HGF-Induced PKCζ Activation Increases Functional CXCR4 Expression in Human Breast Cancer Cells

The chemokine receptor CXCR4 and its ligand CXCL12 have been shown to mediate the metastasis of many malignant tumors including breast carcinoma. Interaction between hepatocyte growth factor (HGF) and the Met receptor tyrosine kinase mediates development and progression of cancers. HGF is able to induce CXCR4 expression and contributes to tumor cell invasiveness in breast carcinoma. However, the mechanism of the CXCR4 expression modulated by c-Met-HGF axis to enhance the metastatic behavior of breast cancer cells is still unclear. In this study, we found that HGF induced functional CXCR4 receptor expression in breast cancer cells. The effect of HGF was specifically mediated by PKCζ activity. After transfection with PKCζ-siRNA, the phosphorylation of PKCζ and CXCR4 was abrogated in breast cancer cells. Interference with the activation of Rac1, a downstream target of HGF, prevented the HGF-induced increase in PKCζ activity and CXCR4 levels. The HGF-induced, LY294002-sensitive translocation of PKCζ from cytosol to plasma membrane indicated that HGF was capable of activating PKCζ, probably via phosphoinositide (PI) 3-kinases. HGF treatment also increased MT1-MMP secretion. Inhibition of PKCζ, Rac-1 and phosphatidylinositol 3-kinase may attenuate MT1-MMP expression in cells exposed to HGF. Functional manifestation of the effects of HGF revealed an increased ability for migration, chemotaxis and metastasis in MDA-MB-436 cells in vitro and in vivo. Our findings thus provided evidence that the process of HGF-induced functional CXCR4 expression may involve PI 3-kinase and atypical PKCζ. Moreover, HGF may promote the invasiveness and metastasis of breast tumor xenografts in BALB/c-nu mice via the PKCζ-mediated pathway, while suppression of PKCζ by RNA interference may abrogate cancer cell spreading

Assessing Tuberculosis Case Fatality Ratio: A Meta-Analysis

Background: Recently, the tuberculosis (TB) Task Force Impact Measurement acknowledged the need to review the assumptions underlying the TB mortality estimates published annually by the World Health Organization (WHO). TB mortality is indirectly measured by multiplying estimated TB incidence with estimated case fatality ratio (CFR). We conducted a meta-analysis to estimate the TB case fatality ratio in TB patients having initiated TB treatment. Methods: We searched for eligible studies in the PubMed and Embase databases through March 4(th) 2011 and by reference listing of relevant review articles. Main analyses included the estimation of the pooled percentages of: a) TB patients dying due to TB after having initiated TB treatment and b) TB patients dying during TB treatment. Pooled percentages were estimated using random effects regression models on the combined patient population from all studies. Main Results: We identified 69 relevant studies of which 22 provided data on mortality due to TB and 59 provided data on mortality during TB treatment. Among HIV infected persons the pooled percentage of TB patients dying due to TB was 9.2% (95% Confidence Interval (CI): 3.7%-14.7%) and among HIV uninfected persons 3.0% (95% CI: 21.2%-7.4%) based on the results of eight and three studies respectively providing data for this analyses. The pooled percentage of TB patients dying during TB treatment was 18.8% (95% CI: 14.8%-22.8%) among HIV infected patients and 3.5% (95% CI: 2.0%-4.92%) among HIV uninfected patients based on the results of 27 and 19 studies respectively. Conclusion: The results of the literature review are useful in generating prior distributions of CFR in countries with vital registration systems and have contributed towards revised estimates of TB mortality This literature review did not provide us with all data needed for a valid estimation of TB CFR in TB patients initiating TB treatmen