<p>PDF file - 213K, Figure S5. Regulation of MYC and cell cycle by Chk1-CIP2A pathway and effect of DNA-PK on CIP2A and pS345-Chk1 levels independent of ATM/ATR.</p>
<div>Abstract<p>Identification of ovarian cancer patient subpopulations with increased sensitivity to targeted therapies could offer significant clinical benefit. We report that 22% of the high-grade ovarian cancer tumors at diagnosis express CIP2A oncoprotein at low levels. Furthermore, regardless of their significantly lower likelihood of disease relapse after standard chemotherapy, a portion of relapsed tumors retain their CIP2A-deficient phenotype. Through a screen for therapeutics that would preferentially kill CIP2A-deficient ovarian cancer cells, we identified reactive oxygen species inducer APR-246, tested previously in ovarian cancer clinical trials. Consistent with CIP2A-deficient ovarian cancer subtype in humans, CIP2A is dispensable for development of MISIIR-Tag–driven mouse ovarian cancer tumors. Nevertheless, CIP2A-null ovarian cancer tumor cells from MISIIR-Tag mice displayed APR-246 hypersensitivity both <i>in vitro</i> and <i>in vivo</i>. Mechanistically, the lack of CIP2A expression hypersensitizes the ovarian cancer cells to APR-246 by inhibition of NF-κB activity. Accordingly, combination of APR-246 and NF-κB inhibitor compounds strongly synergized in killing of CIP2A-positive ovarian cancer cells. Collectively, the results warrant consideration of clinical testing of APR-246 for CIP2A-deficient ovarian cancer tumor subtype patients. Results also reveal CIP2A as a candidate APR-246 combination therapy target for ovarian cancer.</p></div>
Background and study aims: Elevated long-term risk of cholangiocarcinoma is reported after endoscopic sphincterotomy (ES), but in a previous study we found a trend towards a decreased risk. The aim of this study was to evaluate the association in a larger cohort with a longer follow-up. Patients and methods: Data concerning all patients having had an inpatient endoscopic retrograde cholangiopancreatography (ERCP) were collected from the hospital discharge registries of Finland and Sweden. Incident cases of malignancy were identified through linkage to the nationwide Cancer Registries. Patients with a diagnosis of malignancy, before or within 2 years of the ERCP, were excluded. The cohorts were followed until a diagnosis of malignancy, death or emigration, or end of follow-up (end of 2010). The relative risk of malignancy was calculated as standardized incidence ratio (SIR) compared with the general population, inherently adjusting for age, gender, and calendar year of follow-up. Results: A total of 69 925 patients undergoing ERCP from 1976 through 2008 were included in the pooled cohort. ES was performed in 40 193 subjects. The risk of malignancy was elevated in the total cohort (SIR = 2.3; 95 % confidence interval [CI] 2.1 - 2.5) irrespective of whether ES was performed or not. The SIRs diminished with duration of follow-up. Conclusions: We found an elevated risk of malignancy both in the bile ducts alone and in the bile ducts, liver or pancreas together, after ERCP. The risk was the same, regardless of whether ES had been performed or not, so ES was unlikely to be the cause, and a common carcinogenic exposure previous to the ERCP procedure, possibly ductal gallstone disease, was more likely.
Colorectal cancer (CRC) is the third most commonly diagnosed malignancy globally. CRC patients with elevated plasma C-reactive protein (CRP) levels exhibit compromised prognoses. Toll-like receptors (TLRs), activating the innate and adaptive immune systems, may contribute to pro- and antitumorigenic inflammatory responses. We aimed to identify a possible link between local and systemic inflammatory responses in CRC patients by investigating the association between tissue TLRs and plasma CRP.Tissue expressions of TLR2, TLR4, TLR5, and TLR7 were assessed using immunohistochemistry of tissue microarray slides from 549 CRC patients surgically treated between 1998 and 2005. Blood samples were drawn preoperatively, centrifuged, aliquoted, and stored at -80°C until analysis. Plasma CRP was determined through high-sensitivity time-resolved immunofluorometric assay. We investigated the association of TLRs to clinicopathologic variables, plasma CRP, and survival.High TLR2 expression (hazard ratio [HR] 0.59; 95% confidence interval [CI] 0.41-0.85; p = 0.005), high TLR5 expression (HR 0.60; 95% CI 0.45-0.83; p = 0.002), positive TLR7 expression (HR 0.49; 95% CI 0.33-0.72; p < 0.001), and low CRP (HR 1.48; 95% CI 1.08-2.11; p = 0.017) were associated with a better prognosis. A high TLR2 immunoexpression was associated with a better prognosis among low-CRP patients (HR 0.53; 95% CI 0.35-0.80; p = 0.002), high TLR4 expression among high-CRP patients (HR 2.04; 95% CI 1.04-4.00; p = 0.038), high TLR5 expression among low-CRP patients (HR 0.059; 95% CI 0.37-0.92; p = 0.021), and positive TLR7 expression among low-CRP patients (HR 0.53; 95% CI 0.28-1.00; p = 0.049). In multivariate analyses, no biomarkers emerged as significant independent variables.High tissue TLR2, TLR5, and TLR7 levels were associated with a better prognosis. Among low-CRP patients, those with high TLR2, TLR5, and TLR7 immunoexpressions exhibited a better prognosis. Among high CRP patients, a high TLR4 immunoexpression was associated with a better prognosis.
