Cks1 regulates human hepatocellular carcinoma cell progression through osteopontin expression.

Precise cell cycle regulation is critical to prevent aberrant cell proliferation and cancer progression. Cks1 was reported to be an essential accessory factor for SCFSkp2, the ubiquitin ligase that targets p27Kip1 for proteasomal degradation; these actions drive mammalian cell transition from G1 to S phase. In this study, we investigated the role played by Cks1 in the growth and progression of human hepatocellular carcinoma (HCC) cells. Silencing Cks1 expression abrogated osteopontin (OPN) expression in a p27Kip1-dependent manner in Huh7 HCC cells. OPN increased the proliferation, migration and invasion of Huh7 cells. Pharmacological inhibitor studies demonstrated that ERK1/2 signaling is responsible mainly for Cks1-mediated OPN expression. Cks1 appears to regulate ERK1/2 signaling through the expression of dual-specificity phosphatase 16 (DUSP16) because both Cks1 knockdown, which leads to DUSP16 upregulation, and DUSP16 overexpression decreased ERK1/2 phosphorylation and the resulting OPN expression. The same is true for the Cks1-mediated increases in p27Kip1, suggesting that Cks1 regulates OPN expression through activating ERK1/2 signaling either by suppressing DUSP16 expression or by a p27Kip1-dependent mechanism. Cks1 and OPN expression levels were significantly higher, but DUSP16 expression levels were significantly lower in HCC tissues than in normal liver tissues. Both Cks1 and OPN expression were negatively correlated with DUSP16 expression, whereas Cks1 expression was positively correlated with OPN expression. Moreover, combined panels for the expression levels of Cks1, DUSP16 and OPN showed significant prognostic power for the risk assessment of HCC patient overall survival. In conclusion, our data propose a novel function for Cks1 as a tumor promoter through the expression of the strongly oncogenic protein OPN in HCC.

Electrical properties and thermal stability in stack structure of HfO2/Al2O3/InSb by atomic layer deposition.

Changes in the electrical properties and thermal stability of HfO2 grown on Al2O3-passivated InSb by atomic layer deposition (ALD) were investigated. The deposited HfO2 on InSb at a temperature of 200 °C was in an amorphous phase with low interfacial defect states. During post-deposition annealing (PDA) at 400 °C, In-Sb bonding was dissociated and diffusion through HfO2 occurred. The diffusion of indium atoms from the InSb substrate into the HfO2 increased during PDA at 400 °C. Most of the diffused atoms reacted with oxygen in the overall HfO2 layer, which degraded the capacitance equivalent thickness (CET). However, since a 1-nm-thick Al2O3 passivation layer on the InSb substrate effectively reduced the diffusion of indium atoms, we could significantly improve the thermal stability of the capacitor. In addition, we could dramatically reduce the gate leakage current by the Al2O3 passivation layer. Even if the border traps measured by C-V data were slightly larger than those of the as-grown sample without the passivation layer, the interface trap density was reduced by the Al2O3 passivation layer. As a result, the passivation layer effectively improved the thermal stability of the capacitor and reduced the interface trap density, compared with the sample without the passivation layer.

Al2O3 Passivation Effect in HfO2·Al2O3 Laminate Structures Grown on InP Substrates.

The passivation effect of an Al2O3 layer on the electrical properties was investigated in HfO2-Al2O3 laminate structures grown on indium phosphide (InP) substrate by atomic-layer deposition. The chemical state obtained using high-resolution X-ray photoelectron spectroscopy showed that interfacial reactions were dependent on the presence of the Al2O3 passivation layer and its sequence in the HfO2-Al2O3 laminate structures. Because of the interfacial reaction, the Al2O3/HfO2/Al2O3 structure showed the best electrical characteristics. The top Al2O3 layer suppressed the interdiffusion of oxidizing species into the HfO2 films, whereas the bottom Al2O3 layer blocked the outdiffusion of In and P atoms. As a result, the formation of In-O bonds was more effectively suppressed in the Al2O3/HfO2/Al2O3/InP structure than that in the HfO2-on-InP system. Moreover, conductance data revealed that the Al2O3 layer on InP reduces the midgap traps to 2.6 × 1012 eV-1 cm-2 (compared to that of HfO2/InP, that is, 5.4 × 1012 eV-1 cm-2). The suppression of gap states caused by the outdiffusion of In atoms significantly controls the degradation of capacitors caused by leakage current through the stacked oxide layers.

Controlling the defects and transition layer in SiO2 films grown on 4H-SiC via direct plasma-assisted oxidation.

The structural stability and electrical performance of SiO2 grown on SiC via direct plasma-assisted oxidation were investigated. To investigate the changes in the electronic structure and electrical characteristics caused by the interfacial reaction between the SiO2 film (thickness ~5 nm) and SiC, X-ray photoelectron spectroscopy (XPS), X-ray absorption spectroscopy (XAS), density functional theory (DFT) calculations, and electrical measurements were performed. The SiO2 films grown via direct plasma-assisted oxidation at room temperature for 300s exhibited significantly decreased concentrations of silicon oxycarbides (SiOxCy) in the transition layer compared to that of conventionally grown (i.e., thermally grown) SiO2 films. Moreover, the plasma-assisted SiO2 films exhibited enhanced electrical characteristics, such as reduced frequency dispersion, hysteresis, and interface trap density (Dit ≈ 1011 cm-2 · eV-1). In particular, stress induced leakage current (SILC) characteristics showed that the generation of defect states can be dramatically suppressed in metal oxide semiconductor (MOS) structures with plasma-assisted oxide layer due to the formation of stable Si-O bonds and the reduced concentrations of SiOxCy species defect states in the transition layer. That is, energetically stable interfacial states of high quality SiO2 on SiC can be obtained by the controlling the formation of SiOxCy through the highly reactive direct plasma-assisted oxidation process.

Graphene oxide induces apoptotic cell death in endothelial cells by activating autophagy via calcium-dependent phosphorylation of c-Jun N-terminal kinases.

Despite the rapid expansion of the biomedical applications of graphene oxide (GO), safety issues related to GO, particularly with regard to its effects on vascular endothelial cells (ECs), have been poorly evaluated. To explore possible GO-mediated vasculature cytotoxicity and determine lateral GO size relevance, we constructed four types of GO: micrometer-sized GO (MGO; 1089.9±135.3nm), submicrometer-sized GO (SGO; 390.2±51.4nm), nanometer-sized GO (NGO; 65.5±16.3nm), and graphene quantum dots (GQDs). All types but GQD showed a significant decrease in cellular viability in a dose-dependent manner. Notably, SGO or NGO, but not MGO, potently induced apoptosis while causing no detectable necrosis. Subsequently, SGO or NGO markedly induced autophagy through a process dependent on the c-Jun N-terminal kinase (JNK)-mediated phosphorylation of B-cell lymphoma 2 (Bcl-2), leading to the dissociation of Beclin-1 from the Beclin-1-Bcl-2 complex. Autophagy suppression attenuated the SGO- or NGO-induced apoptotic cell death of ECs, suggesting that SGO- or NGO-induced cytotoxicity is associated with autophagy. Moreover, SGO or NGO significantly induced increased intracellular calcium ion (Ca2+) levels. Intracellular Ca2+ chelation with BAPTA-AM significantly attenuated microtubule-associated protein 1A/1B-light chain 3-II accumulation and JNK phosphorylation, resulting in reduced autophagy. Furthermore, we found that SGO or NGO induced Ca2+ release from the endoplasmic reticulum through the PLC ß3/IP3/IP3R signaling axis. These results elucidate the mechanism underlying the size-dependent cytotoxicity of GOs in the vasculature and may facilitate the development of a safer biomedical application of GOs. STATEMENT OF SIGNIFICANCE: Graphene oxide (GO) have received considerable attention with respect to their utilization in biomedical applications. However, GO-related safety issues concerning human vasculature are very limited. In this manuscript, we report for the first time the differential size-related biological effects of GOs on endothelial cells (ECs). Notably, Subnanometer- and nanometersized GOs induce apoptotic death in ECs via autophagy activation. We propose a molecular mechanism for the GO-induced autophagic cell death through the PLCß3/IP3/Ca2+/JNK signaling axis. Our findings could be provide a better understanding of the GO sizedependent cytotoxicity in vasculature and facilitate the future development of safer biomedical applications of GOs.

DUSP1 induces paclitaxel resistance through the regulation of p-glycoprotein expression in human ovarian cancer cells.

The heterogeneity and genetic instability of ovarian cancer cells often lead to the development of drug resistance, closely related with the increased cancer-related mortality. In this study, we investigated the role of dual-specificity phosphatase 1 (DUSP1) in the development of the resistance in human ovarian cancer cells against paclitaxel. Overexpression of DUSP1 in HeyA8 human ovarian cancer cells (HeyA8-DUSP1) up-regulated the expression of the drug efflux pump, p-glycoprotein. Consequently, HeyA8-DUSP1 cells are highly resistant to paclitaxel, with the resistance comparable to that of a multi-drug resistance cell line (HeyA8-MDR). Moreover, over expression of DUSP1 significantly increased the activation of p38 MAPK, leaving the activation of ERK1/2 and JNK1/2 unaffected. Pharmacological suppression of p38 MAPK activity prevents the up-regulation of p-glycoprotein expression and the consequent resistance against paclitaxel in HeyA8-DUSP1 cells. By contrast, HeyA8-MDR cells expressed a significantly higher level of DUSP1, but treatment with small interference RNA against DUSP1 significantly suppressed the expression of p-glycoprotein and the resistance against paclitaxel in HeyA8-MDR cells. Ectopic expression of MKK3, an upstream activator of p38 MAPK, significantly up-regulated the expression of p-glycoprotein and increased the consequent resistance against paclitaxel in HeyA8 cells. Collectively, these data indicated that DUSP1 may induce the resistance against paclitaxel through the p38 MAPK-mediated overexpression of p-glycoprotein in human ovarian cancer cells.

MoS2-InGaZnO Heterojunction Phototransistors with Broad Spectral Responsivity.

We introduce an amorphous indium-gallium-zinc-oxide (a-IGZO) heterostructure phototransistor consisting of solution-based synthetic molybdenum disulfide (few-layered MoS2, with a band gap of ∼1.7 eV) and sputter-deposited a-IGZO (with a band gap of ∼3.0 eV) films as a novel sensing element with a broad spectral responsivity. The MoS2 and a-IGZO films serve as a visible light-absorbing layer and a high mobility channel layer, respectively. Spectroscopic measurements reveal that appropriate band alignment at the heterojunction provides effective transfer of the visible light-induced electrons generated in the few-layered MoS2 film to the underlying a-IGZO channel layer with a high carrier mobility. The photoresponse characteristics of the a-IGZO transistor are extended to cover most of the visible range by forming a heterojunction phototransistor that harnesses a visible light responding MoS2 film with a small band gap prepared through a large-area synthetic route. The MoS2-IGZO heterojunction phototransistors exhibit a photoresponsivity of approximately 1.7 A/W at a wavelength of 520 nm (an optical power of 1 µW) with excellent time-dependent photoresponse dynamics.

Structural and Electrical Properties of EOT HfO2 (<1 nm) Grown on InAs by Atomic Layer Deposition and Its Thermal Stability.

We report on changes in the structural, interfacial, and electrical characteristics of sub-1 nm equivalent oxide thickness (EOT) HfO2 grown on InAs by atomic layer deposition. When the HfO2 film was deposited on an InAs substrate at a temperature of 300 °C, the HfO2 was in an amorphous phase with an sharp interface, an EOT of 0.9 nm, and low preexisting interfacial defect states. During post deposition annealing (PDA) at 600 °C, the HfO2 was transformed from an amorphous to a single crystalline orthorhombic phase, which minimizes the interfacial lattice mismatch below 0.8%. Accordingly, the HfO2 dielectric after the PDA had a dielectric constant of ∼24 because of the permittivity of the well-ordered orthorhombic HfO2 structure. Moreover, border traps were reduced by half than the as-grown sample due to a reduction in bulk defects in HfO2 dielectric during the PDA. However, in terms of other electrical properties, the characteristics of the PDA-treated sample were degraded compared to the as-grown sample, with EOT values of 1.0 nm and larger interfacial defect states (Dit) above 1 × 10(14) cm(-2) eV(-1). X-ray photoelectron spectroscopy data indicated that the diffusion of In atoms from the InAs substrate into the HfO2 dielectric during the PDA at 600 °C resulted in the development of substantial midgap states.

Defect-free erbium silicide formation using an ultrathin Ni interlayer.

An ultrathin Ni interlayer (∼1 nm) was introduced between a TaN-capped Er film and a Si substrate to prevent the formation of surface defects during thermal Er silicidation. A nickel silicide interfacial layer formed at low temperatures and incurred uniform nucleation and the growth of a subsequently formed erbium silicide film, effectively inhibiting the generation of recessed-type surface defects and improving the surface roughness. As a side effect, the complete transformation of Er to erbium silicide was somewhat delayed, and the electrical contact property at low annealing temperatures was dominated by the nickel silicide phase with a high Schottky barrier height. After high-temperature annealing, the early-formed interfacial layer interacted with the growing erbium silicide, presumably forming an erbium silicide-rich Er-Si-Ni mixture. As a result, the electrical contact property reverted to that of the low-resistive erbium silicide/Si contact case, which warrants a promising source/drain contact application for future high-performance metal-oxide-semiconductor field-effect transistors.

Effects of nitrogen incorporation in HfO(2) grown on InP by atomic layer deposition: an evolution in structural, chemical, and electrical characteristics.

We investigated the effects of postnitridation on the structural characteristics and interfacial reactions of HfO2 thin films grown on InP by atomic layer deposition (ALD) as a function of film thickness. By postdeposition annealing under NH3 vapor (PDN) at 600 °C, an InN layer formed at the HfO2/InP interface, and ionized NHx was incorporated in the HfO2 film. We demonstrate that structural changes resulting from nitridation of HfO2/InP depend on the film thickness (i.e., a single-crystal interfacial layer of h-InN formed at thin (2 nm) HfO2/InP interfaces, whereas an amorphous InN layer formed at thick (>6 nm) HfO2/InP interfaces). Consequently, the tetragonal structure of HfO2 transformed into a mixture structure of tetragonal and monoclinic because the interfacial InN layer relieved interfacial strain between HfO2 and InP. During postdeposition annealing (PDA) in HfO2/InP at 600 °C, large numbers of oxidation states were generated as a result of interfacial reactions between interdiffused oxygen impurities and out-diffused InP substrate elements. However, in the case of the PDN of HfO2/InP structures at 600 °C, nitrogen incorporation in the HfO2 film effectively blocked the out-diffusion of atomic In and P, thus suppressing the formation of oxidation states. Accordingly, the number of interfacial defect states (Dit) within the band gap of InP was significantly reduced, which was also supported by DFT calculations. Interfacial InN in HfO2/InP increased the electron-barrier height to ∼0.6 eV, which led to low-leakage-current density in the gate voltage region over 2 V.

Structural evolution and the control of defects in atomic layer deposited HfO2-Al2O3 stacked films on GaAs.

The structural characteristics and interfacial reactions of bilayered dielectric stacks of 3 nm HfO2/2 nm Al2O3 and 3 nm Al2O3/2 nm HfO2 on GaAs, prepared by atomic layer deposition (ALD), were examined during film growth and the postannealing process. During the postdeposition annealing (PDA) of the Al2O3/HfO2/GaAs structures at 700 °C, large amounts of Ga oxides were generated between the Al2O3 and HfO2 films as the result of interfacial reactions between interdiffused oxygen impurities and out-diffused atomic Ga. However, in the case of the HfO2/Al2O3/GaAs structures, the presence of an Al2O3 buffer layer effectively blocked the out-diffusion of atomic Ga, thus suppressing the formation of Ga oxide. Microstructural analyses showed that HfO2 films that were deposited on Al2O3/GaAs had completely crystallized during the PDA process, even at 700 °C, because of the Al2O3 diffusion barrier. Capacitance-voltage measurements showed a relatively large frequency dispersion of the Al2O3/HfO2/GaAs structure in accumulation capacitance compared to the HfO2/Al2O3/GaAs structure due to a higher interface state density. Conductance results revealed that the Al2O3 buffer layer on GaAs resulted in a significant reduction in gap states in GaAs. The induced gap state in the Al2O3/HfO2/GaAs structure originated from the out-diffusion of atomic Ga into the HfO2 film. Density functional theory calculations supported this conclusion.