Chlamydia pneumoniae Infection and Risk for Lung Cancer
ABSTRACT We evaluated the relationship of Chlamydia pneumoniae infection with prospective lung cancer risk using traditional serologic markers [microimmunoflourescence (MIF) IgG and IgA antibodies] and Chlamydia heat shock protein-60 (CHSP-60) antibodies, a marker for chronic chlamydial infection.
We conducted a nested case-control study (593 lung cancers and 671 controls) within the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (N = 77,464). Controls were matched to cases by age, sex, randomization year, follow-up time, and smoking (pack-years of smoking, time since quitting). We assessed C. pneumoniae seropositivity and endpoint antibody titers (IgG and IgA against C. pneumoniae elementary bodies and IgG against CHSP-60).
C. pneumoniae seropositivity by microimmunoflourescence IgG or IgA antibodies was not associated with lung cancer [odds ratio of 0.88 and 95% confidence interval (95% CI) of 0.69-1.13 for IgG; odds ratio of 0.98 and 95% CI of 0.75-1.27 for IgA]. In contrast, individuals seropositive for CHSP-60 IgG antibodies had significantly increased lung cancer risk (odds ratio, 1.30; 95% CI, 1.02-1.67), and risk increased with increasing antibody titers (P trend = 0.006). CHSP-60-related risk did not differ significantly by lung cancer histology, follow-up time, or smoking. CHSP-60 seropositivity was associated with increased risk 2 to 5 years before lung cancer diagnosis (odds ratio, 1.77; 95% CI, 1.16-2.71; P trend = 0.006), thus arguing against reverse causality.
CHSP-60 seropositivity and elevated antibody titers were associated with significantly increased risk for subsequent lung cancer, supporting an etiologic role for C. pneumoniae infection in lung carcinogenesis.
Our results highlight the potential for lung cancer risk reduction through treatments targeted toward C. pneumoniae infections and chronic pulmonary inflammation.
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ABSTRACT: Chlamydia, a major human bacterial pathogen, assumes effective strategies to protect infected cells against death-inducing stimuli, thereby ensuring completion of its developmental cycle. Paired with its capacity to cause extensive host DNA damage, this poses a potential risk of malignant transformation, consistent with circumstantial epidemiological evidence. Here we reveal a dramatic depletion of p53, a tumor suppressor deregulated in many cancers, during Chlamydia infection. Using biochemical approaches and live imaging of individual cells, we demonstrate that p53 diminution requires phosphorylation of Murine Double Minute 2 (MDM2; a ubiquitin ligase) and subsequent interaction of phospho-MDM2 with p53 before induced proteasomal degradation. Strikingly, inhibition of the p53-MDM2 interaction is sufficient to disrupt intracellular development of Chlamydia and interferes with the pathogen's anti-apoptotic effect on host cells. This highlights the dependency of the pathogen on a functional MDM2-p53 axis and lends support to a potentially pro-carcinogenic effect of chlamydial infection.Nature Communications 11/2014; 5:5201. DOI:10.1038/ncomms6201 · 10.74 Impact Factor
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