Loss of p38δ mitogen-activated protein kinase expression promotes oesophageal squamous cell carcinoma proliferation, migration and anchorage-independent growth.

Oesophageal cancer is an aggressive tumour which responds poorly to both chemotherapy and radiation therapy and has a poor prognosis. Thus, a greater understanding of the biology of oesophageal cancer is needed in order to identify novel therapeutic targets. Among these targets p38 MAPK isoforms are becoming increasingly important for a variety of cellular functions. The physiological functions of p38α and -β are now well documented in contrast to -γ and -δ which are comparatively under-studied and ill-defined. A major obstacle to deciphering the role(s) of the latter two p38 isoforms is the lack of specific chemical activators and inhibitors. In this study, we analysed p38 MAPK isoform expression in oesophageal cancer cell lines as well as human normal and tumour tissue. We observed specifically differential p38δ expression. The role(s) of p38δ and active (phosphorylated) p38δ (p-p38δ) in oesophageal squamous cell carcinoma (OESCC) was delineated using wild-type p38δ as well as active p-p38δ, generated by fusing p38δ to its upstream activator MKK6b(E) via a decapeptide (Gly-Glu)5 linker. OESCC cell lines which are p38δ-negative (KE-3 and -8) grew more quickly than cell lines (KE-6 and -10) which express endogenous p38δ. Re-introduction of p38δ resulted in a time-dependent decrease in OESCC cell proliferation which was exacerbated with p-p38δ. In addition, we observed that p38δ and p-p38δ negatively regulated OESCC cell migration in vitro. Finally both p38δ and p-p38δ altered OESCC anchorage-independent growth. Our results suggest that p38δ and p-p38δ have a role in the suppression of OESCC. Our research may provide a new potential target for the treatment of oesophageal cancer.

Investigation of electrically active defects at the interface of high-k dielectrics and compound semiconductors

As silicon based devices in integrated circuits reach the fundamental limits of dimensional scaling there is growing research interest in the use of high electron mobility channel materials, such as indium gallium arsenide (InGaAs), in conjunction with high dielectric constant (high-k) gate oxides, for Metal-Oxide-Semiconductor Field Effect Transistor (MOSFET) based devices. The motivation for employing high mobility channel materials is to reduce power dissipation in integrated circuits while also providing improved performance. One of the primary challenges to date in the field of III-V semiconductors has been the observation of high levels of defect densities at the high-k/III-V interface, which prevents surface inversion of the semiconductor. The work presented in this PhD thesis details the characterization of MOS devices incorporating high-k dielectrics on III-V semiconductors. The analysis examines the effect of modifying the semiconductor bandgap in MOS structures incorporating InxGa1-xAs (x: 0, 0.15. 0.3, 0.53) layers, the optimization of device passivation procedures designed to reduce interface defect densities, and analysis of such electrically active interface defect states for the high-k/InGaAs system. Devices are characterized primarily through capacitance-voltage (CV) and conductance-voltage (GV) measurements of MOS structures both as a function of frequency and temperature. In particular, the density of electrically active interface states was reduced to the level which allowed the observation of true surface inversion behavior in the In0.53Ga0.47As MOS system. This was achieved by developing an optimized (NH4)2S passivation, minimized air exposure, and atomic layer deposition of an Al2O3 gate oxide. An extraction of activation energies allows discrimination of the mechanisms responsible for the inversion response. Finally a new approach is described to determine the minority carrier generation lifetime and the oxide capacitance in MOS structures. The method is demonstrated for an In0.53Ga0.47As system, but is generally applicable to any MOS structure exhibiting a minority carrier response in inversion.