Showing papers by "Leo E. Otterbein published in 2009"
TL;DR: Gene expression profiling of EVTs and CTBs can be used to unravel novel regulators of cell invasion and identify HO-1 as a negative regulator of trophoblast motility acting via up-regulation of PPARgamma.
Abstract: Invasion of cytotrophoblasts (CTBs) into uterine tissues is essential for placental development. To identify molecules regulating trophoblast invasion, mRNA signatures of purified villous (CTB, poor invasiveness) and extravillous trophoblasts (EVTs) (high invasiveness) isolated from first trimester human placentae and villous explant cultures, respectively, were compared using GeneChip analyses yielding 991 invasion/migration-related transcripts. Several genes involved in physiological and pathological cell invasion, including A disintegrin and metalloprotease-12, -19, -28, as well as Spondin-2, were up-regulated in EVTs. Pathway prediction analyses identified several functional modules associated with either the invasive or noninvasive trophoblast phenotype. One of the genes that was down-regulated in the invasive mRNA pool, heme oxygenase-1 (HO-1), was selected for functional analyses. Real-time PCR analyses, Western blotting, and immunofluorescence of first trimester placentae and differentiating villous explant cultures demonstrated down-regulation of HO-1 in invasive EVTs as compared with CTBs. Modulation of HO-1 expression in loss-of as well as gain-of function cell models (BeWo and HTR8/SVneo, respectively) demonstrated an inverse relationship of HO-1 expression with trophoblast migration in transwell and wound healing assays. Importantly, HO-1 expression led to an increase in protein levels and activity of the nuclear hormone receptor peroxisome proliferator activated receptor (PPAR) gamma. Pharmacological inhibition of PPARgamma abrogated the inhibitory effects of HO-1 on trophoblast migration. Collectively, our results demonstrate that gene expression profiling of EVTs and CTBs can be used to unravel novel regulators of cell invasion. Accordingly, we identify HO-1 as a negative regulator of trophoblast motility acting via up-regulation of PPARgamma.
114 citations
TL;DR: The findings elucidate a potentially important new molecular mechanism by which BV, through the enzymatic activity and phosphorylation of surface BVR (BVR)surf modulates the inflammatory response.
102 citations
TL;DR: A novel role is uncovered for cystatin C and its associated cellular pathways in prostate cancer invasion and metastasis as well as the association with matrix metalloproteinases 2 and androgen receptor (AR) in a tissue microarray comparing benign and malignant specimens.
Abstract: Cystatin C is believed to prevent tumor progression by inhibiting the activities of a family of lysosomal cysteine proteases. However, little is known about the precise mechanism of cystatin C function in prostate cancer. In the present study, we examined the expression of cystatin C and its association with matrix metalloproteinases 2 (MMP2) and androgen receptor (AR) in a tissue microarray comparing benign and malignant specimens from 448 patients who underwent radical prostatectomy for localized prostate cancer. Cystatin C expression was significantly lower in cancer specimens than in benign tissues (p<0.001) and there was a statistically significant inverse correlation between expression of cystatin C and MMP2 (r(s) (2) = -0.056, p = 0.05). There was a clear trend that patients with decreased level of cystatin C had lower overall survival. Targeted inhibition of cystatin C using specific siRNA resulted in an increased invasiveness of PC3 cells, whereas induction of cystatin C overexpression greatly reduced invasion rate of PC3 in vitro. The effect of cystatin C on modulating the PC3 cell invasion was provoked by Erk2 inhibitor that specifically inhibited MAPK/Erk2 activity. This suggests that cystatin C may mediate tumor cell invasion by modulating the activity of MAPK/Erk cascades. Consistent with our immunohistochemical findings that patients with low expression of cystatin C and high expression of androgen receptor (AR) tend to have worse overall survival than patients with high expression of cystatin C and high AR expression, induced overexpression of AR in PC3 cells expressing cystatin C siRNA greatly enhanced the invasiveness of PC3 cells. This suggests that there may be a crosstalk between cystatin C and AR-mediated pathways. Our study uncovers a novel role for cystatin C and its associated cellular pathways in prostate cancer invasion and metastasis.
66 citations
TL;DR: As CO moves ahead in the clinic, there is sound preclinical evidence that, at a low concentration, CO has benefits in numerous and diverse diseases in rodents, large animals, and humans.
Abstract: The discovery that carbon monoxide (CO)-a highly publicized toxic gas molecule-can have powerful benefits and curative effects not only changed how we view CO, but has, with tremendous contradiction, resulted in clinical trials of CO for the treatment of various pathologies. There is sound preclinical evidence that, at a low concentration, CO has benefits in numerous and diverse diseases in rodents, large animals, and humans. CO especially has potential benefits in inflammatory disorders. As CO moves ahead in the clinic, we continue to advance our understanding of how it functions, especially as the number of potential clinical applications expands. CO's mechanisms of action at the cellular level depend on the disease and the experimental focus, but the one constant is that CO reestablishes homeostasis.
48 citations
TL;DR: Reports that have propelled and challenged the paradoxical use of CO, once viewed as a toxic molecule, now as a host defense molecule agent against microbes are reviewed.
48 citations