OSCC progression via the AKT/GSK-3β/β-catenin signaling pathway, which could induce the epithelial-mesenchymal transition (EMT) to promote cancer cells metastasis. The miR-34a-5p/AXL axis enhanced nuclear translocation of β-catenin and then induced transcriptional upregulation of SNAIL, which in turn activated both MMP-2 and MMP-9.InterpretationThe miR-34a-5p/AXL axis confers aggressiveness in oral cancer cells through the AKT/GSK-3β/β-catenin/Snail signaling cascade and might represent a therapeutic target for OSCC.FundNational Natural Science Foundation of China.

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Plant resistance to herbivores is a key component in integrated pest management. In most cases, silicon (Si) amendment to plants enhances resistance to herbivorous insects. The increase of plant physical barrier and altered insect behaviors are proposed as mechanisms for the enhanced resistance in Si-amended plants, but our understanding of the induced mechanisms involved in Si-enhanced plant resistance to phloem-feeding insects remains unclear. Here, we show that Si amendment to rice (Oryza sativa) plants impacts multiple plant defense responses induced by a phloem-feeder, the brown planthopper (Nilaparvata lugens, BPH). Si amendment improved silicification of leaf sheaths that BPH feed on. Si addition suppressed the increase of malondialdehyde concentration while encouraged increase of H2O2 concentration in plants attacked by BPH. Higher activities of catalase and superoxide dismutase were recorded in Si-amended than in non-amended BPH-infested plants. BPH infestation activated synthases for secondary metabolites, polyphenol oxidase and pheny-lalanine ammonia-lyase, and β-1,3-glucanase, but the activation was greater in Si-amended than in non-amended plants. Taken together, our findings demonstrate that Si amendment interacts with BPH infestation in the induction of plant defense responses and consequently, to confer enhanced rice plant resistance.

BackgroundMechanical overloading can lead to disc degeneration. Nucleus pulposus (NP) cell senescence is aggravated within the degenerated disc. This study was designed to investigate the effects of high compression on NP cell senescence and the underlying molecular mechanism of this process.MethodsRat NP cells seeded in decalcified bone matrix were subjected to non-compression (control) or compression (2% or 20% deformation, 1.0 Hz, 6 hours/day). The reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) and the p38 MAPK inhibitor SB203580 were used to investigate the roles of the ROS and p38 MAPK pathway under high-magnitude compression. Additionally, we studied the effects of compression (0.1 or 1.3 MPa, 1.0 Hz, 6 hours/day) in a rat disc organ culture.ResultsBoth in scaffold and organ cultures, high-magnitude compression (20% deformation or 1.3 MPa) increased senescence-associated β-galactosidase (SA-β-Gal) activity, senescence marker (p16 and p53) expression, G1 cell cycle arrest, and ROS generation, and decreased cell proliferation, telomerase activity and matrix (aggrecan and collagen II) synthesis. Further analysis of the 20% deformation group showed that NAC inhibited NP cell senescence but had no obvious effect on phospho-p38 MAPK expression and that SB203580 significantly attenuated ROS generation and NP cell senescence.ConclusionsHigh-magnitude compression can accelerate NP cell senescence through the p38 MAPK-ROS pathway.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1384-z) contains supplementary material, which is available to authorized users.

Different loading regimens of cyclic tensile strain impose different effects on cell proliferation and tenogenic differentiation of TDSCs in three-dimensional (3D) culture in vitro, which has been little reported in previous literatures. In this study we assessed the efficacy of TDSCs in a poly(L-lactide-co-ε-caprolactone)/collagen (P(LLA-CL)/Col) scaffold under mechanical stimulation in the custom-designed 3D tensile bioreactor, which revealed that cyclic tensile strain with different frequencies (0.3 Hz, 0.5 Hz, and 1.0 Hz) and amplitudes (2%, 4%, and 8%) had no influence on TDSC viability, while it had different effects on the proliferation and the expression of type I collagen, tenascin-C, tenomodulin, and scleraxis of TDSCs, which was most obvious at 0.5 Hz frequency with the same amplitude and at 4% amplitude with the same frequency. Moreover, signaling pathway from microarray analysis revealed that reduced extracellular matrix (ECM) receptor interaction signaling initiated the tendon genius switch. Cyclic tensile strain highly upregulated genes encoding regulators of NPM1 and COPS5 transcriptional activities as well as MYC related transcriptional factors, which contributed to cell proliferation and differentiation. In particular, the transcriptome analysis provided certain new insights on the molecular and signaling networks for TDSCs loaded in these conditions.

Osmolarity fluctuations are inevitable within the nucleus pulposus (NP). However, the effects of osmolarity on NP cell apoptosis within the organ-cultured disc remain unclear. The objective of this study was to investigate effects of different osmolarity levels (hypo-, iso-, and hyper-) and osmolarity modes (constant and cyclic) on NP cell apoptosis in a disc perfusion culture and to study the role of the ERK1/2 pathway in this regulatory process. Porcine discs were cultured for 7 days in different osmotic medium, including constant hypo-, iso-, and hyper-osmolarity (330, 430, and 550 mOsm/L, respectively) and cyclic-osmolarity (430 mOsm/L for 8 h, followed by 550 mOsm/L for 16 h). The role of the ERK1/2 pathway was investigated by using the pharmacological inhibitor U0126. NP cell apoptosis was analyzed by TUNEL staining, caspase-3 activity, gene expression of Bcl-2, Bax and caspase-3 and protein expression of cleaved caspase-3, and cleaved PARP. Our results showed that NP cell apoptosis was increased in hypo-and hyperosmolarity cultures compared to iso-or cyclic-osmolarity culture, whereas the level of apoptosis in the iso-osmolarity culture was lower than that in the cyclic-osmolarity culture. When the ERK1/2 pathway was inhibited in the iso-and cyclic-osmolarity cultures, the level of NP cell apoptosis was significantly increased. In conclusion, the effects of osmolarity on NP cell apoptosis depend on the osmolarity level (hypo-, iso-, or hyper-) and osmolarity mode (constant or cyclic). Futhermore, inhibition of the ERK1/2 pathway promotes NP cell apoptosis in this process. Keywords: intervertebral disc; osmolarity; apoptosis; nucleus pulposus; ERK1/2Intervertebral disc degeneration (IDD) affects approximately 80% of adult humans and is the primary cause of lower back pain which leads to personal disability and a heavy socioeconomic burden. 1 Although many research programs and clinical studies have been performed, the accurate etiopathogenesis of disc degeneration remains unclear.The intervertebral disc (IVD) consists of the surrounding annulus fibrosus (AF), the central nucleus pulposus (NP) and the upper and lower cartilage endplates (CEP). 2 With these three structurally distinct parts, the IVD has an outstanding mechanical property of supporting spine motion and stability. During disc degeneration, the decrease of viable NP cells can lead to decreased NP matrix production and ultimately changes in the disc structure and/or disc function. 3,4 Moreover, apoptosis of NP cells is a typical cellular phenomenon, which is closely associated with disc degeneration. 5 Therefore, NP cell apoptosis during disc degeneration has become a new area of research focus.Apoptosis is a process of programmed cell death executed through the activation of caspases, such as caspase-3, 6, and 7) 6 and may be a critical cause of the loss of disc cellularity during degeneration. 3,7 It is universally accepted that un-physiologic loading is implicated in the initiation and progression of disc degeneration. 8 Previous st...