Alteration of CEACAM1 gene transcription in prostate cancer cells: The role of AR, Sp2, and HDAC

Cell to cell adhesion molecule (CEACAM1), a type II tumor suppressor, has been found to be down-regulated in prostate cancer cells. The mechanism that causes CEACAM1's down-regulation in tumorigenesis is unknown. Here we show that the transcriptional activity of CEACAM1 is decreased in prostate cancer cells. This decrease is not due to methylation of the CEACAM1's promoter, but rather to the alteration of transcription factors regulating CEACAM1 expression. ^ Since androgen/androgen receptors (AR) are potent regulators of prostate growth and differentiation, their role on CEACAM1 gene transcription was examined. The androgen receptor could directly increase CEACAM1 transcriptional activity in a ligand dependent manner by interacting with an AR consensus element that resides in the CEACAM1 promoter. However, AR binding to the CEACAM1 promoter is not related to the loss of CEACAM1 during prostate cancer progression. ^ Further analysis enabled us to determine the particular region in the CEACAM1 promoter that mediates a decrease in CEACAM1 transcriptional activity in prostate cancer cells. Upon further examination, we found that this CEACAM1 promoter region interacts with the Sp1, Sp2, and Sp3 transcription factors. However, only Sp2 expression was found to increase in prostate cancer cells. Inhibiting Sp2 from binding to the CEACAM1 promoter caused an increase in CEACAM1 transcriptional activity in prostate cancer cells. In addition, over-expressing Sp2 in normal prostate cells resulted in a decrease in CEACAM1 transcriptional activity and endogenous protein expression. These observations suggest that Sp2 is a transcription repressor of CEACAM1. Furthermore, prostate cancer cells treated with trichostatin A (TSA), a specific histone deacetylase (HDAC) inhibitor, activated CEACAM1 transcriptional activity. This implies that HDACs are involved in CEACAM1 transcriptional activity. Mutation of the Sp2 DNA binding region on the CEACAM1 promoter inhibited TSA activation of CEACAM1 transcriptional activity. This indicates that HDACs inhibit CEACAM1 transcriptional activity through Sp2. Base on these results, we propose that Sp2 is critical for down-regulating CEACAM1 expression, and one mechanism by which Sp2 represses CEACAM1 expression is by recruiting HDAC to the CEACAM1 promoter in prostate cancer cells. Collectively, these findings provide novel insights into mechanisms that cause the down-regulation of CEACAM1 expression in prostate cancer cells. ^

The identification and characterization of the Staphylococcus aureus microbial immunomodulatory molecules (MIMS) Map and Efb

Staphylococcus aureus is an opportunistic pathogen that is a major health threat in the clinical and community settings. An interesting hallmark of patients infected with S. aureus is that they do not usually develop a protective immune response and are susceptible to reinfection, in part because of the ability of S. aureus to modulate host immunity. The ability to evade host immune responses is a key contributor to the infection process and is critical in S. aureus survival and pathogenesis. This study investigates the immunomodulatory effects of two secreted proteins produced by S. aureus, the MHC class II analog protein (Map) and the extracellular fibrinogen-binding protein (Efb). Map has been demonstrated to modulate host immunity by interfering with T cell function. Map has been shown to significantly reduce T cell proliferative responses and significantly reduce delayed-type hypersensitivity responses to challenge antigen. In addition, the effects of Map on the infection process were tested in a mouse model of infection. Mice infected with Map− S. aureus (Map deficient strain) presented with significantly reduced levels of arthritis, osteomyelitis and abscess formation compared to mice infected with the wild-type Map+S. aureus strain suggesting that Map−S. aureus is much less virulent than Map+S. aureus. Furthermore, Map−S. aureus-infected nude mice developed arthritis and osteomyelitis to a severity similar to Map +S. aureus-infected controls, suggesting that T cells can affect disease outcome following S. aureus infection and Map may attenuate cellular immunity against S. aureus. The extracellular fibrinogen-binding protein (Efb) was identified when cultured S. aureus supernatants were probed with the complement component C3. The binding of C3 to Efb resulted in studies investigating the effects of Efb on complement activation. We have demonstrated that Efb can inhibit both the classical and alternative complement pathways. Moreover, we have shown that Efb can inhibit complement mediated opsonophagocytosis. Further studies have characterized the Efb-C3 binding interaction and localized the C3-binding domain to the C-terminal region of Efb. In addition, we demonstrate that Efb binds specifically to a region within the C3d fragment of C3. This study demonstrates that Map and Efb can interfere with both the acquired and innate host immune pathways and that these proteins contribute to the success of S. aureus in evading host immunity and in establishing disease. ^

Effect of the emergence of community acquired methicillin resistant Staphylococcus aureus on microbial resistance patterns seen during a seven year study of minocycline/rifampin catheter use

Background. Health care associated catheter related blood stream infections (CRBSI) represent a significant public health concern in the United States. Several studies have suggested that precautions such as maximum sterile barrier and use of antimicrobial catheters are efficacious at reducing CRBSI, but there is concern within the medical community that the prolonged use of antimicrobial catheters may be associated with increased bacterial resistance. Clinical studies have been done showing no association and a significant decrease in microbial resistance with prolonged minocycline/rifampin (M/R) catheter use. One explanation is the emergence of community acquired methicillin resistant Staphylococcus aureus (MRSA), which is more susceptible to antibiotics, as a cause of CRBSI.^ Methods. Data from 323 MRSA isolates cultured from cancer patients at The University of Texas MD Anderson Cancer center from 1997-2007 displaying MRSA infection were analyzed to determine whether there is a relationship between resistance to minocycline and rifampin and prolonged wide spread use of minocycline (M/R) catheters. Analysis was also conducted to determine whether there was a significant change in the prevalence community acquired MRSA (CA-MRSA) during this time period and if this emergence act as a confounder masquerading the true relationship between microbial resistance and prolonged M/R catheter use.^ Results. Our study showed that the significant (p=0.008) change in strain type over time is a confounding variable; the adjusted model showed a significant protective effect (OR 0.000281, 95% CI 1.4x10 -4-5.5x10-4) in the relationship between MRSA resistance to minocycline and prolonged M/R catheter use. The relationship between resistance to rifampin and prolonged M/R catheter use was not significant.^ Conclusion. The emergence of CA-MRSA is a confounder and in the relationship between resistance to minocycline and rifampin and prolonged M/R catheter use. However, despite the adjustment for the more susceptible CA-MRSA the widespread use of M/R catheters does not promote microbial resistance. ^

Pathogenesis of antibiotic-associated diarrhea (AAD)---a systematic review

A common complication of antibiotic use is the development of diarrheal illness. The pathogenesis of antibiotic associated diarrhea (AAD) may be mediated through alteration of intestinal microbiota, overgrowth of opportunistic pathogens, and direct drug toxicity on the gut. Alterations in the intestinal microbiota result in metabolic imbalances, loss of colonization resistance and in turn allow proliferation of opportunistic pathogens. Currently less than 33% of AAD cases can be attributable to Clostridium difficile leaving a large number of cases undiagnosed and poorly treated. Although the pathogenesis of Clostridium difficile infection (CDI) has been well documented, the role of other putative microbial etiologies (Clostridium perfringens, Staphylococcus aureus, Klebsiella oxytoca, Candida species) and their pathogenic mechanisms in AAD has been unclear. This review provides a comprehensive and systematic approach to the existing data on AAD and includes concise descriptions of the pathogenesis of CDI and non-CDI AAD in the form of figures.^